90% of smokers reported noticing a package warning in the previous 30 days. The percentage of smokers thinking about quitting because of the warnings was >50% in six countries and >25% in men and women in all countries except Poland. WHO has identified providing tobacco health information, including graphic health warnings on tobacco packages, as a powerful \"best buy\" in combating noncommunicable disease (2). Implementing effective warning labels as a component of a comprehensive approach can help decrease tobacco use and its many health consequences.\nGATS is a nationally representative household survey conducted among persons aged ≥15 years using a standardized questionnaire, sample design, data collection method, and analysis protocol to obtain measures on key tobacco control indicators and ensure comparability across countries.* GATS was conducted once in each of the 14 countries during 2008-2010 by national governments, ministries of health, survey-implementing agencies, and international partners. In each country, a multistage cluster sample design is used, with households selected proportional to population size. Data are weighted to reflect the noninstitutionalized population aged ≥15 years in each country. For this analysis, current smokers of manufactured cigarettes † were asked whether they had noticed health warnings on a cigarette package in the previous 30 days, and whether the label led them to think about quitting smoking. § Responses were analyzed by sex and, within sex strata, by age and education level using bivariate analysis within individual countries. Differences in response estimates were considered statistically significant if 95% confidence intervals did not overlap. Overall response rates ranged from 65.1% in Poland to 97.7% in Russia.\nThe health warnings on cigarette packages in each country at the time GATS was conducted were described according to WHO FCTC guidelines (3,4). All GATS countries had warning labels on cigarette packages describing harmful effects of smoking at the time their survey was conducted. Four of the 14 countries (Brazil, Egypt, Thailand, and Uruguay) had pictorial warnings. A fifth country, India, introduced pictorial warnings in 2009, and had both text and pictorial warnings in circulation when GATS was conducted (Table 1).\nIn all 14 countries, men were more likely to be cigarette smokers than women. Among men, prevalence of smoking ranged from 9.6% in India to 59.3% in Russia (Table 2). Among women, prevalence of smoking was <25% in all countries and <2% in Bangladesh, China, Egypt, India, Thailand, and Vietnam. and Egypt, not enough women reported current smoking to calculate this percentage.\nSmokers aged ≥65 years were less likely to notice warnings in Bangladesh (men), Brazil (men and women), Mexico (men), Philippines (men and women), Thailand (men), and Ukraine (men) (Table 2). Smokers who had not completed primary school education were less likely to have noticed warnings in Bangladesh (men), China (men and women), India (men), Mexico (women), Philippines (men and women), Turkey (women), and Vietnam (men) (Table 2).\nAmong smokers who noticed a package warning, the percentage thinking about quitting because of the warning was >50% in six GATS countries (Bangladesh, Brazil, India, Thailand, Ukraine, and Vietnam) and >25% for men and women in all countries except one (Poland). Older male smokers were less likely to think about quitting in India and Uruguay; no other age group differences were noted. This report is the first to provide survey results from all 14 countries that participated in GATS during 2008-2010. In these countries, the prevalence of smoking manufactured cigarettes varied widely and was more common among men. Warning the public about the dangers of tobacco is one of the strategies in WHO's MPOWER package to combat the tobacco epidemic (3). Most of these countries had met the minimum WHO FCTC health warning label criteria for cigarette packages at the time GATS was conducted. The majority of smokers noticed the health warnings, and in most countries >25% who noticed the warnings said they were led to think about quitting. These results indicate that package warnings can be effective for various populations and settings, including countries in which cigarette smoking prevalence currently is low.\nTo be effective, cigarette package warnings must capture smokers' attention and educate them about the health effects of tobacco use (5). The WHO FCTC guidelines provide parameters to accomplish these objectives by emphasizing features that increase the salience of warnings (1,4). Prominent, pictorial warnings have been found to be the most effective in communicating the harms of smoking in several studies (4,6). Smokers who perceive a greater health risk from smoking are more likely to think about quitting and to quit successfully (6). Further, evidence indicates that warnings are more likely to be effective if they elicit strong emotions, such as fear, seem personally relevant, and increase confidence in the ability to quit (4,7). For example, a comparative analysis of responses to labels in Brazil, Mexico, and Uruguay found that the Brazilian warnings depicting human suffering had the strongest impact on thinking about quitting (8). Rotating warnings also is important because the impact of an individual label will decrease over time (5). Thus, a warning that is small in total size or font size, has been in circulation for a long time, or lacks informational content that generates an emotional response likely will not have the strongest possible impact.\nGraphic warnings have the potential to reach those who do not notice or read text-only warnings; they also have the potential to better evoke emotional responses, increase knowledge of health risks, and reinforce motivations to quit smoking (9). Therefore, the WHO FCTC guidelines strongly encourage the use of graphic warnings (5). Low education level and older age were associated with not noticing warnings in some countries; virtually all of these countries had text-only warnings. Women were less likely to notice warnings than men in India, China, and Vietnam, countries where cigarette smoking prevalence is very low among women. These findings emphasize the importance of using warnings that are effective in communicating the risks of smoking to all cigarette smokers and using other What is already known on this topic?\nWarning the public about the dangers of tobacco is one of the key strategies in the World Health Organization's MPOWER package to combat tobacco use.\n# What is added by this report?\nFor the first time, data from all 14 Global Adult Tobacco Survey (GATS) countries are available. In these countries, the prevalence of smoking manufactured cigarettes varies widely and is more common among men. The majority of smokers noticed package warning labels. Among smokers who noticed a health warning, the percentage thinking about quitting because of the warning was >50% in six GATS countries.\nWhat are the implications for public health practice?\nStrong health warning labels on cigarette packages are effective in motivating smokers to consider quitting. These findings emphasize the importance of using warnings that are effective in communicating the risks of smoking to all cigarette smokers. evidence-based tobacco control measures that reach populations that are not frequently exposed to cigarette packages.\nWarnings were more effective at getting smokers to think about quitting in some countries than in others. Brazil and Thailand, countries with numerous prominent and graphic pictorial warnings in rotation, had among the highest prevalences of smokers thinking about quitting because of the warnings; these warnings received WHO's highest rating (3). However, reported thinking about quitting smoking also was relatively high in Bangladesh and Vietnam, where warnings covered less of the package and were text-only. The reasons for these findings are not immediately clear but might relate to the relative importance of package warnings among other contextual factors such as smokers' baseline knowledge about health risks, level of interest in quitting, and level of tobacco dependence, as well as concurrent tobacco control efforts and social norms surrounding tobacco use (7). Further research might be helpful in elucidating these factors and in determining the extent to which thinking about quitting because of warnings leads to quit attempts in GATS countries.\nThe findings in this report are subject to at least five limitations. First, all data were self reported, and social norms (e.g., unacceptability in some countries of women smoking) might have affected responses. Second, the education categories used in Brazil are not comparable to the categories used in this analysis, so Brazil's data were not evaluated for differences in prevalence by education. Third, this analysis included only smokers of manufactured cigarettes; however, other tobacco products (e.g., bidis, kreteks, hand-rolled cigarettes, waterpipes, and smokeless tobacco) are commonly used in India and other GATS countries. Fourth, the prevalence of smoking among women is low in some countries, so analyzing or interpreting results on the impact of package warnings among women was not possible. Finally, GATS was not designed to evaluate the effectiveness of individual health warning labels, and its core questions did not distinguish between the different labels in circulation in a country.\nAfter GATS was conducted, Mexico, Philippines, Turkey, and Ukraine passed legislation requiring pictorial warning labels, and Thailand and Uruguay increased the size of their warnings. Worldwide, a majority of countries now have warnings on cigarette packages, but their features and strength vary (7). As of 2010, approximately 30 countries had pictorial warning labels covering at least 50% of the package (7), and additional countries were developing such labels. ¶ Future GATS will allow tracking of progress toward key tobacco use and control indicators. Smokers view their cigarette packages every time they remove a cigarette; therefore, the cigarette package represents a powerful vehicle to deliver health warnings directly to smokers. Nonsmokers and former smokers also can be discouraged from smoking by viewing comprehensive warnings (7). WHO has identified price increases; smoke-free policies; bans on tobacco advertising, promotion, and sponsorship; and providing tobacco health information via mass media campaigns and graphic health warnings to the public as tobacco \"best buys\"** because they can reduce tobacco initiation, help to prevent progression from initiation to addiction, increase cessation, decrease consumption, and change social norms (2). Providing information about the dangers of using tobacco products with package warnings is a simple and cost-effective strategy to motivate quit attempts, thus helping to prevent the life-threatening effects of tobacco use (9,10). Jamestown Canyon virus (JCV) is a mosquito-borne zoonotic pathogen belonging to the California serogroup of bunyaviruses. Although JCV is widely distributed throughout temperate North America, reports of human JCV infection in the United States are rare. This is the first report of human JCV infection detected in Montana, one of only 15 cases reported in the United States since 2004, when JCV became reportable. On May 26, 2009, a man aged 51 years with no travel history outside of Montana went to a local emergency department immediately following onset of fever, severe frontal headache, dizziness, left-sided numbness, and tingling. His blood pressure was elevated. Stroke was ruled out, oxygen was administered, medication was prescribed for hypertension, and the patient was sent home. One week later, the patient visited his primarycare physician complaining of continued neurologic symptoms consistent with acute febrile encephalitis and recent mosquito bites. Although West Nile virus (WNV) disease was diagnosed based on detection of WNV-immunoglobulin M (IgM) and G (IgG) antibodies, subsequent testing indicated that the WNV antibodies were from a past infection and that his illness was caused by JCV. The final diagnosis of JCV infection was based on positive JCV-specific IgM enzyme-linked immunosorbent assay (ELISA) results and a fourfold rise in paired sample JCV plaque reduction neutralization test (PRNT) titers. This finding represents a previously unrecognized risk for JCV infection in Montana; clinicians should consider JCV infection when assessing patients for suspected arboviral infections.\n# Case Report\nOn May 26, 2009, a previously healthy man aged 51 years with no travel history outside of Montana went to a local emergency department immediately following onset of fever, severe acute frontal headache, dizziness, left-sided numbness, and tingling. No other symptoms were noted. Results of a physical examination were normal, except for an elevated blood pressure of 214/119 mmHg. Blood chemistries and cardiac enzyme tests were within normal limits, except for an elevated glucose of 130 mg/dL (normal: 70-110 mg/dL). Results of an electrocardiogram, magnetic resonance imaging, and computed tomography scan of the brain were normal. Oxygen was administered to the patient, telmisartan was prescribed for hypertension, and he was sent home. A week later, on June 2, the patient visited his primary-care physician complaining of fever, persistent headache, and new onset of muscle pain and weakness. The physician considered the patient's symptoms to be consistent with a neurologic illness and evaluated the patient further for a possible stroke or arboviral infection. A carotid Doppler test showed no evidence of abnormal arterial blood flow. A lumbar puncture performed on June 11 showed clear, colorless cerebrospinal fluid with no leukocytes or erythrocytes, and bacterial culture showed no growth at 72 hours; no tests for virus were performed. The patient was referred to and visited a neurologist on July 6. The neurologist found no evidence of stroke, diagnosed a complex migraine, and prescribed medication for headache management. The patient's symptoms gradually improved, and he reported no residual symptoms 6 months after illness onset.\nOn visiting his primary-care physician and during interviews conducted by the local health department and Montana Department of Public Health and Human Services (DPHHS), the patient reported recent exposure to mosquitoes while working outdoors around his home, which was located in a rural area of Montana. An acute-phase serum sample collected on June 2 (1 week after symptom onset) tested positive for WNV-specific IgM and IgG by ELISA at the Montana Public Health Laboratory (MTPHL). These laboratory results, in combination with the patient's symptoms and history of recent mosquito bites, supported a presumptive diagnosis of WNV disease.\nThe acute sample was then sent to CDC's arbovirus diagnostic laboratory (CDC-ADL) in Fort Collins, Colorado, to confirm the diagnosis by PRNT. Testing at CDC-ADL was positive for WNV-specific IgM and IgG antibodies, with a neutralizing titer of 320. Testing also was positive for St. Louis encephalitis virus (SLEV)-specific IgG antibodies, but a negative SLEV-specific IgM antibody test and a neutralizing titer of 10 suggested cross-reactive flaviviral antibodies. An initial convalescent serum sample drawn on June 11 (16 days after symptom onset) also tested positive for WNV-specific IgM and IgG by ELISA at MTPHL but was not available for testing at CDC-ADL. However, another convalescent serum sample was obtained on December 1 (189 days after symptom onset) and was tested at CDC-ADL. Results indicated persistence of WNV-specific IgM and IgG antibodies and stable neutralizing titers (Table ). Because the stable titers suggested a previously acquired WNV infection (>6 months before illness onset), WNV avidity testing was obtained from the Viral Zoonoses Section, National Microbiology Laboratory, Public Health Agency of Canada (NML-PHAC), in Winnipeg, Manitoba, Canada. Testing found high-avidity WNV IgG, strongly suggesting that the WNV antibodies were from a past WNV infection (1).\nIn addition to WNV testing, CDC-ADL tested the acute specimen collected on June 2 for antibodies against other\n# Human Jamestown Canyon Virus Infection -Montana, 2009\narboviruses. Results were equivocal for IgM and IgG antibodies against La Crosse virus (LACV) by ELISA. Neutralizing titers of 40 against LACV and 80 against JCV suggested a possible recent infection with a California serogroup virus (Table ). Follow-up testing on the day 189 sample was negative for LACV IgM antibodies by ELISA, but showed a twofold increase in LACV neutralizing titers and a fourfold increase in JCV titers. These results suggested that the patient's infection most likely was JCV. To confirm the diagnosis, samples were sent to NML-PHAC for testing with their recently developed IgM ELISA assays incorporating JCV antigen. Patient sera obtained June 11 and December 1 were positive for JCVspecific IgM antibodies (Table ).\nThe presence of JCV-specific IgM and the fourfold diagnostic rise in JCV-neutralizing antibody titers confirmed the diagnosis of JCV infection. This finding indicated that JCV is present in Montana and that a risk for human infection exists. \n# Editorial Note\nArthropod-borne viruses (i.e., arboviruses) are transmitted to humans primarily through bites from infected mosquitoes or ticks. Most arboviruses of public health importance belong to one of three virus genera: Flavivirus, Alphavirus, and Bunyavirus. Human cases caused by the following domestic arboviruses are nationally reportable to CDC: West Nile, St. Louis encephalitis, Powassan, eastern equine encephalitis, western equine encephalitis, and California serogroup viruses (i.e., La Crosse, Jamestown Canyon, California encephalitis, Keystone, snowshoe hare, and trivittatus).\nJCV is distributed throughout temperate North America, where it circulates primarily between deer and various mosquito species (2)(3)(4). Despite its wide geographic range, only 15 human JCV infections (mean: <3 per year) have been reported in the United States since 2004, when JCV became a reportable condition, and those have originated predominantly from the midwestern and northeastern states. JCV infections initially were described in the early 1970s to cause a mild febrile illness in humans (5). Serosurveys in Connecticut and New York have shown evidence of JCV infection in up to 12% of the population (3,6). Despite descriptions of mild illness caused by JCV, at least 11 subsequent cases with moderate-to-severe meningoencephalitis have been described; 10 in the early 1980s and one in 2001 (3,6). A retrospective study of patients with central nervous system manifestations and serologic findings for California serogroup viruses during 1971-1981 confirmed that 41 of 53 patients (77%) had antibodies to JCV, indicating that JCV originally was underdiagnosed in these patients (7). In comparison with clinical illness caused by LACV, JCV has been described as affecting adults and is more likely to cause meningitis (6,7). Furthermore, while seasonal distribution of LACV infections in humans generally occurs in August, JCV infections can occur earlier, in May and June, and continue through the end of summer, likely because the seasonal distribution of mosquito vectors differs for each virus (8).\nAlthough the Montana patient with JCV infection was suspected to have an acute WNV infection, human cases of WNV infection in Montana typically are not reported until late July, with the majority of cases occurring in late August and early September. The onset of illness for this patient was during late spring, which is consistent with approximately 40% of recognized human JCV infections. The differences in the seasonal distribution of these diseases likely are related to the mosquito species that transmit the viruses. Mosquitoes belonging to snow-melt Aedes species are common vectors of JCV, emerge early in spring, and are distributed throughout Montana (3,9). Vertical transmission of JCV in mosquitoes, overwintering of the virus in mosquito eggs, and larval maturation in temporary ponds produced by melting snow increase the likelihood of human JCV transmission in the spring (10). Detection of JCV previously has relied on cross-reactive antibodies in the LACV-specific ELISA (6,7). Testing of the acute serum sample for this case yielded equivocal anti-LACV IgM results, with a slightly higher neutralizing antibody titer against JCV than LACV. The titers against JCV and LACV were not different enough to determine the etiology. Although the convalescent sample confirmed a fourfold rise in JCV-neutralizing antibody titers, testing of paired acute and convalescent samples using a JCV antigen-specific ELISA was necessary to confirm JCV IgM positive results. The discordant anti-LACV and JCV IgM results suggested that cross-reactivity between LACV and JCV antibodies in the LACV-specific ELISA was incomplete, and that sole reliance on the LACV-specific ELISA to detect JCV can lead to missed JCV infections. In response to this, CDC has developed a JCV-specific IgM ELISA. Currently, testing is available only at CDC on request. As more information about the distribution and frequency of JCV infections and disease is known, testing might be expanded to include regional or state laboratories. The availability of this test will enable clinicians and public health officials to quickly differentiate between arboviral infections, especially within the California serogroup.\nInitial diagnostic tests in this case included testing for several arboviral diseases. However, the lack of a readily available diagnostic test specific to JCV delayed the diagnosis and led the clinician to consider noninfectious causes of illness. For the patient, the delayed diagnosis resulted in unnecessary medical procedures, including a carotid Doppler ultrasound, plus several hours of travel, and lost work to seek additional medical evaluation from a specialist. Clinically, patient care might not have differed significantly; however, supportive care, including headache management and patient prognosis, would have been established more quickly. Treatment for JCV infection typically includes supportive care and management of complications, such as relieving increased intracranial pressure. This case underscores the importance of Montana clinicians considering JCV infection in patients with a febrile neurologic illness when an arboviral infection is suspected and WNV testing is inconclusive. Improved and timely diagnosis will aid clinicians in making patient-care and management decisions, help public health professionals perform accurate epidemiologic investigations and implement preventive measures, and provide a better understanding of California serogroup virus distribution.\nWhat is already known on this topic? Jamestown Canyon virus (JCV) circulates widely in North America, primarily between deer and various mosquito species. Reports of human JCV infections in the United States have been rare and are confined primarily to the midwestern and northeastern states. JCV's nonspecific clinical presentation and the limited availability of sensitive tests for JCV might contribute to many human infections going undetected.\n# What is added by this report?\nThis first reported human case of JCV in Montana suggests that the geographic distribution of human JCV infection is wider than previously recognized, and that increased JCV surveillance is needed to determine whether mosquito-borne arboviruses other than West Nile virus (WNV) pose a substantial risk to humans in the region.\n# What are the implications for public health practice?\nClinicians should consider JCV infection in differential diagnoses when an arboviral infection is suspected to be causing a febrile neurologic illness, but WNV testing is inconclusive. Improved and timely arboviral disease diagnostics will aid clinicians in making patient-care and management decisions, help public health professionals perform accurate epidemiologic investigations and target preventive measures, and provide a better understanding of arboviral disease distribution in the United States.\nRegular physical activity helps maintain healthy weight and reduces the likelihood of developing chronic diseases. The 2008 Physical Activity Guidelines for Americans (1) are derived from the most recent scientific review of physical activity health benefits and do not differentiate among physical activity for leisure, transportation, work, or other purposes. To examine the potential influence of occupational physical activity on meeting minimum weekly aerobic physical activity guidelines, the Washington State Department of Health (WADOH) analyzed demographic patterns in physical activity levels with and without consideration of occupational physical activity using 2007 Behavioral Risk Factor Surveillance System (BRFSS) data. This report describes the results of that analysis, which indicated that, approximately two thirds (64.3%) of U.S. adults met minimum physical activity guidelines through nonoccupational physical activity. When occupational physical activity (defined as reported work activity of mostly walking or heavy labor) was considered, an additional 6.5% of adults likely met the guidelines. The increase was greatest for Hispanic men (14.4%) and men with less than a high school education (15.9%). Public health agencies conducting surveillance of population physical activity levels also should consider including occupational physical activity, which will help to identify demographic groups for targeted programs that increase physical activity.\nBRFSS is a state-based, random-digit-dialed telephone survey of the noninstitutionalized, U.S. civilian adult population. The Council of American Survey Research Organizations (CASRO) median response rate for the 2007 BRFSS survey was 50.6%. Among 430,912 respondents, complete occupational and nonoccupational physical activity data were available for 386,397 respondents from 50 states and the District of Columbia.\nBRFSS collects data on frequency and duration of nonoccupational physical activity, which includes leisure, transportation (e.g., walking), and maintaining a home. WADOH computed the products of activity frequency (days per week) and duration (minutes per day) for moderate-intensity and vigorousintensity activities. Consistent with the guidelines, WADOH classified respondents as having met guidelines if they reported weekly nonoccupational physical activity of ≥150 minutes of moderate-intensity activity (e.g., brisk walking or gardening), ≥75 minutes of vigorous-intensity activity (e.g., running or heavy yard work), or a combination of moderate-intensity and vigorous-intensity activity (with vigorous-intensity activity minutes multiplied by two) totaling ≥150 minutes.\nBRFSS does not collect data on occupational physical activity frequency and duration; instead, respondents who indicate employment are asked whether their activity at work is mostly standing or sitting, mostly walking, or mostly heavy labor or physically demanding work.* For this analysis, respondents who did not meet guidelines through nonoccupational physical activity were coded as meeting the guidelines if they reported mostly walking or mostly heavy labor or physically demanding work (Figure).\nWADOH computed age-adjusted prevalence of meeting physical activity guidelines by selected demographic characteristics and calculated age-adjusted prevalence ratios (PRs) for meeting guidelines by fitting two sets of Poisson regressions in which the outcome measures were meeting recommendations (in the first set through nonoccupational activity and in the second set through either nonoccupational or occupational activity). Each Poisson regression contained age and, except for the analysis in which age was the only predictor, an additional predictor variable: race/ethnicity, annual household income, or education. All analyses were stratified by sex and conducted using statistical software that accounted for the complex sampling design. * Regarding occupational physical activity, respondents were asked the following: \"When you are at work, which of the following best describes what you do? Would you say 1) mostly sitting or standing; 2) mostly walking; or 3) mostly heavy labor or physically demanding work?\" Responses of \"don't know/not sure\" and a respondent's refusal to respond (\"refused\") also were included. Additional information available at http://www.cdc.gov/brfss/questionnaires/pdfques/2007brfss.pdf. \n# FIGURE. Classification for meeting 2008 physical activity guidelines*\n\n# Contribution of Occupational Physical Activity Toward Meeting Recommended Physical Activity Guidelines -United States, 2007\nApproximately two thirds (68.5%) of men met guidelines through nonoccupational physical activity. When occupational physical activity levels also were considered, the proportion meeting guidelines increased from 68.5% to 76.3% (Table 1); 14.8% (95% confidence interval [CI] = 14.4%-15.3%) of men reported \"mostly walking,\" and 14.3% (CI = 13.9%-14.7%) reported \"mostly heavy labor\" at work. For women, the proportion increased from 60.4% to 65.7% (Table 2); 12.7% (CI = 12.4%-13.0%) of women reported \"mostly walking,\" and 3.4% (CI = 3.3%-3.6%) of women reported \"mostly heavy labor\" at work. Hispanic men and men with less than a high school education exhibited the greatest absolute gains in the proportion meeting guidelines when occupational physical activity was included (from 60.6% to 75.0% and from 55.7% to 71.6%, respectively). Among Hispanic men, 24.3% (CI = 22.6%-26.2%) reported \"mostly walking,\" and 15.0% (CI = 13.5%-16.5%) reported \"mostly heavy labor\" at work; among men with less than a high school education 21.2% (CI = 19.4%-23.2%) reported \"mostly walking,\" and 18.4% (CI = 16.8% -20.0%) reported \"mostly heavy labor.\"\nHispanic men had a lower prevalence of meeting guidelines through nonoccupational physical activity compared with non-Hispanic white men (PR = 0.85) (Table 1). However, when occupational physical activity was included, the PR was attenuated (i.e., it approached 1.0; PR = 0.97). Similarly, men with less than a high school education had lower prevalence of meeting physical activity guidelines through nonoccupational physical activity compared with men with a college degree (PR = 0.75). When occupational physical activity was included, the PR was attenuated (PR = 0.93). Similar patterns in attenuation of PRs were noted when comparing men with reported annual household incomes of ≤$35,000 with those As expected, findings from this report provide evidence for a modest contribution of occupational physical activity toward successfully meeting minimum physical activity guidelines among U.S. adults, with a larger impact for some subpopulations than others. National Health Interview Survey (NHIS) data from 1990 and earlier revealed that approximately half of respondents classified as sedentary in leisure time reported ≥1 hour of strenuous occupational activity daily; that report indicated that assessing only leisure activity might underestimate physical activity (2). Recent analyses from NHIS are not available because questions regarding the amount of jobrelated physical activity have not been asked since 1990. The findings presented in this report are consistent with reports of Hispanic persons expending more energy at work than persons of other racial/ethnic groups (3). In addition, education and income are strong predictors of leisure-time physical activity, and they remain important predictors of total activity, even though including occupational activity attenuates the association between education and physical activity for men. Although the BRFSS occupational physical activity question has been reported as valid and reliable for classifying physical activities at work (4-6), the question does not quantify the intensity or duration of continuous occupational physical activity. For this report, the analysis assumed that \"mostly walking\" included moderate-intensity activity in ≥10-minute intervals for ≥150 minutes per week and \"mostly heavy labor\" included vigorous-intensity activity in ≥10-minute intervals for ≥75 minutes per week. If the actual time spent in activity of sufficient intensity is less than this, then the effect of occupational physical activity on meeting the minimum aerobic activity guidelines will be overestimated. Relative to a standard work week of 40 hours, these assumptions seem reasonable. Also, a variety of occupational walking activities are in the \"moderate\" range, and a variety of heavy labor activities are in the \"vigorous\" range, based on comparisons of energy need while performing a task to energy need at rest (5,7). However, a more detailed assessment of occupational physical activities would be needed to confirm these assumptions.\nThe findings in this report are subject to at least three limitations. First, because the duration of \"mostly\" walking or heavy physical labor is unavailable, it was not possible to assess whether respondents who did not meet guidelines through nonoccupational activity alone might meet guidelines through the combination of occupational and nonoccupational physical activity. As such, the proportions of persons meeting guidelines might have been underestimated. Second, BRFSS excludes persons in households without landline telephones. Finally, the 2007 BRFSS survey had a low CASRO response rate. These latter two factors can lead to bias, especially if physical activity patterns differ between those with and without landline telephones and between respondents and nonrespondents. The directions of these potential biases are unknown.\nAs one of the 10 leading health indicators in the United States (8), physical activity is monitored at state and national levels to provide information for public health program planning, implementation, and evaluation. The state of Washington has used combined occupational and nonoccupational physical activity data as part of its assessment to target communities for policy and environmental changes. Debate about the health benefits of physical activity at work is ongoing, but the current guidelines do not distinguish between occupational and nonoccupational physical activity. Thus, public health surveillance that includes both occupational and nonoccupational physical activity more accurately describes whether persons meet guidelines than surveillance that includes only nonoccupational physical activity. Because demographic groups vary in amounts of physical activity at work (9), surveillance that includes both occupational and nonoccupational physical activity can be used to target groups that could derive health benefits by being more physically active.\n# What is already known on this topic?\nPrevalence estimates of physical activity predominately focus on nonoccupational physical activity; however, physical activity at work also can contribute to levels of physical activity sufficient to meet physical activity recommendations.\n# What is added by this report?\nThis report is the first to provide estimates based on national surveillance data of the potential contribution of occupational physical activity toward meeting physical activity guidelines described in the 2008 Physical Activity Guidelines for Americans; when occupational physical activity was considered, an estimated additional 6.5% of adults overall very likely met the guidelines, and, for some groups, an estimated additional 14%-16% met the guidelines.\nWhat are the implications for public health practice?\nPending evaluation of the usefulness of collecting information on occupational physical activity frequency and duration, consideration of occupational physical activity in the monitoring of population physical activity levels can help to identify demographic groups for targeted programs to increase physical activity. Japanese encephalitis (JE) virus, a mosquito-borne flavivirus, is an important cause of encephalitis in Asia with a case fatality rate of 20%-30% and neurologic or psychiatric sequelae in 30%-50% of survivors (1). Travelers to JE-endemic countries and laboratory personnel who work with infectious JE virus are at potential risk for JE virus infection. In 2010, CDC's Advisory Committee on Immunization Practices (ACIP) updated recommendations for prevention of JE. The updated recommendations included information on use of a new inactivated, Vero cell culture-derived JE vaccine (JE-VC [manufactured as Ixiaro]) that was licensed in the United States in 2009. Data on the need for and timing of booster doses with JE-VC were not available when the vaccine was licensed. This report summarizes new data on the persistence of neutralizing antibodies following primary vaccination with JE-VC and the safety and immunogenicity of a booster dose of JE-VC. The report also provides updated guidance to health-care personnel regarding use of a booster dose of JE-VC for U.S. travelers and laboratory personnel. ACIP recommends that if the primary series of JE-VC was administered >1 year previously, a booster dose may be given before potential JE virus exposure.\n# Background\nFor most travelers to Asia, the risk for JE is very low but varies based on destination, duration, season, and activities (2). ACIP recommends JE vaccine for travelers who plan to spend a month or longer in JE-endemic areas during the JE virus transmission season. JE vaccine should be considered for short-term travelers (<1 month) if they plan to travel outside of an urban area and have an itinerary or activities that will increase the risk of JE virus exposure. JE vaccine also is recommended for laboratory personnel with a potential for exposure to infectious JE virus (1).\nIn 2009, the Food and Drug Administration (FDA) licensed JE-VC for use in persons aged ≥17 years. JE-VC is manufactured by Intercell Biomedical (Livingston, United Kingdom) and is distributed in the United States by Novartis Vaccines (Cambridge, Massachusetts). JE-VC is administered in a 2-dose primary series at 0 and 28 days. Another JE vaccine, an inactivated mouse brain-derived vaccine (JE-VAX [JE-MB]), has been licensed in the U.S since 1992. However, JE-MB is no longer being produced and remaining doses expire in May 2011.\nAdditional JE-VC study data have become available since the vaccine's licensure. The ACIP JE Vaccines Workgroup reviewed JE-VC clinical trial data on the persistence of neutralizing antibodies following primary vaccination with JE-VC and the safety and immunogenicity of a booster dose of JE-VC. These were primarily from published, peer-reviewed studies; however, unpublished data also were considered. FDA approved an update to the prescribing information for JE-VC in September 2010. No previous guidelines have been given on booster doses with JE-VC. At the February 2011 ACIP meeting, the workgroup presented data supporting use of a booster dose and proposed recommendations for a booster dose. ACIP approved the booster dose recommendations at the meeting.\n# Persistence of protective neutralizing antibodies after primary vaccination with JE-VC\nThree clinical trials have provided data on persistence of protective neutralizing antibodies after a primary 2-dose series of JE-VC. In JE vaccine clinical trials, JE virus neutralizing antibody levels measured by plaque reduction neutralization test (PRNT) can be used as a surrogate for protection. A 50% PRNT (PRNT 50 ) titer of ≥10 is accepted as an immunologic correlate of protection from JE in humans (3). In a study performed in central Europe (Austria, Germany, and Romania) to evaluate persistence of neutralizing antibodies among subjects who received 2 doses of JE-VC, 95% (172 of 181), 83% (151 of 181), 82% (148 of 181) and 85% (129 of 152) had protective antibodies at 6 months, 12 months, 24 months, and 36 months after receiving the first dose, respectively (Table 1) (4-6). A study that used similar methods but was performed in western and northern Europe (Germany and Northern Ireland) found that among adults receiving 2 doses of JE-VC, seroprotection rates were 83% (96 of 116) at 6 months, 58% (67 of 116) at 12 months, and 48% (56 of 116) at 24 months after their first vaccination (Table 1) (7). The manufacturer suggested that the different seroprotection rates in the two populations may have resulted from differences in prior vaccination against tick-borne encephalitis (TBE) virus, a related flavivirus. An estimated 75% of subjects in the first study might have received prior TBE vaccine compared with none of the subjects in the second study. A higher JE virus neutralizing antibody response after the first dose of JE-VC previously had been found in subjects with preexisting TBE\n# Recommendations for Use of a Booster Dose of Inactivated Vero Cell\nCulture-Derived Japanese Encephalitis Vaccine -Advisory Committee on Immunization Practices, 2011 antibodies compared with those without TBE antibodies (8). In a third clinical trial, conducted in Austria and Germany, at 15 months after the first dose of a 2-dose JE-VC immunization series, 69% (137 of 198) of subjects had a protective neutralizing antibody titer (Table 1) (9).\n# Safety and immunogenicity of a booster dose of JE-VC\nTwo clinical trials have provided data on the response to a booster dose of JE-VC. In a study conducted in Austria and Germany, 198 adults aged ≥18 years who had received a 2-dose primary series of JE-VC were administered a booster dose 15 months after the first dose (9). The percentage of subjects with a protective neutralizing antibody titer increased from 69% (137 of 198) on Day 0 before the booster dose to 100% (198 of 198) at Day 28 after the booster dose. Protective titers were found in 98% (194 of 197) at 6 months and 98% (191 of 194) at 12 months after the booster dose (Table 2). The geometric mean titer (GMT) before the booster was 23 and increased 40-fold to 900 at Day 28 after the booster dose. GMTs were 487 and 361 at 6 and 12 months after the booster, respectively (Table 2). During the 7 days following the booster dose, local adverse events were reported in subject diaries by 31% (60 of 195) of subjects. The most frequent local reactions were tenderness in 19% (37 of 193) and pain in 13% (25 of 195) (Table 3). Systemic adverse events were reported by 23% (44 of 190) of subjects within 7 days of the booster dose. The most commonly reported systemic reactions were headache in 11% (21 of 194) and fatigue in 10% (18 of 188) (6). No serious adverse events were reported during the 28 days following the booster dose.\nIn a second study, a booster dose administered to 40 subjects who had received primary immunization but no longer had protective neutralizing antibody titers resulted in protective titers in all subjects when the booster was administered at 11 months (n = 16) or 23 months (n = 24) after the first dose (7). GMTs at 1 month after the booster increased to 676 and to 2,496 in the groups administered the dose at 11 months and 23 months after the first dose, respectively. Among the 16 subjects who received the booster dose at 11 months, all still had seroprotective titers 13 months later.\n# Guidelines for use of a booster dose of JE-VC\nACIP recommends that if the primary series of JE-VC was administered >1 year previously, a booster dose may be given before potential JE virus exposure. ACIP recommendations should be consulted for information on prevention of JE and settings in which JE vaccine is recommended, can be considered, or is not recommended (1). Data on the response to a booster dose administered >2 years after the primary series of JE-VC are not available. Data on the need for and timing of additional booster doses also are not available.\nNo data exist on the use of JE-VC as a booster dose after a primary series with inactivated mouse brain-derived JE vaccine (JE-MB [manufactured as JE-Vax]). Adults aged ≥17 years who have received JE-MB previously and require further vaccination against JE virus should receive a 2-dose primary series of JE-VC.\nACIP will review any additional data that are made available. Recommendations will be updated as needed. Inactivated mouse brain-derived Japanese encephalitis (JE) vaccine (JE-MB [manufactured as JE-Vax]), the only JE vaccine that is licensed for use in children in the United States, is no longer available. This notice provides updated information regarding options for obtaining JE vaccine for U.S. children.\n# TABLE 2. Number and percentage of subjects with a protective Japanese encephalitis virus neutralizing antibody titer (≥10) and the geometric mean titers (GMT) prior to and at day 28, month 6, and month 12 after a booster dose of inactivated Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [manufactured as Ixiaro]) administered 15 months after dose 1 of a 2-dose primary JE-VC series\n\n# JE among U.S. travelers\nJE virus is the leading cause of vaccine-preventable encephalitis in Asia and the western Pacific. For most travelers to Asia, the risk for JE is low but varies on the basis of destination, duration, season, and activities. During the past 4 decades, 17 cases of JE have been reported among U.S. travelers and expatriates, including three cases among U.S. children aged <18 years (1,2). JE is a severe disease; 20%-30% of patients die, and 30%-50% of survivors have neurologic or psychiatric sequelae (3).\n# Recommendations for prevention of JE among travelers\nThe Advisory Committee on Immunization Practices (ACIP) recommends that all travelers, including children, take precautions to avoid mosquito bites to reduce the risk for JE and other vector-borne infectious diseases (3). These precautions include using insect repellent, permethrin-impregnated clothing, and bed nets, and staying in accommodations with screened or air-conditioned rooms. Additional information on protection against mosquitoes and other arthropods is available in CDC's Health Information for International Travel (Yellow Book) (4). For some travelers who will be in a high-risk setting on the basis of season, location, duration, and activities, JE vaccine can reduce the risk for disease further (3).\n# JE vaccine for U.S. children\nJE-MB has been licensed in the United States since 1992 for use in adults and children aged ≥1 year. JE-MB has been associated with serious, but rare, allergic and neurologic adverse events (3). During 2002-2009, a total of 848,571 doses of JE-MB were distributed in the United States (mean: 106,071 doses per year), of which 534,330 (63%) doses were distributed to military health-care providers (5). During this period, an estimated 2,000-3,000 doses of JE-MB were distributed for use in U.S. children each year (Sanofi Pasteur, unpublished data, 2011). However, JE-MB is no longer being produced, and all remaining doses expire in May 2011.\nIn 2009, the Food and Drug Administration (FDA) approved an inactivated Vero cell culture-derived JE vaccine (JE-VC [manufactured as Ixiaro]) for use in adults aged ≥17 years. One pediatric dose-ranging study has been completed among 60 children aged 12-35 months in India (48 children received JE-VC, and 12 children received another inactivated mouse brain-derived JE vaccine [manufactured as JenceVac]) (6). A safety and immunogenicity study is ongoing among approximately 1,900 children aged 2 months-17 years in the Philippines, and a safety and immunogenicity bridging study has been initiated in the United States and other nonendemic countries with a targeted enrollment of approximately 100 children. Despite these ongoing studies, it likely will be several years before JE-VC is licensed in the United States for use in children. JE-VC product information is available online from FDA at http://www.fda.gov/biologicsbloodvaccines/vaccines/ approvedproducts/ucm179132.htm.\n# Current options for obtaining JE vaccine for U.S. children\nFor U.S. health-care providers interested in obtaining JE vaccine for pediatric patients they judge to be at risk, current options include 1) enroll children in the ongoing clinical trial, 2) administer JE-VC off-label, or 3) receive JE vaccine at an international travelers' health clinic in Asia.\nThe ongoing pediatric safety and immunogenicity trial with JE-VC is enrolling children aged 2 months-17 years at five U.S. sites (trial identifier NCT01047839). The study is open-label, and all enrollees receive 2 doses of JE-VC administered 28 days apart. A third study visit is required at 56 days after the first dose of vaccine. Additional information about the clinical trial is available online from the National Institutes of Health at http://clinicaltrials.gov/ct2/show/nct01047839. In addition, a list of U.S. clinical trial sites and contact information is available online from CDC at http://www.cdc.gov/ncidod/dvbid/ jencephalitis/children.htm.\nJE-VC is FDA-licensed for use in adults aged ≥17 years. However, a health-care provider may choose to administer the vaccine off-label in children aged <17 years. Data from the one completed pediatric study have been published (6). Additional information about the use of JE-VC in children is available from Novartis Medical Communications by telephone (877-683-4732) or e-mail (vaccineinfo.us@novartis.com).\nSeveral JE vaccines are manufactured and available for pediatric use in Asia but are not licensed in the United States.\n# Update on Japanese Encephalitis Vaccine for Children -United States, May 2011\nVaccines available at international travelers' health clinics in Asia include another inactivated mouse brain-derived JE vaccine manufactured in South Korea, live attenuated SA 14-14-2 vaccine manufactured in China, or another Vero cell culturederived JE vaccine manufactured in Japan. The recommended number of doses and schedule varies by vaccine and country.\nA partial list of international travelers' health clinics in Asia that administer JE vaccines to children is available online from CDC at http://www.cdc.gov/ncidod/dvbid/jencephalitis/ children.htm.\n# On May 24, this report was posted as an MMWR Early Release on the MMWR website (http://www.cdc.gov/mmwr).\nMeasles is a highly contagious, acute viral illness that can lead to serious complications and death. Endemic or sustained measles transmission has not occurred in the United States since the late 1990s, despite continued importations (1). During 2001-2008, a median of 56 (range: 37-140) measles cases were reported to CDC annually (2); during the first 19 weeks of 2011, 118 cases of measles were reported, the highest number reported for this period since 1996. Of the 118 cases, 105 (89%) were associated with importation from other countries, including 46 importations (34 among U.S. residents traveling abroad and 12 among foreign visitors). Among those 46 cases, 40 (87%) were importations from the World Health Organization (WHO) European and South-East Asia regions. Of the 118, 105 (89%) patients were unvaccinated. Forty-seven (40%) patients were hospitalized and nine had pneumonia. The increased number of measles importations into the United States this year underscores the importance of vaccination to prevent measles and its complications.\nMeasles cases are reported by state health departments to CDC, and confirmed cases are reported via the National Notifiable Disease Surveillance System (NNDSS) using standard case definitions (3). Cases are considered internationally imported if at least some of the exposure period (7-21 days before rash onset) occurred outside the United States and rash occurred within 21 days of entry into the United States, with no known exposure to measles in the United States during that time. Import-associated cases include 1) internationally imported cases; 2) cases that are related epidemiologically to imported cases; and 3) imported virus cases for which an epidemiologic link has not been identified but the viral genotype detected suggests recent importation.* Laboratory confirmation of measles is made by detection in serum of measles-specific immunoglobulin M antibodies, isolation of measles virus, or detection of measles virus RNA by nucleic acid amplification in an appropriate clinical specimen (e.g., nasopharyngeal/oropharyngeal swabs, nasal aspirates, throat washes, or urine). For this report, persons with reported unknown or undocumented vaccination status are considered unvaccinated. An outbreak of measles is defined as a chain of transmission with three or more confirmed cases.\nDuring January 1-May 20, 2011, a total of 118 cases were reported from 23 states and New York City (Figure 1), the highest reported number for the same period since 1996 (Figure 2). Patients ranged in age from 3 months to 68 years; 18 (15%) were aged <12 months, 24 (20%) were aged 1-4 years, 23 (19%) were aged 5-19 years, and 53 (45%) were aged ≥20 years. Measles was laboratory-confirmed in 105 (89%) cases, and measles virus RNA was detected in 52 (44%) cases. Among the 118 cases, 105 (89%) were import-associated, of which 46 (44%) were importations from at least 15 countries (Table ), 49 (47%) were import-linked, and 10 (10%) were imported virus cases. The source of 13 cases not import-associated could not be determined. Among the 46 imported cases, most were among persons who acquired the disease in the WHO European Region (20) or South-East Asia Region (20), and 34 (74%) occurred in U.S. residents traveling abroad.\nOf the 118 cases, 47 (40%) resulted in hospitalization. Nine patients had pneumonia, but none had encephalitis and none died. All but one hospitalized patient were unvaccinated. The vaccinated patient reported having received 1 dose of measlescontaining vaccine and was hospitalized for observation only. Hospitalization rates were highest among infants and children aged <5 years (52%), but rates also were high among children and adults aged ≥5 years (33%).\nUnvaccinated persons accounted for 105 (89%) of the 118 cases. Among the 45 U.S. residents aged 12 months−19 years who acquired measles, 39 (87%) were unvaccinated, including 24 whose parents claimed a religious or personal exemption and eight who missed opportunities for vaccination. Among the 42 U.S. residents aged ≥20 years who acquired measles, 35 (83%) were unvaccinated, including six who declined vaccination because of philosophical objections to vaccination. Of the\n# Measles -United States, January-May 20, 2011 FIGURE 1. Distribution and origin of reported measles cases (N = 118) -United States, January 1-May 20, 2011\nImport associated Unknown source\n! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !! ! ! ! ! ! ! ! ! ! ! ! !! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !\n* Additional information is available at http://www.cdc.gov/osels/ph_surveillance/ nndss/casedef/measles_2010.htm.\n33 U.S. residents who were vaccine-eligible and had traveled abroad, 30 were unvaccinated and one had received only 1 of the 2 recommended doses. Nine outbreaks accounted for 58 (49%) of the 118 cases. The median outbreak size was four cases (range: 3-21). In six outbreaks, the index case acquired measles abroad; the source of the other three outbreaks could not be determined. Transmission occurred in households, child care centers, shelters, schools, emergency departments, and at a large community event. The largest outbreak occurred among 21 persons in a Minnesota population in which many children were unvaccinated because of parental concerns about the safety of measles, mumps, and rubella (MMR) vaccine. That outbreak resulted in exposure to many persons and infection of at least seven infants too young to receive MMR vaccine (4).\n# Reported by\n\n# Div of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC. Corresponding contributor: Huong\nMcLean, hmclean@cdc.gov, 404-639-7714.\n# Editorial Note\nAs a result of high vaccination coverage, measles elimination (i.e., the absence of endemic transmission) was achieved in the United States in the late 1990s (1) and likely in the rest of the Americas since the early 2000s (5). However, as long as measles remains endemic in the rest of the world, importations into the Western Hemisphere will continue.\nThe unusually large number of importations into the United States in the first 19 weeks of 2011 is related to recent increases in measles in countries visited by U.S. travelers. The most frequent sources of importation in 2011 were countries in the WHO European Region, which has accounted for the majority of measles importations in the United States since 2005 (2), and the South-East Asia Region. This year, 33 countries in the WHO European Region have reported an increase in measles. France, the source of most of the importations from the European Region, is experiencing a large outbreak, with approximately 10,000 cases reported during the first 4 months of 2011, including 12 cases of encephalitis, a complication that often results in permanent neurologic sequelae, 360 cases of severe measles pneumonia, and six measles-related deaths (6).\nMeasles can be severe and is highly infectious; following exposure, up to 90% of susceptible persons develop measles. Measles can lead to life-threatening complications. During 1989-1991, a resurgence of measles in the United States resulted in >100 deaths among >55,000 cases reported, reminding U.S. residents of the potential severity of measles, even in the era of modern medical care (7). In the years that followed, the United States witnessed the return of subacute sclerosing panencephalitis among U.S. children, a rare, fatal neurologic complication of measles that had all but disappeared after measles vaccine was introduced in the 1960s (8).\nChildren and adults who remain unvaccinated and develop measles also put others in their community at risk. For infants too young for routine vaccination (age <12 months) and persons with medical conditions that contraindicate measles * Patient had visited more than one country where measles are endemic during the incubation period, and exposure could have occurred in any of the countries listed. † Although the patient acquired measles in the Dominican Republic, the likely source of infection was a French tourist with measles who stayed in an adjacent room at the same resort at the same time as the patient. The genotype identified in this patient was D4, a genotype commonly circulating in France. MMR vaccine is safe and highly effective in preventing measles and its complications. MMR vaccine is recommended routinely for all children at age 12-15 months, with a second dose at age 4-6 years. For adults with no evidence of immunity to measles, † 1 dose of MMR vaccine is recommended unless the adult is in a high-risk group (i.e., health care personnel, international travelers, or students at post-high school educational institutions), in which case, 2 doses of MMR vaccine are recommended. Measles is endemic in many countries, and exposures might occur in airports and in countries of travel. All travelers aged ≥6 months are eligible to receive MMR vaccine and should be vaccinated before travel (10). Maintaining high immunization rates with MMR vaccine is the cornerstone of outbreak prevention. immunization, the risk for measles complications is particularly high. These persons depend on high MMR vaccination coverage among those around them to protect them from exposure. In the United States this year, infants aged <12 months accounted for 15% of cases and 15% of hospitalizations. In Europe in recent years, measles has been fatal for several children and adolescents, including some who could not be vaccinated because they were immune compromised.\nRapid control efforts by state and local public health agencies, which are both time intensive and costly, have been a key factor in limiting the size of outbreaks and preventing the spread of measles into communities with increased numbers of unvaccinated persons. Nonetheless, maintenance of high 2-dose MMR vaccination coverage is the most critical factor for sustaining elimination. For measles, even a small decrease in coverage can increase the risk for large outbreaks and endemic transmission, as occurred in the United Kingdom in the past decade (9).\nBecause of ongoing importations of measles to the United States, health-care providers should suspect measles in persons with a febrile rash illness and clinically compatible symptoms (e.g., cough, coryza, and/or conjunctivitis) who have recently traveled abroad or have had contact with travelers. Providers should isolate and report suspected measles cases immediately to their local health department and obtain specimens for measles testing, including viral specimens for confirmation and genotyping.\nWhat is already known on this topic? Measles, mumps, and rubella (MMR) vaccine is highly effective in preventing measles and its complications. Sustained measles transmission was eliminated from the United States in the late 1990s, but the disease remains common in many countries globally, and cases of measles are imported into the United States regularly.\nWhat is added by this report?\nDuring the first 19 weeks of 2011, 118 cases of measles were reported in the United States, the highest number for the same period in any year since 1996, and hospitalization rates were high (40%). Importations accounted for 46 (40%) cases, including 34 (74%) cases among U.S. residents who had recently traveled abroad, among 105 import-associated cases.\nWhat are the implications for public health practice? High 2-dose MMR vaccine coverage is critical for decreasing the risk for reestablishment of endemic measles transmission after importation of measles into the United States. Before any international travel, infants aged 6-11 months should receive 1 dose of MMR vaccine and persons aged ≥12 months should receive 2 doses of MMR vaccine at least 28 days apart or have other evidence of immunity to measles.\n# Notice to Readers\n\n# Updated \"N\" Indicators for the Year 2010 in National Notifiable Diseases Surveillance System Tables\nThe 2010 Council of State and Territorial Epidemiologists (CSTE) State Reportable Conditions Assessment (2010 SRCA) has collected data from 55 reporting jurisdictions (50 U.S. states, the District of Columbia, New York City, and three territories [American Samoa, Guam, and Puerto Rico]) to determine which of the nationally notifiable conditions (NNC) were reportable in each reporting jurisdiction in 2010. The 2010 SRCA gathered information regarding whether the condition is 1) explicitly reportable (i.e., listed as a specific disease or as a category of diseases on reportable disease lists), 2) implicitly reportable (i.e., included in a general category of the reportable disease list, such as \"rare diseases of public health importance\"), or 3) not reportable within each jurisdiction. Only conditions that were explicitly reportable were considered reportable based on the 2010 SRCA methodology.\nResults of the 2010 SRCA will be used to indicate whether each NNC is or is not reportable for the specified period and reporting jurisdiction. NNC that are not reportable are noted with an \"N\" indicator (for \"not reportable\") in the MMWR Table II weekly update (Provisional cases of selected notifiable diseases, United States) and in the MMWR Summary of Notifiable Diseases-United States, 2010. This notation will allow readers to distinguish whether 1) no cases were reported even though the condition is reportable or 2) no cases were reported because the condition is not reportable.\nThe 2010 SRCA data collection and validation concluded in April 2011; results will be used to populate the \"N\" indicators for National Notifiable Diseases Surveillance System (NNDSS) data in the 2011 MMWR tables for the current week and for both the 2010 and 2011 cumulative year columns. The 2011 NNDSS data displayed in the MMWR weekly provisional tables will reflect reporting requirements gathered from the 2010 SRCA until 2011 SRCA official results are available.\n# Announcement Preventive Medicine Residency and Fellowship Applications Deadline -September 15, 2011\nThe Preventive Medicine Residency and Fellowship (PMR/F) programs are accepting applications from physicians for the residency and from veterinarians, dentists, nurses, physician assistants, and international medical graduates for the fellowship. Applicants with public health and applied epidemiologic practice experience who seek to become preventive medicine and population health specialists and public health leaders are encouraged to apply.\nThe PMR/F prepares clinicians for leadership roles in public health at international, federal, state, and local levels through instruction and supervised practical experiences focused on translating epidemiology to public health practice, management, and policy and program development. Development of leadership and management competency is emphasized. Residents and fellows conduct their training at a CDC location or in a state or local health department.\nPMR/F alumni occupy many leadership positions at CDC, at state and local health departments, in academia, and in private-sector agencies. Completion of the residency, which is accredited by the Accreditation Council for Graduate Medical Education for 24 months of training, qualifies graduates to apply for certification by the American Board of Preventive Medicine (ABPM) in Public Health and General Preventive Medicine. Select candidates can be considered for 1 year of residency training that also should qualify for application for ABPM certification. Training for PMF clinicians also is 1 year.\nApplications are being accepted for the class that begins in mid-June 2012. Applications must be submitted online by September 15, 2011, and supporting documents must be received in the PMR/F office by that same day. Additional information regarding the programs, eligibility criteria, and application process is available at http://www.cdc.gov/prevmed, by telephone at 404-498-6140, or by e-mail at prevmed@cdc.gov.\n# Erratum\n\n# Vol. 60, No. RR-3\nIn the MMWR Recommendations and Reports \"Updated Norovirus Outbreak Management and Disease Prevention Guidelines,\" an error occurred on page 9. The second sentence under the heading \"Environmental Specimens\" should read: \"If a food or a water source is strongly suspected as the source of an outbreak, a sample should be obtained as early as possible with respect to the time of exposure, and CDC or FDA should be contacted for further guidance on testing. Food samples should be stored frozen at -4°F (-20°C), and water samples should be stored refrigerated or chilled on ice at 39°F (4°C).\" * Hypertension was defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or currently taking medication to lower blood pressure, based on positive responses to the following questions: \"Because of your high blood pressure/hypertension have you ever been told to take prescribed medicine?\" and \"Are you now taking a prescribed medicine?\" Undiagnosed hypertension was a finding of hypertension and a negative response to the following question: \"Have you ever been told by a doctor or other health professional that you had hypertension, also called high blood pressure?\" † Health insurance coverage is at the time of interview. Public coverage includes Medicaid, Children's Health Insurance Program (CHIP) state-sponsored or other government-sponsored health plan, Medicare (disability), or military health plan (TRICARE, VA, or CHAMP-VA). Persons with both public and private insurance coverage were included in the private coverage category only. § 95% confidence interval.\nDuring 2005-2008, among U.S. adults aged 20-64 years with hypertension, 40% of those with no health insurance had hypertension that was undiagnosed, compared with 21% of those with private insurance and 16% of those with public insurance. In the 20-39 years and 40-64 years age groups, undiagnosed hypertension also was more common among persons with no health insurance compared with those with private or public insurance. \n- 0 1 - 1 - 0 1 - - - 0 1 - - Mountain - 0 0 - - - 0 0 - - - 0 1 2 - Arizona - 0 0 - - - 0 0 - - - 0 1 2 - Colorado N 0 0 N N N 0 0 N N N 0 0 N N Idaho § N 0 0 N N N 0 0 N N N 0 0 N N Montana § N 0 0 N N N 0 0 N N N 0 0 N N Nevada § N 0 0 N N N 0 0 N N N 0 0 N N New Mexico § N 0 0 N N N 0 0 N N N 0 0 N N Utah - 0 0 - - - 0 0 - - - 0 0 - - Wyoming § - 0 0 - - - 0 0 - - - 0 0 - - Pacific - 0 1 - 1 - 0 0 - - - 0 1 1 2 Alaska N 0 0 N N N 0 0 N N N 0 0 N N California - 0 1 - 1 - 0 0 - - - 0 1 1 2 Hawaii N 0 0 N N N 0 0 N N N 0 0 N N Oregon - 0 0 - - - 0 0 - - - 0 0 - - Washington - 0 0 - - - 0 0 - - - 0 0 - -\n# Territories\n\n# Territories\n* Case counts for reporting year 2010 and 2011 are provisional and subject to change. For further information on interpretation of these data, see http://www.cdc.gov/osels/ph_surveillance/ nndss/phs/files/ProvisionalNationa%20NotifiableDiseasesSurveillanceData20100927.pdf. Data for TB are displayed in Table IV, which appears quarterly. † Dengue Fever includes cases that meet criteria for Dengue Fever with hemorrhage, other clinical and unknown case classifications. § DHF includes cases that meet criteria for dengue shock syndrome (DSS), a more severe form of DHF. ¶ Contains data reported through the National Electronic Disease Surveillance System (NEDSS). The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format. To receive an electronic copy each week, visit MMWR's free subscription page at http://www.cdc.gov/mmwr/mmwrsubscribe. html. Paper copy subscriptions are available through the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone 202-512-1800.\nData presented by the Notifiable Disease Data Team and 122 Cities Mortality Data Team in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. Address all inquiries about the MMWR Series, including material to be considered for publication, to Editor, MMWR Series, Mailstop E-90, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333 or to mmwrq@cdc.gov.\nAll material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated.\nUse of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.\nReferences to non-CDC sites on the Internet are provided as a service to MMWR readers and do not constitute or imply endorsement of these organizations or their programs by CDC or the U.S. Department of Health and Human Services. CDC is not responsible for the content of these sites. URL addresses listed in MMWR were current as of the date of publication."},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":268,"cells":{"id":{"kind":"string","value":"d75fe9d0f4b21ac7a2f12bcaa5636737a7ce49a3"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR TOLUENE DIISOCYANATE\n\n# RECOMMENDATIONS FOR A TOLUENE DIISOCYANATE STANDARD\nThe\nAdministrative controls can also be used to reduce exposure to TDI. does not exceed 100 times the time-weighted average for continuous work, or 100 times the ceiling for work of short duration, eg 20 minutes or less.\n( Rubbers shall be decontaminated and ventilated after contamination.\nLeather shoes which have been contaminated with TDI shall be decontaminated or disposed of.\nWorkers within 10 feet of spray operations, or at greater distances when there is a greater drift of spray, shall be protected with impervious clothing, gloves, and footwear in addition to a supplied air impervious hood.\n(2) Chemical workers' goggles shall be worn where splashes are likely to occur. The two isomers are believed to have similar physiological properties.\n Their physical and chemical properties are very similar except that the 2,6 isomer has a lower freezing point.\n The 80% 2,4:20% 2,6 mixture represents better than 95% of industrial usage.\nProperties of commercial samples of this mixture are listed in\n\n# R-NCO + H20 yields RNH-COOH which yields R-NH2 + C02\nThe primary amine so produced will react further with excess TDI with the formation of a urea derivative: Probably because it reacts avidly with all proteins, its direct effects are, in accidental or occupational exposure of man, virtually confined to its reaction upon the surface membranes of the body.\nSystemic absorption of TDI, with toxic effects upon internal organs, has not been reported in man, except in the special sense of the hypothetical immunologic involvement of the reticuloendothelial system in those subjects who become sensitized to TDI.\nIn the occupational exposure of man to TDI in the vapor or aerosol phase, its impact upon the respiratory tract is overwhelmingly the most important. Its topical effects upon other tissues will be briefly considered first. In a plant producing slabs of polyurethane foam by a continuous process air levels of TDI and the workers' health were studied for a period of 2-1/2 years.\n More than 1,000 air samples were analyzed. The extreme range of air level values at various sites and times was a reported 0.00 to 3.0 ppm. The range of average values for the various sites was given as 0.00 to 2.6 ppm. It is impossible to determine a time-weighted average level from the data published, but monthly average levels throughout the plant were reported to be in the 0.00 to 0.15 ppm range.\nDuring the study period a total of 83 illnesses attributed to TDI required medical attention. Twenty of the original cohort of workers had by 1969 been followed at 6-monthly intervals for a total of two years (five series of examinations).\n During the second year of follow-up the decline of FEV 1.0 had continued at a mean annual rate of 0.11 liters, which exceeds the predicted rate of decline due to aging alone. It is confirmed in this report that acute daily changes in ventilatory capacity continued to occur in workers after two years and more continued exposure to TDI at low levels, that workers with respiratory symptoms showed a greater acute and cumulative response to TDI than asymptomatic workers, that there was a strong correlation between oneday change and cumulative effect, and that the effect of smoking does not seem important. For the highly sensitized individual it is doubtful whether there is a measurable safe level for TDI below which that individual is completely safe from response.\nWhether there is a measurable level below which no one will become sensitized de novo is not completely clear from the available evidence to date, although this is the intended basis for the TLV of 0.02 ppm\n(1) Additional company analyses verify that air levels were high.\n(2) The workers wore respirators, which probably indicates acute irritation.\n(3) Some workers had been transferred after complaints.\n\n# method.\n[ The calibration instrument will be connected in sequence to the impinger unit which will be followed by the sampler pump. In this way, the calibration instrument will be at atmospheric pressure.\nIf the personal sampler pump is used, each pump must be calibrated separately.\nIf the burette is used, it should be set up so that the flow is toward the narrow end of the unit.\nFrom these data, it can be seen that at all exposure levels of 0.01 ppm or higher, some cases of TDI toxicity occurred, but there were no cases at 0.007 or lower. At 0.009 ppm, there were no established cases, but one questionable one; there were several established cases at 0.008 ppm. It is concluded that the timeweighted average environmental limit should be below 0.01 ppm, and should be 0.005 ppm to ensure some margin of safety."},"raw_text":{"kind":"string","value":"# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR TOLUENE DIISOCYANATE\n\n# RECOMMENDATIONS FOR A TOLUENE DIISOCYANATE STANDARD\nThe\nAdministrative controls can also be used to reduce exposure to TDI. does not exceed 100 times the time-weighted average for continuous work, or 100 times the ceiling for work of short duration, eg 20 minutes or less.\n( Rubbers shall be decontaminated and ventilated after contamination.\nLeather shoes which have been contaminated with TDI shall be decontaminated or disposed of.\nWorkers within 10 feet of spray operations, or at greater distances when there is a greater drift of spray, shall be protected with impervious clothing, gloves, and footwear in addition to a supplied air impervious hood.\n(2) Chemical workers' goggles shall be worn where splashes are likely to occur. The two isomers are believed to have similar physiological properties.\n[1] Their physical and chemical properties are very similar except that the 2,6 isomer has a lower freezing point.\n[2] The 80% 2,4:20% 2,6 mixture represents better than 95% of industrial usage.\n[3]\nProperties of commercial samples of this mixture are listed in \n# R-NCO + H20 yields RNH-COOH which yields R-NH2 + C02\nThe primary amine so produced will react further with excess TDI with the formation of a urea derivative: Probably because it reacts avidly with all proteins, its direct effects are, in accidental or occupational exposure of man, virtually confined to its reaction upon the surface membranes of the body.\nSystemic absorption of TDI, with toxic effects upon internal organs, has not been reported in man, except in the special sense of the hypothetical immunologic involvement of the reticuloendothelial system in those subjects who become sensitized to TDI.\nIn the occupational exposure of man to TDI in the vapor or aerosol phase, its impact upon the respiratory tract is overwhelmingly the most important. Its topical effects upon other tissues will be briefly considered first. In a plant producing slabs of polyurethane foam by a continuous process air levels of TDI and the workers' health were studied for a period of 2-1/2 years.\n[17] More than 1,000 air samples were analyzed. The extreme range of air level values at various sites and times was a reported 0.00 to 3.0 ppm. The range of average values for the various sites was given as 0.00 to 2.6 ppm. It is impossible to determine a time-weighted average level from the data published, but monthly average levels throughout the plant were reported to be in the 0.00 to 0.15 ppm range.\nDuring the study period a total of 83 illnesses attributed to TDI required medical attention. Twenty of the original cohort of workers had by 1969 been followed at 6-monthly intervals for a total of two years (five series of examinations).\n[42] During the second year of follow-up the decline of FEV 1.0 had continued at a mean annual rate of 0.11 liters, which exceeds the predicted rate of decline due to aging alone. It is confirmed in this report [42] that acute daily changes in ventilatory capacity continued to occur in workers after two years and more continued exposure to TDI at low levels, that workers with respiratory symptoms showed a greater acute and cumulative response to TDI than asymptomatic workers, that there was a strong correlation between oneday change and cumulative effect, and that the effect of smoking does not seem important. For the highly sensitized individual it is doubtful whether there is a measurable safe level for TDI below which that individual is completely safe from response.\nWhether there is a measurable level below which no one will become sensitized de novo is not completely clear from the available evidence to date, although this is the intended basis for the TLV of 0.02 ppm \n(2)\n(3)\n(1) Additional company analyses verify that air levels were high.\n(2) The workers wore respirators, which probably indicates acute irritation.\n(3) Some workers had been transferred after complaints.\n# method.\n[ The calibration instrument will be connected in sequence to the impinger unit which will be followed by the sampler pump. In this way, the calibration instrument will be at atmospheric pressure.\nIf the personal sampler pump is used, each pump must be calibrated separately.\nIf the burette is used, it should be set up so that the flow is toward the narrow end of the unit. \n# \nFrom these data, it can be seen that at all exposure levels of 0.01 ppm or higher, some cases of TDI toxicity occurred, but there were no cases at 0.007 or lower. At 0.009 ppm, there were no established cases, but one questionable one; there were several established cases at 0.008 ppm. It is concluded that the timeweighted average environmental limit should be below 0.01 ppm, and should be 0.005 ppm to ensure some margin of safety. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":269,"cells":{"id":{"kind":"string","value":"a2e0ddb96714cb5ae3252756abebaccc4e90112b"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"# Table of Contents\n\n# I. Executive Summary\nThis guideline updates and expands the original Centers for Disease Control and Prevention (CDC) Guideline for Prevention of Catheter-associated Urinary Tract Infections (CAUTI) published in 1981. Several developments necessitated revision of the 1981 guideline, including new research and technological advancements for preventing CAUTI, increasing need to address patients in non-acute care settings and patients requiring long-term urinary catheterization, and greater emphasis on prevention initiatives as well as better defined goals and metrics for outcomes and process measures. In addition to updating the previous guideline, this revised guideline reviews the available evidence on CAUTI prevention for patients requiring chronic indwelling catheters and individuals who can be managed with alternative methods of urinary drainage (e.g., intermittent catheterization). The revised guideline also includes specific recommendations for implementation, performance measurement, and surveillance. Although the general principles of CAUTI prevention have not changed from the previous version, the revised guideline provides clarification and more specific guidance based on a defined, systematic review of the literature through July 2007. For areas where knowledge gaps exist, recommendations for further research are listed. Finally, the revised guideline outlines highpriority recommendations for CAUTI prevention in order to offer guidance for implementation. This document is intended for use by infection prevention staff, healthcare epidemiologists, healthcare administrators, nurses, other healthcare providers, and persons responsible for developing, implementing, and evaluating infection prevention and control programs for healthcare settings across the continuum of care. The guideline can also be used as a resource for societies or organizations that wish to develop more detailed implementation guidance for prevention of CAUTI.\nOur goal was to develop a guideline based on a targeted systematic review of the best available evidence, with explicit links between the evidence and recommendations. To accomplish this, we used an adapted GRADE system approach for evaluating quality of evidence and determining strength of recommendations. The methodology, structure, and components of this guideline are approved by HICPAC and will be used for subsequent guidelines issued by HICPAC. A more detailed description of our approach is available in the Methods section.\nTo evaluate the evidence on preventing CAUTI, we examined data addressing three key questions and related subquestions: Evidence addressing the key questions was used to formulate recommendations, and explicit links between the evidence and recommendations are available in the Evidence Review in the body of the guideline and Evidence Tables and GRADE Tables in the Appendices (). It is important to note that Category I recommendations are all considered strong recommendations and should be equally implemented; it is only the quality of the evidence underlying the recommendation that distinguishes between levels A and B. Category IC recommendations are required by state or federal regulation and may have any level of supporting evidence.\nThe categorization scheme used in this guideline is presented in Table 1 in the Summary of Recommendations and described further in the Methods section.\nThe Summary of Recommendations is organized as follows:\n1. recommendations for who should receive indwelling urinary catheters (or, for certain populations, alternatives to indwelling catheters);\n2. recommendations for catheter insertion; 3. recommendations for catheter maintenance; 4. quality improvement programs to achieve appropriate placement, care, and removal of catheters;\n5. administrative infrastructure required; and 6. surveillance strategies.\nThe Implementation and Audit section includes a prioritization of recommendations (i.e., highpriority recommendations that are essential for every healthcare facility), organized by modules, in order to provide facilities more guidance on implementation of these guidelines. A list of recommended performance measures that can potentially be used for internal reporting purposes is also included.\nAreas in need of further research identified during the evidence review are outlined in the Recommendations for Further Research. This section includes guidance for specific methodological approaches that should be used in future studies.\nReaders who wish to examine the primary evidence underlying the recommendations are referred to the Evidence Review in the body of the guideline, and the Evidence Tables and GRADE Tables in the Appendices (). The Evidence Review includes narrative summaries of the data presented in the Evidence Tables and GRADE Tables. The Evidence Tables include all study-level data used in the guideline, and the GRADE Tables assess the overall quality of evidence for each question. The Appendices also contain a clearly delineated search strategy that will be used for periodic updates to ensure that the guideline remains a timely resource as new information becomes available.\n\n# II. Summary of Recommendations\n\n# B. Examples of Inappropriate Uses of Indwelling Catheters\n- As a substitute for nursing care of the patient or resident with incontinence.\n- As a means of obtaining urine for culture or other diagnostic tests when the patient can voluntarily void. - For prolonged postoperative duration without appropriate indications (e.g., structural repair of urethra or contiguous structures, prolonged effect of epidural anaesthesia, etc.).\n\n# II. Proper Techniques for Urinary Catheter Insertion\n\n# III. Implementation and Audit\n\n# Prioritization of Recommendations\nIn this section, the recommendations considered essential for all healthcare facilities caring for patients requiring urinary catheterization are organized into modules in order to provide more guidance to facilities on implementation of these guidelines. The high-priority recommendations were chosen by a consensus of experts based on strength of recommendation as well as on the likely impact of the strategy in preventing CAUTI. The administrative functions and infrastructure listed above in the summary of recommendations are necessary to accomplish the high priority recommendations and are therefore critical to the success of a prevention program. In addition, quality improvement programs should be implemented as an active approach to accomplishing these recommendations and when process and outcome measure goals are not being met based on internal reporting.\n\n# Priority Recommendations for Appropriate Urinary Catheter Use (Module 1)\n- Insert catheters only for appropriate indications (see Table 2), and leave in place only as long as needed. Conduct random audits of selected units and calculate compliance rate:\n- Numerator: number of patients on unit with catheters with proper documentation of insertion and removal dates - Denominator: number of patients on the unit with a catheter in place at some point during admission - Standardization factor: 100 (i.e., multiply by 100 so that measure is expressed as a percentage) c) Compliance with documentation of indication for catheter placement: Conduct random audits of selected units and calculate compliance rate\n\n# IV. Recommendations for Further Research\nOur literature review revealed that many of the studies addressing strategies to prevent CAUTI were not of sufficient quality to allow firm conclusions regarding the benefit of certain interventions. Future studies of CAUTI prevention should: 1. Be primary analytic research (i.e. systematic reviews, meta-analyses, interventional studies, and observational studies ) 2. Evaluate clinically relevant outcomes (e.g., SUTI, bloodstream infections secondary to CAUTI) 3. Adjust for confounders as needed using multivariable analyses 4. Stratify outcomes by patient populations at risk for CAUTI 5. Ensure adequate statistical power to detect differences\nThe following is a compilation of recommendations for further research:\n\n# V. Background\nUrinary tract infections are the most common type of healthcare-associated infection, accounting for more than 30% of infections reported by acute care hospitals. 19 Virtually all healthcare-associated UTIs are caused by instrumentation of the urinary tract. Catheterassociated urinary tract infection (CAUTI) has been associated with increased morbidity, mortality, hospital cost, and length of stay. In addition, bacteriuria commonly leads to unnecessary antimicrobial use, and urinary drainage systems are often reservoirs for multidrugresistant bacteria and a source of transmission to other patients. 10,11\n\n# Definitions\nAn indwelling urinary catheter is a drainage tube that is inserted into the urinary bladder through the urethra, is left in place, and is connected to a closed collection system. Alternative methods of urinary drainage may be employed in some patients. Intermittent (\"in-and-out\") catheterization involves brief insertion of a catheter into the bladder through the urethra to drain urine at intervals. An external catheter is a urine containment device that fits over or adheres to the genitalia and is attached to a urinary drainage bag. The most commonly used external catheter is a soft flexible sheath that fits over the penis (\"condom\" catheter). A suprapubic catheter is surgically inserted into the bladder through an incision above the pubis. The limitations and heterogeneity of definitions of CAUTI used in various studies present major challenges in appraising the quality of evidence in the CAUTI literature. Study investigators have used numerous different definitions for CAUTI outcomes, ranging from simple bacteriuria at a range of concentrations to, less commonly, symptomatic infection defined by combinations of bacteriuria and various signs and symptoms. Futhermore, most studies that used CDC/NHSN definitions for CAUTI did not distinguish between SUTI and ASB in their analyses. 30 The heterogeneity of definitions used for CAUTI may reduce the quality of evidence for a given intervention and often precludes meta-analyses.\nThe clinical significance of ASB in catheterized patients is undefined. Approximately 75% to 90% of patients with ASB do not develop a systemic inflammatory response or other signs or symptoms to suggest infection. 6,31 Monitoring and treatment of ASB is also not an effective prevention measure for SUTI, as most cases of SUTI are not preceded by bacteriuria for more than a day. 25 Treatment of ASB has not been shown to be clinically beneficial and is associated with the selection of antimicrobial-resistant organisms.\n\n# Epidemiology\nBetween 15% and 25% of hospitalized patients may receive short-term indwelling urinary catheters. 12,13 In many cases, catheters are placed for inappropriate indications, and healthcare providers are often unaware that their patients have catheters, leading to prolonged, unnecessary use. In acute care hospitals reporting to NHSN in 2006, pooled mean urinary catheter utilization ratios in ICU and non-ICU areas ranged from 0.23-0.91 urinary catheterdays/patient-days. 17 While the numbers of units reporting were small, the highest ratios were in trauma ICUs and the lowest in inpatient medical/surgical wards. The overall prevalence of longterm indwelling urethral catheterization use is unknown. The prevalence of urinary catheter use in residents in long-term care facilities in the United States is on the order of 5%, representing approximately 50,000 residents with catheters at any given time. 18 This number appears to be declining over time, likely because of federally mandated nursing home quality measures. However, the high prevalence of urinary catheters in patients transferred to skilled nursing facilities suggests that acute care hospitals should focus more efforts on removing unnecessary catheters prior to transfer. 18 Reported rates of UTI among patients with urinary catheters vary substantially. National data from NHSN acute care hospitals in 2006 showed a range of pooled mean CAUTI rates of 3.1-7.5 infections per 1000 catheter-days. 17 The highest rates were in burn ICUs, followed by inpatient medical wards and neurosurgical ICUs, although these sites also had the fewest numbers of locations reporting. The lowest rates were in medical/surgical ICUs.\nAlthough morbidity and mortality from CAUTI is considered to be relatively low compared to other HAIs, the high prevalence of urinary catheter use leads to a large cumulative burden of infections with resulting infectious complications and deaths. An estimate of annual incidence of HAIs and mortality in 2002, based on a broad survey of US hospitals, found that urinary tract infections made up the highest number of infections (> 560,000) compared to other HAIs, and attributable deaths from UTI were estimated to be over 13,000 (mortality rate 2.3%). 19 And while fewer than 5% of bacteriuric cases develop bacteremia, 6 CAUTI is the leading cause of secondary nosocomial bloodstream infections; about 17% of hospital-acquired bacteremias are from a urinary source, with an associated mortality of approximately 10%. 20 In the nursing home setting, bacteremias are most commonly caused by UTIs, the majority of which are catheterrelated. 21 An estimated 17% to 69% of CAUTI may be preventable with recommended infection control measures, which means that up to 380,000 infections and 9000 deaths related to CAUTI per year could be prevented. 22\n\n# Pathogenesis and Microbiology\nThe source of microorganisms causing CAUTI can be endogenous, typically via meatal, rectal, or vaginal colonization, or exogenous, such as via contaminated hands of healthcare personnel or equipment. Microbial pathogens can enter the urinary tract either by the extraluminal route, via migration along the outside of the catheter in the periurethral mucous sheath, or by the intraluminal route, via movement along the internal lumen of the catheter from a contaminated collection bag or catheter-drainage tube junction. The relative contribution of each route in the pathogenesis of CAUTI is not well known. The marked reduction in risk of bacteriuria with the introduction of the sterile, closed urinary drainage system in the1960's 23 suggests the importance of the intraluminal route. However, even with the closed drainage system, bacteriuria inevitably occurs over time either via breaks in the sterile system or via the extraluminal route. 24 The daily risk of bacteriuria with catheterization is 3% to 10%, 25,26 approaching 100% after 30 days, which is considered the delineation between short and longterm catheterization. 27 Formation of biofilms by urinary pathogens on the surface of the catheter and drainage system occurs universally with prolonged duration of catheterization. 28 Over time, the urinary catheter becomes colonized with microorganisms living in a sessile state within the biofilm, rendering them resistant to antimicrobials and host defenses and virtually impossible to eradicate without removing the catheter. The role of bacteria within biofilms in the pathogenesis of CAUTI is unknown and is an area requiring further research. Antimicrobial resistance among urinary pathogens is an ever increasing problem. About a quarter of E. coli isolates and one third of P. aeruginosa isolates from CAUTI cases were fluoroquinolone-resistant. Resistance of gram-negative pathogens to other agents, including third-generation cephalosporins and carbapenems, was also substantial 5 . The proportion of organisms that were multidrug-resistant, defined by non-susceptibility to all agents in 4 classes, was 4% of P. aeruginosa, 9% of K. pneumoniae, and 21% of Acinetobacter baumannii. 29\n\n# VI. Scope and Purpose\nThis guideline updates and expands the original CDC Guideline for Prevention of CAUTI published in 1981. The revised guideline addresses the prevention of CAUTI for patients in need of either short-or long-term (i.e., > 30 days) urinary catheterization in any type of healthcare facility and evaluates evidence for alternative methods of urinary drainage, including intermittent catheterization, external catheters, and suprapubic catheters. The guideline also includes specific recommendations for implementation, performance measurement, and surveillance. Recommendations for further research are also provided to address the knowledge gaps in CAUTI prevention identified during the literature review.\nTo evaluate the evidence on preventing CAUTI, we examined data addressing three key questions and related subquestions: This document is intended for use by infection prevention staff, healthcare epidemiologists, healthcare administrators, nurses, other healthcare providers, and persons responsible for developing, implementing, and evaluating infection prevention and control programs for healthcare settings across the continuum of care. The guideline can also be used as a resource for societies or organizations that wish to develop more detailed implementation guidance for prevention of CAUTI.\n\n# VII. Methods\nThis guideline was based on a targeted systematic review of the best available evidence on CAUTI prevention. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to provide explicit links between the available evidence and the resulting recommendations. Our guideline development process is outlined in Figure 1.\n\n# Figure 1. The Guideline Development Process\n\n# Development of Key Questions\nWe first conducted an electronic search of the National Guideline Clearinghouse® (\n\n# Literature Search\nFollowing the development of the key questions, search terms were developed for identifying literature relevant to the key questions. For the purposes of quality assurance, we compared these terms to those used in relevant seminal studies and guidelines. These search terms were then incorporated into search strategies for the relevant electronic databases. Searches were performed in Medline® (National Library of Medicine) using the Ovid® Platform (Ovid Technologies, Wolters Kluwer, New York, NY), EMBASE® (Elsevier BV, Amsterdam, Netherlands), CINAHL® (Ebsco Publishing, Ipswich, MA) and Cochrane® (Cochrane Collaboration, Oxford, UK) (all databases were searched in July 2007), and the resulting references were imported into a reference manager, where duplicates were resolved. For Cochrane reviews ultimately included in our guideline, we checked for updates in July 2008.\nThe detailed search strategy used for identifying primary literature and the results of the search can be found in Appendix 1B ().\n\n# Study Selection\nTitles and abstracts from references were screened by a single author (C.V.G, R.K.A., or D.A.P.) and the full text articles were retrieved if they were 1. relevant to one or more key questions, 2. primary analytic research, systematic reviews or meta-analyses, and 3. written in English.\nLikewise, the full-text articles were screened by a single author (C.V.G. or D.A.P.) using the same criteria, and included studies underwent a second review for inclusion by another author (R.K.A.). Disagreements were resolved by the remaining authors. The results of this process are depicted in Figure 2.\n\n# Data Extraction and Synthesis\nData on the study author, year, design, objective, population, setting, sample size, power, followup, and definitions and results of clinically relevant outcomes were extracted into evidence tables (Appendix 2 ()). Three evidence tables were developed, each of which represented one of our key questions. Studies were extracted into the most relevant evidence table . Then, studies were organized by the common themes that emerged within each evidence table. Data were extracted by one author (R.K.A.) and cross-checked by another (C.V.G.). Disagreements were resolved by the remaining authors. Data and analyses were extracted as originally presented in the included studies. Meta-analyses were performed only where their use was deemed critical to a recommendation, and only in circumstances where multiple studies with sufficiently homogenous populations, interventions, and outcomes could be analyzed. Systematic reviews were included in our review. To avoid duplication of data, we excluded primary studies if they were also included in a systematic review captured by our search. The only exception to this was if the primary study also addressed a relevant question that was outside the scope of the included systematic review. Before exclusion, data from the primary studies that we originally captured were abstracted into the evidence tables and reviewed. We also excluded systematic reviews that analyzed primary studies that were fully captured in a more recent systematic review. The only exception to this was if the older systematic review also addressed a relevant question that was outside the scope of the newer systematic review. To ensure that all relevant studies were captured in the search, the bibliography was vetted by a panel of clinical experts.\n\n# Grading of Evidence\nFirst, the quality of each study was assessed using scales adapted from existing methodology checklists, and scores were recorded in the evidence tables. Appendix 3 () includes the sets of questions we used to assess the quality of each of the major study designs. Next, the quality of the evidence base was assessed using methods adapted from the GRADE Working Group. 32 Briefly, GRADE tables were developed for each of the interventions or questions addressed within the evidence tables. Included in the GRADE tables were the intervention of interest, any outcomes listed in the evidence tables that were judged to be clinically important, the quantity and type of evidence for each outcome, the relevant findings, and the GRADE of evidence for each outcome, as well as an overall GRADE of the evidence base for the given intervention or question. The initial GRADE of evidence for each outcome was deemed high if the evidence base included a randomized controlled trial (RCT) or a systematic review of RCTs, low if the evidence base included only observational studies, or very low if the evidence base consisted only of uncontrolled studies. The initial GRADE could then be modified by eight criteria. 34 Criteria which could decrease the GRADE of an evidence base included quality, consistency, directness, precision, and publication bias. Criteria that could increase the GRADE included a large magnitude of effect, a dose-response gradient, or inclusion of unmeasured confounders that would increase the magnitude of effect (Table 3). GRADE definitions are as follows:\n1. High -further research is very unlikely to change confidence in the estimate of effect 2. Moderate -further research is likely to affect confidence in the estimate of effect and may change the estimate 3. Low -further research is very likely to affect confidence in the estimate of effect and is likely to change the estimate 4. Very low -any estimate of effect is very uncertain After determining the GRADE of the evidence base for each outcome of a given intervention or question, we calculated the overall GRADE of the evidence base for that intervention or question. The overall GRADE was based on the lowest GRADE for the outcomes deemed critical to making a recommendation.\n\n# Table 3. Rating the Quality of Evidence Using the GRADE Approach\nThe format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Rating the\n\n# Formulating Recommendations\nNarrative evidence summaries were then drafted by the working group using the evidence and GRADE tables. One summary was written for each theme that emerged under each key question. The working group then used the narrative evidence summaries to develop guideline recommendations. Factors determining the strength of a recommendation included 1. the values and preferences used to determine which outcomes were \"critical,\" 2. the harms and benefits that result from weighing the \"critical\" outcomes, and 3. the overall GRADE of the evidence base for the given intervention or question (Table 4). 33 If weighing the \"critical outcomes\" for a given intervention or question resulted in a \"net benefit\" or a \"net harm,\" then a \"Category I Recommendation\" was formulated to strongly recommend for or against the given intervention respectively. If weighing the \"critical outcomes\" for a given intervention or question resulted in a \"trade off\" between benefits and harms, then a \"Category II Recommendation\" was formulated to recommend that providers or institutions consider the intervention when deemed appropriate. If weighing the \"critical outcomes\" for a given intervention or question resulted in an \"uncertain trade off\" between benefits and harms, then a \"No Recommendation\" was formulated to reflect this uncertainty. No recommendation/ Unresolved issue for which there is low to very low quality evidence with unresolved issue uncertain trade offs between benefits and harms.\nCategory I recommendations are defined as strong recommendations with the following implications: 1. For patients: Most people in the patient's situation would want the recommended course of action and only a small proportion would not; request discussion if the intervention is not offered. 2. For clinicians: Most patients should receive the recommended course of action. 3. For policymakers: The recommendation may be adopted as a policy.\nCategory II recommendations are defined as weak recommendations with the following implications:\n1. For patients: Most people in the patient's situation would want the recommended course of action, but many would not. 2. For clinicians: Different choices will be appropriate for different patients, and clinicians must help each patient to arrive at a management decision consistent with her or his values and preferences. 3. For policymakers: Policy making will require substantial debate and involvement of many stakeholders.\nIt should be noted that Category II recommendations are discretionary for the individual institution and are not intended to be enforced.\nThe wording of each recommendation was carefully selected to reflect the recommendation's strength. In most cases, we used the active voice when writing Category I recommendationsthe strong recommendations. Phrases like \"do\" or \"do not\" and verbs without auxiliaries or conditionals were used to convey certainty. We used a more passive voice when writing Category II recommendations -the weak recommendations. Words like \"consider\" and phrases like \"is preferable,\" \"is suggested,\" \"is not suggested,\" or \"is not recommended\" were chosen to reflect the lesser certainty of the Category II recommendations. Rather than a simple statement of fact, each recommendation is actionable, describing precisely a proposed action to take.\nThe category \"No recommendation/unresolved issue\" was most commonly applied to situations where either 1. the overall quality of the evidence base for a given intervention was low to very low and there was no consensus on the benefit of the intervention or 2. there was no published evidence on outcomes deemed critical to weighing the risks and benefits of a given intervention. If the latter was the case, those critical outcomes will be noted at the end of the relevant evidence summary.\nOur evidence-based recommendations were cross-checked with those from guidelines identified in our original systematic search. Recommendations from previous guidelines for topics not directly addressed by our systematic review of the evidence were included in our \"Summary of Recommendations\" if they were deemed critical to the target users of this guideline. Unlike recommendations informed by our literature search, these recommendations are not linked to a key question. These recommendations were agreed upon by expert consensus and are designated either IB if they represent a strong recommendation based on accepted practices (e.g., aseptic technique) or II if they are a suggestion based on a probable net benefit despite limited evidence.\nAll recommendations were approved by HICPAC. Recommendations focused only on efficacy, effectiveness, and safety. The optimal use of these guidelines should include a consideration of the costs relevant to the local setting of guideline users.\n\n# Reviewing and Finalizing the Guideline\nAfter a draft of the tables, narrative summaries, and recommendations was completed, the working group shared the draft with the expert panel for in-depth review. While the expert panel was reviewing this draft, the working group completed the remaining sections of the guideline, including the executive summary, background, scope and purpose, methods, summary of recommendations, and recommendations for guideline implementation, audit, and further research. The working group then made revisions to the draft based on feedback from members of the expert panel and presented the entire draft guideline to HICPAC for review. The guideline was then posted on the Federal Register for public comment. After a period of public comment, the guideline was revised accordingly, and the changes were reviewed and voted on by HICPAC. The final guideline was cleared internally by CDC and published and posted on the HICPAC website.\n\n# Updating the Guideline\nFuture revisions to this guideline will be dictated by new research and technological advancements for preventing CAUTI and will occur at the request of HICPAC.\n\n# VIII. Evidence Review\n\n# Q1. Who should receive urinary catheters?\nTo answer this question, we focused on three subquestions: A. When is urinary catheterization necessary? B. What are the risk factors for CAUTI? and C. What populations are at highest risk of mortality from urinary catheters?\n\n# Q1A. When is urinary catheterization necessary?\nThe available data examined five main populations. In all populations, we considered CAUTI outcomes as well as other outcomes we deemed critical to weighing the risks and benefits of catheterization. The evidence for this question consists of 1 systematic review, 37 9 RCTs, and 12 observational studies. The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1A.\nFor operative patients, low-quality evidence suggested a benefit of avoiding urinary catheterization. This was based on a decreased risk of bacteriuria/unspecified UTI, no effect on bladder injury, and increased risk of urinary retention in patients without catheters. Urinary retention in patients without catheters was specifically seen following urogenital surgeries. The most common surgeries studied were urogenital, gynecological, laparoscopic, and orthopedic surgeries. Our search did not reveal data on the impact of catheterization on peri-operative hemodynamic management.\nFor incontinent patients, low-quality evidence suggested a benefit of avoiding urinary catheterization. 45, This was based on a decreased risk of both SUTI and bacteriuria/unspecified UTI in male nursing home residents without urinary catheters compared to those with continuous condom catheters. We found no difference in the risk of UTI between having a condom catheter only at night and having no catheter. Our search did not reveal data on the impact of catheterization on skin breakdown.\nFor patients with bladder outlet obstruction, very low-quality evidence suggested a benefit of a urethral stent over an indwelling catheter. 53 This was based on a reduced risk of bacteriuria in those receiving a urethral stent. Our search did not reveal data on the impact of catheterization versus stent placement on urinary complications.\nFor patients with spinal cord injury, very low-quality evidence suggested a benefit of avoiding indwelling urinary catheters. 54,56 This was based on a decreased risk of SUTI and bacteriuria in those without indwelling catheters (including patients managed with spontaneous voiding, clean intermittent catheterization , and external striated sphincterotomy with condom catheter drainage), as well as a lower risk of urinary complications, including hematuria, stones, and urethral injury (fistula, erosion, stricture).\nFor children with myelomeningocele and neurogenic bladder, very low-quality evidence suggested a benefit of CIC compared to urinary diversion or self voiding. 46,57,58 This was based on a decreased risk of bacteriuria/unspecified UTI in patients receiving CIC compared to urinary diversion, and a lower risk of urinary tract deterioration (defined by febrile urinary tract infection, vesicoureteral reflux, hydronephrosis, or increases in BUN or serum creatinine) compared to self-voiding and in those receiving CIC early ( 3 years of age).\n\n# Evidence Review Table 1A. When is urinary catheterization necessary?\n1A.1. Use urinary catheters in operative patients only as necessary, rather than routinely.\n\n# Q1B. What are the risk factors for CAUTI?\nTo answer this question, we reviewed the quality of evidence for those risk factors examined in more than one study. We considered the critical outcomes for decision-making to be SUTI and bacteriuria. The evidence for this question consists of 11 RCTs 59-69 and 37 observational studies. 9,50,54, The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1B.\nFor SUTI, 50,54,61,62,74,75,79,83,102,103\n\n# Q1C. What populations are at highest risk of mortality from urinary catheters?\nTo answer this question, we reviewed the quality of evidence for those risk factors examined in more than one study. The evidence for this question consists of 2 observational studies. 7,74 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1C.\nLow-quality evidence suggested that older age, higher severity of illness, and being on an internal medicine service compared to a surgical service were independent risk factors for mortality in patients with indwelling urinary catheters. Both studies evaluating these risk factors found the highest risk of mortality in patients over 70 years of age. Low-quality evidence also suggested that CAUTI was a risk factor for mortality in patients with catheters.\nEvidence Review Table 1C. What populations are at highest risk of mortality from catheters?\n1C.1. Minimize urinary catheter use and duration in all patients, particularly those who may be at higher risk for mortality due to catheterization, such as the elderly and patients with severe illness. (Category IB)\n\n# Q2. For those who may require urinary catheters, what are the best practices?\nTo answer this question, we focused on four subquestions: A. What are the risks and benefits associated with different approaches to catheterization? B. What are the risks and benefits associated with different types of catheters or collecting systems? C. What are the risks and benefits associated with different catheter management techniques D. What are the risks and benefits associated with different systems interventions?\n\n# Q2A. What are the risks and benefits associated with different approaches to catheterization?\nThe available data examined the following comparisons of different catheterization approaches:\n1. External versus indwelling urethral 2. Intermittent versus indwelling urethral 3. Intermittent versus suprapubic 4. Suprapubic versus indwelling urethral 5. Clean intermittent versus sterile intermittent For all comparisons, we considered SUTI, bacteriuria/unspecified UTI, or combinations of these outcomes depending on availability, as well as other outcomes critical to weighing the risks and benefits of different catheterization approaches. The evidence for this question consists of 6 systematic reviews, 37, 16 RCTs, 62,63, and 18 observational studies. 54,73,81,84, The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2A\n\n# Q2A.1. External versus indwelling urethral\nLow-quality evidence suggested a benefit of using external catheters over indwelling urethral catheters in male patients who require a urinary collection device but do not have an indication for an indwelling catheter such as urinary retention or bladder outlet obstruction. 81,109,123 This was based on a decreased risk of a composite outcome of SUTI, bacteriuria, or death as well as increased patient satisfaction with condom catheters. Differences were most pronounced in men without dementia. Statistically significant differences were not found or reported for the individual CAUTI outcomes or death. Our search did not reveal data on differences in local complications such as skin maceration or phimosis.\n\n# Q2A.2. Intermittent versus indwelling urethral\nLow-quality evidence suggested a benefit of using intermittent catheterization over indwelling urethral catheters in selected populations. 84,135,136 This was based on a decreased risk of SUTI and bacteriuria/unspecified UTI but an increased risk of urinary retention in postoperative patients with intermittent catheterization. In one study, urinary retention and bladder distension were avoided by performing catheterization at regular intervals (every 6-8 hrs) until return of voiding. Studies of patients with neurogenic bladder most consistently found a decreased risk of CAUTI with intermittent catheterization. Studies in operative patients whose catheters were removed within 24 hrs of surgery found no differences in bacteriuria with intermittent vs. indwelling catheterization, while studies where catheters were left in for longer durations had mixed results. Our search did not reveal data on differences in patient satisfaction.\n\n# Q2A.3. Intermittent versus suprapubic\nVery low-quality evidence suggested a benefit of intermittent over suprapubic catheterization in selected populations 115,116, based on increased patient acceptability and decreased risk of urinary complications (bladder calculi, vesicoureteral reflux, and upper tract abnormalities). Although we found a decreased risk of bacteriuria/unspecified UTI with suprapubic catheterization, there were no differences in SUTI. The populations studied included women undergoing urogynecologic surgery and spinal cord injury patients.\n\n# Q2A.4. Suprapubic versus indwelling urethral\nLow-quality evidence suggested a benefit of suprapubic catheters over indwelling urethral catheters in selected populations. 37,62,104,107,108,135,136 This was based on a decreased risk of bacteriuria/unspecified UTI, recatheterization, and urethral stricture, and increased patient comfort and satisfaction. However, there were no differences in SUTI and an increased risk of longer duration of catheterization with suprapubic catheters. Studies involved primarily postoperative and spinal cord injury patients. Our search did not reveal data on differences in complications related to catheter insertion or the catheter site.\n\n# Q2A.5. Clean intermittent versus sterile intermittent\nModerate-quality evidence suggested no benefit of using sterile over clean technique for intermittent catheterization. 63,73,105, No differences were found in the risk of SUTI or bacteriuria/unspecified UTI. Study populations included nursing home residents and adults and children with neurogenic bladder/spinal cord injury.\n\n# Q2B. What are the risks and benefits associated with different catheters or collecting systems?\nThe available data examined the following comparisons between different types of catheters and drainage systems:\n1. Antimicrobial/antiseptic catheters vs. standard catheters a. Silver-coated catheters vs. standard catheters b. Nitrofurazone-impregnated catheters vs. standard catheters 2. Hydrophilic catheters vs. standard catheters 3. Closed vs. open drainage systems 4. Complex vs. simple drainage systems 5. Preconnected/sealed junction catheters vs. standard catheters 6. Catheter valves vs. catheter bags For all comparisons, we considered CAUTI outcomes as well as other outcomes critical to weighing the risks and benefits of different types of catheters or collecting systems. The evidence for this question consists of 5 systematic reviews, 37, 17 RCTs, 64, 23 observational studies, 82,86,89,97, and 3 economic analyses. 179180,181 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2B.\n\n# Q2B.1.a. Silver-coated catheters vs. standard catheters\nLow-quality evidence suggested a benefit of silver-coated catheters over standard latex catheters. 37,82,86,137-139,143,159-163, 165,166 This was based on a decreased risk of bacteriuria/unspecified UTI with silver-coated catheters and no evidence of increased urethral irritation or antimicrobial resistance in studies that reported data on microbiological outcomes. Differences were significant for silver alloy-coated catheters but not silver oxide-coated catheters. In a meta-analysis of randomized controlled trials (see Appendix), silver alloy-coated catheters reduced the risk of asymptomatic bacteriuria compared to standard latex catheters (control latex catheters were either uncoated or coated with hydrogel, Teflon®, or silicone), whereas there were no differences when compared to standard, all silicone catheters. The effect of silver alloy catheters compared to latex catheters was more pronounced when used in patients catheterized <1 week. The results were robust to inclusion or exclusion of non peerreviewed studies. Only one observational study found a decrease in SUTI with silver alloycoated catheters. 166 The setting was a burn referral center, where the control catheters were latex, and patients in the intervention group had new catheters placed on admission, whereas the control group did not. Recent observational studies in hospitalized patients found mixed results for bacteriuria/unspecified UTI.\n\n# Q2B.1.b. Nitrofurazone-impregnated catheters vs. standard catheters\nLow-quality evidence suggested a benefit of nitrofurazone-impregnated catheters in patients catheterized for short periods of time. 137,138 This was based on a decreased risk of bacteriuria and no evidence of increased antimicrobial resistance in studies that reported microbiological outcomes. Differences were significant in a meta-analysis of three studies examining nitrofurazone-impregnated catheters (only one individual study significant) when duration of catheterization was 1 week, although the meta-analysis was borderline significant.\n\n# Q2B.2. Hydrophilic catheters vs. standard catheters\nVery low-quality evidence suggested a benefit of hydrophilic catheters over standard nonhydrophilic catheters in specific populations undergoing clean intermittent catheterization. 137,169 This was based on a decreased risk of SUTI, bacteriuria, hematuria, and pain during insertion, and increased patient satisfaction. Differences in CAUTI outcomes were limited to one study of spinal cord injury patients and one study of patients receiving intravesical immunochemoprophylaxis for bladder cancer, while multiple other studies found no significant differences.\n\n# Q2B.3. Closed vs. open drainage systems\nVery low-quality evidence suggested a benefit of using a closed rather than open urinary drainage system. 89,171 This was based on a decreased risk of bacteriuria with a closed drainage system. One study also found a suggestion of a decreased risk of SUTI, bacteremia, and UTIrelated mortality associated with closed drainage systems, but differences were not statistically significant. Sterile, continuously closed drainage systems became the standard of care based on an uncontrolled study published in 1966 demonstrating a dramatic reduction in the risk of infection in short-term catheterized patients with the use of a closed system. 23 Recent data also include the finding that disconnection of the drainage system is a risk factor for bacteriuria (Q1B).\n\n# Q2B.4. Complex vs. simple drainage systems\nLow-quality evidence suggested no benefit of complex closed urinary drainage systems over simple closed urinary drainage systems. 154,172,176,177 Although there was a decreased risk of bacteriuria with the complex systems, differences were found only in studies published before 1990, and not in more recent studies. The complex drainage systems studied included various mechanisms for reducing bacterial entry, such as antiseptic-releasing cartridges at the drain port of the urine collection bag; see evidence table for systems evaluated.\n\n# Q2B.5. Preconnected/sealed junction catheters vs. standard catheters\nLow-quality evidence suggested a benefit of using preconnected catheters with junction seals over catheters with unsealed junctions to reduce the risk of disconnections. 64,153,156,175 This was based on a decreased risk of SUTI and bacteriuria with preconnected sealed catheters. Studies that found differences had higher rates of CAUTI in the control group than studies that did not find an effect.\n\n# Q2B.6. Catheter valves vs. drainage bags\nModerate-quality evidence suggested a benefit of catheter valves over drainage bags in selected patients with indwelling urinary catheters. 140 Catheter valves led to greater patient satisfaction but no differences in bacteriuria/unspecified UTI or pain/bladder spasms. Details regarding the setting for recruitment and follow-up of the patients in the studies were unclear, and the majority of subjects were men. Our search did not reveal data on the effect of catheter valves on bladder function, bladder/urethral trauma, or catheter blockage.\n\n# Q2C. What are the risks and benefits associated with different catheter management techniques?\nThe available data examined the following catheter management techniques: For all comparisons, we considered CAUTI outcomes as well as other outcomes critical to weighing the risks and benefits of different catheter management techniques. The evidence for this question consists of 6 systematic reviews, 37,105,106, 56 RCTs, 60,61,143,158,158, 34 observational studies, 83,85,88,90,96,102,133,167,178, and 1 economic analysis. 180 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2C.\n\n# Q2C.1. Antimicrobial prophylaxis\nLow-quality evidence suggested no benefit of antimicrobial prophylaxis in patients undergoing short-term catheterization. 37,60,61,83,85,133,158,178,182,185,186, This was based on heterogeneous results for SUTI and bacteriuria/unspecified UTI and no adverse events related to antimicrobials. Lack of consistency in specific factors, such as patient population, antimicrobial agents, timing of administration, and duration of follow-up, did not allow for a summary of evidence of the effect of antimicrobial prophylaxis on CAUTI in patients undergoing short term catheterization. Only two studies evaluated adverse events related to antimicrobials. Our search did not reveal data on antimicrobial resistance or Clostridium difficile infection.\nLow-quality evidence suggested no benefit of antimicrobial prophylaxis in patients undergoing long-term catheterization (indwelling and clean intermittent catheterization). 106,183,192,194,235,238 This was based on a decreased risk of bacteriuria, heterogeneous results for SUTI, and no differences reported for catheter encrustation or adverse events, although data were sparse. One systematic review suggested an increase in antimicrobial resistance with antimicrobial use.\n\n# Q2C.2. Urinary antiseptics\nLow-quality evidence suggested a benefit of methenamine for short-term catheterized patients. 196,197 This was based on a reduced risk of SUTI and bacteriuria and no differences in adverse events. Evidence was limited to two studies of patients following gynecological surgery in Norway and Sweden.\nVery low-quality evidence suggested a benefit of methanamine for long-term catheterized patients. 106, This was based on a reduced risk of encrustation but no differences in risk of SUTI or bacteriuria. Data on encrustation was limited to one study. Studies involved primarily elderly and spinal cord injury patients with chronic indwelling catheters\n\n# Q2C.3. Bladder irrigation\nLow-quality evidence suggested no benefit of bladder irrigation in patients with indwelling or intermittent catheters. 66,69, This was based on no differences in SUTI and heterogeneous findings for bacteriuria.\n\n# Q2C.4. Antiseptic instillation in the drainage bag\nLow-quality evidence suggested no benefit of antiseptic instillation in urinary drainage bags. 90, This was based on no differences in SUTI and heterogeneous results for bacteriuria.\n\n# Q2C.5. Periurethral care\nLow-quality evidence suggested no benefit of antiseptic meatal cleaning regimens before or during catheterization to prevent CAUTI. 65,67,68,88,158,246,247 This was based on no difference in the risk of bacteriuria in patients receiving periurethral care regimens compared to those not receiving them. One study found a higher risk of bacteriuria with cleaning of the urethral meatus-catheter junction (either twice daily application of povidine-iodine or once daily cleaning with a non-antiseptic solution of green soap and water) in a subgroup of women with positive meatal cultures and in patients not receiving antimicrobials. Periurethral cleaning with chlorhexidine before catheter insertion did not have an effect in two studies.\n\n# Q2C.6. Routine catheter or bag change\nLow-quality evidence suggested no benefit of routine catheter or drainage bag changes to prevent CAUTI. 102,248,249 This was based on no difference or an increased risk of SUTI and no difference in bacteriuria with routine compared to as-needed changes or with more frequent changing intervals. One study in nursing home residents found no differences in SUTI with routine monthly catheter changes compared to changing only for obstruction or infection, but the study was underpowered to detect a difference. Another study in home care patients found an increased risk of SUTI when catheters were changed more frequently than monthly.\n\n# Q2C.7. Catheter lubricants\nVery low-quality evidence suggested a benefit of using lubricants for catheter insertion. 167, This was based on a decreased risk of SUTI and bacteriuria with the use of a prelubricated catheter compared to a catheter lubricated by the patient and a decreased risk of bacteriuria with use of a lubricant versus no lubricant. Studies were heterogeneous both in the interventions and outcomes studied. Several studies comparing antiseptic lubricants to nonantiseptic lubricants found no significant differences.\n\n# Q2C.8. Securing devices\nLow-quality evidence suggested no benefit of using catheter securing devices to prevent CAUTI. 224 This was based on no significant difference in the risk of SUTI or meatal erosion. The only study in this category looked at one particular product.\n\n# Q2C.9. Bacterial interference\nModerate-quality evidence suggested a benefit of using bacterial interference in catheterized patients. 225 In the one study evaluating this intervention, urinary colonization with a nonpathogenic Escherichia coli was associated with a decreased risk of SUTI in adults with spinal cord injury and a history of frequent CAUTI.\n\n# Q2C.10. Catheter cleansing\nVery low-quality evidence suggested a benefit of wet versus dry storage procedures for catheters used in clean intermittent catheterization. 255 This was based on a decreased risk of SUTI with a wet storage procedure in one study of spinal cord injury patients undergoing clean intermittent catheterization compared to a dry storage procedure where the catheter was left to air dry after washing. In the wet procedure, the catheter was stored in a dilute povidone-iodine solution after washing with soap and water.\n\n# Q2C.11. Catheter removal strategies a. Clamping vs. free drainage prior to removal\nLow-quality evidence suggested no benefit of clamping versus free drainage before catheter removal. 37,184 This was based on no difference in risk of bacteriuria, urinary retention, or recatheterization between the two strategies. One study comparing a clamp and release strategy to free drainage over 72 hours found a greater risk of bacteriuria in the clamping group.\n\n# b. Postoperative duration of catheterization\nModerate-quality evidence suggested a benefit of shorter versus longer postoperative durations of catheterization. 37,184,227,228 This was based on a decreased risk of bacteriuria/unspecified UTI, decreased time to ambulation and length of stay, no differences in urinary retention and SUTI, and increased risk of recatheterization. Significant decreases in bacteriuria/unspecified UTI were found specifically for comparisons of 1 day versus 3 or 5 days of postoperative catheterization. Recatheterization risk was greater in only one study comparing immediate removal to removal 6 or 12 hours after hysterectomy.\n\n# Q2C.12. Assessment of urine volumes\nLow-quality evidence suggested a benefit of using portable ultrasound to assess urine volume in patients undergoing intermittent catheterization. 229,230 This was based on fewer catheterizations but no reported differences in risk of unspecified UTI. Patients studied were adults with neurogenic bladder in inpatient rehabilitation centers. Our search did not reveal data on the use of ultrasound in catheterized patients in other settings. We considered CAUTI outcomes, duration of catheterization, recatheterization, and transmission of pathogens when weighing the risks and benefits of different systems interventions. The evidence for this question consists of 1 RCT 259 and 19 observational studies. 3,25, The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2D.\n\n# Q2D.1. Multifaceted infection control/quality improvement programs\nLow-quality evidence suggested a benefit of multifaceted infection control/quality improvement programs to reduce the risk of CAUTI. 3, This was based on a decreased risk of SUTI, bacteriuria/unspecified UTI, and duration of catheter use with implementation of such programs. Studies evaluated various multifaceted interventions. The studies with significant findings included:\n1. education and performance feedback regarding compliance with catheter care, emphasizing hand hygiene, and maintaining unobstructed urine flow;\n2. computerized alerts to physicians, nurse-driven protocols to remove catheters, and use of handheld bladder scanners to assess for urinary retention;\n3. guidelines and education focusing on perioperative catheter management; and 4. a multifaceted infection control program including guidelines for catheter insertion and maintenance. A program using a checklist and algorithm for appropriate catheter use also suggested a decrease in unspecified UTI and catheter duration, but statistical differences were not reported.\n\n# Q2D.2. Reminders\nVery low-quality evidence suggested a benefit of using urinary catheter reminders to prevent CAUTI. This was based on a decreased risk of bacteriuria and duration of catheterization and no differences in recatheterization or SUTI when reminders were used. Reminders to physicians included both computerized and non-computerized alerts about the presence of urinary catheters and the need to remove unnecessary catheters.\n\n# Q2D.3. Bacteriologic monitoring\nVery low-quality evidence suggested no benefit of bacteriologic monitoring to prevent CAUTI. 25,271 Although one study found a decreased risk of bacteriuria during a period of bacteriologic monitoring and feedback, only 2% of SUTI episodes were considered potentially preventable with the use of bacteriologic monitoring.\n\n# Q2D.4. Hand hygiene\nVery low-quality evidence suggested a benefit of using alcohol hand sanitizer in reducing CAUTI. This was based on one study in a rehabilitation facility that found a decrease in unspecified UTI, although no statistical differences were reported. 272 A separate multifaceted study that included education and performance feedback on compliance with catheter care and hand hygiene showed a decrease in risk of SUTI. 265\n\n# Q2D.5. Patient placement\nVery low-quality evidence suggested a benefit of spatially separating patients to prevent transmission of urinary pathogens. 273 This was based on a decreased risk of transmission of urinary bacterial pathogens in nursing home residents in separate rooms compared to residents in the same rooms.\n\n# Q2D.6. Catheter team versus self-catheterization\nVery low-quality evidence suggested no benefit of a catheter team to prevent CAUTI among patients requiring intermittent catheterization. 274 This was based on one study showing no difference in unspecified UTI between use of a catheter care team and self-catheterization for intermittent catheterization in paraplegic patients.\n\n# Q2D.7. Feedback\nVery low-quality evidence suggested a benefit of using nursing feedback to prevent CAUTI. 275 This was based on a decreased risk of unspecified UTI during an intervention where nursing staff were provided with regular reports of unit-specific rates of CAUTI.\n\n# Q2D.8. Nurse-directed catheter removal\nVery low-quality evidence suggested a benefit of a nurse-directed catheter removal program to prevent CAUTI. 276 This was based on a decreased risk of unspecified UTI during an intervention where criteria were developed that allowed a registered nurse to remove a catheter without a physician's order when no longer medically necessary. Of the three intensive care units where the intervention was implemented, differences were significant only in the coronary intensive care unit.\nEvidence Review Table 2D\n\n# Q3: What are the best practices for preventing UTI associated with obstructed urinary catheters?\nThe available data examined the following practices:\n1. Methods to prevent/reduce encrustations or blockage 2. Catheter materials preventing blockage For this question, available relevant outcomes included blockage/encrustation. We did not find data on the outcomes of CAUTI. The evidence for this question consists of 1 systematic review, 277 2 RCTs, 278,279 and 2 observational studies. 280,281 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 3.\n\n# Q3.1. Methods to prevent/reduce encrustations or blockage\nLow-quality evidence suggested a benefit of acidifying solutions or oral acetohydroxamic acid in preventing or reducing catheter encrustations and blockage in long-term catheterized patients. 277,278,280,281 No differences were seen with daily catheter irrigation with normal saline.\n\n# Q3.2. Catheter materials preventing blockage\nLow-quality evidence suggested a benefit of silicone over latex or Teflon-coated catheters in prevention or reducing catheter encrustations in long-term catheterized patients who were prone to blockage. No differences were seen with different materials in patients considered \"nonblockers.\" 279 Evidence Review Table 3. What are the best practices for preventing UTI associated with obstructed urinary catheters?\n\n# Abbreviations Abbreviation"},"raw_text":{"kind":"string","value":"# Table of Contents\n\n# I. Executive Summary\nThis guideline updates and expands the original Centers for Disease Control and Prevention (CDC) Guideline for Prevention of Catheter-associated Urinary Tract Infections (CAUTI) published in 1981. Several developments necessitated revision of the 1981 guideline, including new research and technological advancements for preventing CAUTI, increasing need to address patients in non-acute care settings and patients requiring long-term urinary catheterization, and greater emphasis on prevention initiatives as well as better defined goals and metrics for outcomes and process measures. In addition to updating the previous guideline, this revised guideline reviews the available evidence on CAUTI prevention for patients requiring chronic indwelling catheters and individuals who can be managed with alternative methods of urinary drainage (e.g., intermittent catheterization). The revised guideline also includes specific recommendations for implementation, performance measurement, and surveillance. Although the general principles of CAUTI prevention have not changed from the previous version, the revised guideline provides clarification and more specific guidance based on a defined, systematic review of the literature through July 2007. For areas where knowledge gaps exist, recommendations for further research are listed. Finally, the revised guideline outlines highpriority recommendations for CAUTI prevention in order to offer guidance for implementation. This document is intended for use by infection prevention staff, healthcare epidemiologists, healthcare administrators, nurses, other healthcare providers, and persons responsible for developing, implementing, and evaluating infection prevention and control programs for healthcare settings across the continuum of care. The guideline can also be used as a resource for societies or organizations that wish to develop more detailed implementation guidance for prevention of CAUTI.\nOur goal was to develop a guideline based on a targeted systematic review of the best available evidence, with explicit links between the evidence and recommendations. To accomplish this, we used an adapted GRADE system approach for evaluating quality of evidence and determining strength of recommendations. The methodology, structure, and components of this guideline are approved by HICPAC and will be used for subsequent guidelines issued by HICPAC. A more detailed description of our approach is available in the Methods section.\nTo evaluate the evidence on preventing CAUTI, we examined data addressing three key questions and related subquestions: Evidence addressing the key questions was used to formulate recommendations, and explicit links between the evidence and recommendations are available in the Evidence Review in the body of the guideline and Evidence Tables and GRADE Tables in the Appendices (https://www.cdc.gov/infectioncontrol/guidelines/pdf/cauti-guidelines-appendix.pdf). It is important to note that Category I recommendations are all considered strong recommendations and should be equally implemented; it is only the quality of the evidence underlying the recommendation that distinguishes between levels A and B. Category IC recommendations are required by state or federal regulation and may have any level of supporting evidence.\nThe categorization scheme used in this guideline is presented in Table 1 in the Summary of Recommendations and described further in the Methods section.\nThe Summary of Recommendations is organized as follows:\n1. recommendations for who should receive indwelling urinary catheters (or, for certain populations, alternatives to indwelling catheters);\n2. recommendations for catheter insertion; 3. recommendations for catheter maintenance; 4. quality improvement programs to achieve appropriate placement, care, and removal of catheters;\n5. administrative infrastructure required; and 6. surveillance strategies.\nThe Implementation and Audit section includes a prioritization of recommendations (i.e., highpriority recommendations that are essential for every healthcare facility), organized by modules, in order to provide facilities more guidance on implementation of these guidelines. A list of recommended performance measures that can potentially be used for internal reporting purposes is also included.\nAreas in need of further research identified during the evidence review are outlined in the Recommendations for Further Research. This section includes guidance for specific methodological approaches that should be used in future studies.\nReaders who wish to examine the primary evidence underlying the recommendations are referred to the Evidence Review in the body of the guideline, and the Evidence Tables and GRADE Tables in the Appendices (https://www.cdc.gov/infectioncontrol/guidelines/pdf/cautiguidelines-appendix.pdf). The Evidence Review includes narrative summaries of the data presented in the Evidence Tables and GRADE Tables. The Evidence Tables include all study-level data used in the guideline, and the GRADE Tables assess the overall quality of evidence for each question. The Appendices also contain a clearly delineated search strategy that will be used for periodic updates to ensure that the guideline remains a timely resource as new information becomes available. \n# II. Summary of Recommendations\n\n# B. Examples of Inappropriate Uses of Indwelling Catheters\n• As a substitute for nursing care of the patient or resident with incontinence.\n• As a means of obtaining urine for culture or other diagnostic tests when the patient can voluntarily void. • For prolonged postoperative duration without appropriate indications (e.g., structural repair of urethra or contiguous structures, prolonged effect of epidural anaesthesia, etc.). \n# II. Proper Techniques for Urinary Catheter Insertion\n\n# III. Implementation and Audit\n\n# Prioritization of Recommendations\nIn this section, the recommendations considered essential for all healthcare facilities caring for patients requiring urinary catheterization are organized into modules in order to provide more guidance to facilities on implementation of these guidelines. The high-priority recommendations were chosen by a consensus of experts based on strength of recommendation as well as on the likely impact of the strategy in preventing CAUTI. The administrative functions and infrastructure listed above in the summary of recommendations are necessary to accomplish the high priority recommendations and are therefore critical to the success of a prevention program. In addition, quality improvement programs should be implemented as an active approach to accomplishing these recommendations and when process and outcome measure goals are not being met based on internal reporting.\n# Priority Recommendations for Appropriate Urinary Catheter Use (Module 1)\n• Insert catheters only for appropriate indications (see Table 2), and leave in place only as long as needed. Conduct random audits of selected units and calculate compliance rate:\n• Numerator: number of patients on unit with catheters with proper documentation of insertion and removal dates • Denominator: number of patients on the unit with a catheter in place at some point during admission • Standardization factor: 100 (i.e., multiply by 100 so that measure is expressed as a percentage) c) Compliance with documentation of indication for catheter placement: Conduct random audits of selected units and calculate compliance rate \n•\n# IV. Recommendations for Further Research\nOur literature review revealed that many of the studies addressing strategies to prevent CAUTI were not of sufficient quality to allow firm conclusions regarding the benefit of certain interventions. Future studies of CAUTI prevention should: 1. Be primary analytic research (i.e. systematic reviews, meta-analyses, interventional studies, and observational studies [cohort, case-control, analytic cross-sectional studies]) 2. Evaluate clinically relevant outcomes (e.g., SUTI, bloodstream infections secondary to CAUTI) 3. Adjust for confounders as needed using multivariable analyses 4. Stratify outcomes by patient populations at risk for CAUTI 5. Ensure adequate statistical power to detect differences\nThe following is a compilation of recommendations for further research: \n# V. Background\nUrinary tract infections are the most common type of healthcare-associated infection, accounting for more than 30% of infections reported by acute care hospitals. 19 Virtually all healthcare-associated UTIs are caused by instrumentation of the urinary tract. Catheterassociated urinary tract infection (CAUTI) has been associated with increased morbidity, mortality, hospital cost, and length of stay. [6][7][8][9] In addition, bacteriuria commonly leads to unnecessary antimicrobial use, and urinary drainage systems are often reservoirs for multidrugresistant bacteria and a source of transmission to other patients. 10,11 \n# Definitions\nAn indwelling urinary catheter is a drainage tube that is inserted into the urinary bladder through the urethra, is left in place, and is connected to a closed collection system. Alternative methods of urinary drainage may be employed in some patients. Intermittent (\"in-and-out\") catheterization involves brief insertion of a catheter into the bladder through the urethra to drain urine at intervals. An external catheter is a urine containment device that fits over or adheres to the genitalia and is attached to a urinary drainage bag. The most commonly used external catheter is a soft flexible sheath that fits over the penis (\"condom\" catheter). A suprapubic catheter is surgically inserted into the bladder through an incision above the pubis. The limitations and heterogeneity of definitions of CAUTI used in various studies present major challenges in appraising the quality of evidence in the CAUTI literature. Study investigators have used numerous different definitions for CAUTI outcomes, ranging from simple bacteriuria at a range of concentrations to, less commonly, symptomatic infection defined by combinations of bacteriuria and various signs and symptoms. Futhermore, most studies that used CDC/NHSN definitions for CAUTI did not distinguish between SUTI and ASB in their analyses. 30 The heterogeneity of definitions used for CAUTI may reduce the quality of evidence for a given intervention and often precludes meta-analyses.\nThe clinical significance of ASB in catheterized patients is undefined. Approximately 75% to 90% of patients with ASB do not develop a systemic inflammatory response or other signs or symptoms to suggest infection. 6,31 Monitoring and treatment of ASB is also not an effective prevention measure for SUTI, as most cases of SUTI are not preceded by bacteriuria for more than a day. 25 Treatment of ASB has not been shown to be clinically beneficial and is associated with the selection of antimicrobial-resistant organisms.\n# Epidemiology\nBetween 15% and 25% of hospitalized patients may receive short-term indwelling urinary catheters. 12,13 In many cases, catheters are placed for inappropriate indications, and healthcare providers are often unaware that their patients have catheters, leading to prolonged, unnecessary use. [14][15][16] In acute care hospitals reporting to NHSN in 2006, pooled mean urinary catheter utilization ratios in ICU and non-ICU areas ranged from 0.23-0.91 urinary catheterdays/patient-days. 17 While the numbers of units reporting were small, the highest ratios were in trauma ICUs and the lowest in inpatient medical/surgical wards. The overall prevalence of longterm indwelling urethral catheterization use is unknown. The prevalence of urinary catheter use in residents in long-term care facilities in the United States is on the order of 5%, representing approximately 50,000 residents with catheters at any given time. 18 This number appears to be declining over time, likely because of federally mandated nursing home quality measures. However, the high prevalence of urinary catheters in patients transferred to skilled nursing facilities suggests that acute care hospitals should focus more efforts on removing unnecessary catheters prior to transfer. 18 Reported rates of UTI among patients with urinary catheters vary substantially. National data from NHSN acute care hospitals in 2006 showed a range of pooled mean CAUTI rates of 3.1-7.5 infections per 1000 catheter-days. 17 The highest rates were in burn ICUs, followed by inpatient medical wards and neurosurgical ICUs, although these sites also had the fewest numbers of locations reporting. The lowest rates were in medical/surgical ICUs.\nAlthough morbidity and mortality from CAUTI is considered to be relatively low compared to other HAIs, the high prevalence of urinary catheter use leads to a large cumulative burden of infections with resulting infectious complications and deaths. An estimate of annual incidence of HAIs and mortality in 2002, based on a broad survey of US hospitals, found that urinary tract infections made up the highest number of infections (> 560,000) compared to other HAIs, and attributable deaths from UTI were estimated to be over 13,000 (mortality rate 2.3%). 19 And while fewer than 5% of bacteriuric cases develop bacteremia, 6 CAUTI is the leading cause of secondary nosocomial bloodstream infections; about 17% of hospital-acquired bacteremias are from a urinary source, with an associated mortality of approximately 10%. 20 In the nursing home setting, bacteremias are most commonly caused by UTIs, the majority of which are catheterrelated. 21 An estimated 17% to 69% of CAUTI may be preventable with recommended infection control measures, which means that up to 380,000 infections and 9000 deaths related to CAUTI per year could be prevented. 22 \n# Pathogenesis and Microbiology\nThe source of microorganisms causing CAUTI can be endogenous, typically via meatal, rectal, or vaginal colonization, or exogenous, such as via contaminated hands of healthcare personnel or equipment. Microbial pathogens can enter the urinary tract either by the extraluminal route, via migration along the outside of the catheter in the periurethral mucous sheath, or by the intraluminal route, via movement along the internal lumen of the catheter from a contaminated collection bag or catheter-drainage tube junction. The relative contribution of each route in the pathogenesis of CAUTI is not well known. The marked reduction in risk of bacteriuria with the introduction of the sterile, closed urinary drainage system in the1960's 23 suggests the importance of the intraluminal route. However, even with the closed drainage system, bacteriuria inevitably occurs over time either via breaks in the sterile system or via the extraluminal route. 24 The daily risk of bacteriuria with catheterization is 3% to 10%, 25,26 approaching 100% after 30 days, which is considered the delineation between short and longterm catheterization. 27 Formation of biofilms by urinary pathogens on the surface of the catheter and drainage system occurs universally with prolonged duration of catheterization. 28 Over time, the urinary catheter becomes colonized with microorganisms living in a sessile state within the biofilm, rendering them resistant to antimicrobials and host defenses and virtually impossible to eradicate without removing the catheter. The role of bacteria within biofilms in the pathogenesis of CAUTI is unknown and is an area requiring further research. Antimicrobial resistance among urinary pathogens is an ever increasing problem. About a quarter of E. coli isolates and one third of P. aeruginosa isolates from CAUTI cases were fluoroquinolone-resistant. Resistance of gram-negative pathogens to other agents, including third-generation cephalosporins and carbapenems, was also substantial 5 . The proportion of organisms that were multidrug-resistant, defined by non-susceptibility to all agents in 4 classes, was 4% of P. aeruginosa, 9% of K. pneumoniae, and 21% of Acinetobacter baumannii. 29 \n# VI. Scope and Purpose\nThis guideline updates and expands the original CDC Guideline for Prevention of CAUTI published in 1981. The revised guideline addresses the prevention of CAUTI for patients in need of either short-or long-term (i.e., > 30 days) urinary catheterization in any type of healthcare facility and evaluates evidence for alternative methods of urinary drainage, including intermittent catheterization, external catheters, and suprapubic catheters. The guideline also includes specific recommendations for implementation, performance measurement, and surveillance. Recommendations for further research are also provided to address the knowledge gaps in CAUTI prevention identified during the literature review.\nTo evaluate the evidence on preventing CAUTI, we examined data addressing three key questions and related subquestions: This document is intended for use by infection prevention staff, healthcare epidemiologists, healthcare administrators, nurses, other healthcare providers, and persons responsible for developing, implementing, and evaluating infection prevention and control programs for healthcare settings across the continuum of care. The guideline can also be used as a resource for societies or organizations that wish to develop more detailed implementation guidance for prevention of CAUTI.\n1.\n# VII. Methods\nThis guideline was based on a targeted systematic review of the best available evidence on CAUTI prevention. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach [32][33][34] to provide explicit links between the available evidence and the resulting recommendations. Our guideline development process is outlined in Figure 1.\n# Figure 1. The Guideline Development Process\n\n# Development of Key Questions\nWe first conducted an electronic search of the National Guideline Clearinghouse® ( \n# Literature Search\nFollowing the development of the key questions, search terms were developed for identifying literature relevant to the key questions. For the purposes of quality assurance, we compared these terms to those used in relevant seminal studies and guidelines. These search terms were then incorporated into search strategies for the relevant electronic databases. Searches were performed in Medline® (National Library of Medicine) using the Ovid® Platform (Ovid Technologies, Wolters Kluwer, New York, NY), EMBASE® (Elsevier BV, Amsterdam, Netherlands), CINAHL® (Ebsco Publishing, Ipswich, MA) and Cochrane® (Cochrane Collaboration, Oxford, UK) (all databases were searched in July 2007), and the resulting references were imported into a reference manager, where duplicates were resolved. For Cochrane reviews ultimately included in our guideline, we checked for updates in July 2008.\nThe detailed search strategy used for identifying primary literature and the results of the search can be found in Appendix 1B (https://www.cdc.gov/infectioncontrol/guidelines/pdf/cautiguidelines-appendix.pdf).\n# Study Selection\nTitles and abstracts from references were screened by a single author (C.V.G, R.K.A., or D.A.P.) and the full text articles were retrieved if they were 1. relevant to one or more key questions, 2. primary analytic research, systematic reviews or meta-analyses, and 3. written in English.\nLikewise, the full-text articles were screened by a single author (C.V.G. or D.A.P.) using the same criteria, and included studies underwent a second review for inclusion by another author (R.K.A.). Disagreements were resolved by the remaining authors. The results of this process are depicted in Figure 2. \n# Data Extraction and Synthesis\nData on the study author, year, design, objective, population, setting, sample size, power, followup, and definitions and results of clinically relevant outcomes were extracted into evidence tables (Appendix 2 (https://www.cdc.gov/infectioncontrol/guidelines/pdf/cauti-guidelines-appendix.pdf)). Three evidence tables were developed, each of which represented one of our key questions. Studies were extracted into the most relevant evidence table . Then, studies were organized by the common themes that emerged within each evidence table. Data were extracted by one author (R.K.A.) and cross-checked by another (C.V.G.). Disagreements were resolved by the remaining authors. Data and analyses were extracted as originally presented in the included studies. Meta-analyses were performed only where their use was deemed critical to a recommendation, and only in circumstances where multiple studies with sufficiently homogenous populations, interventions, and outcomes could be analyzed. Systematic reviews were included in our review. To avoid duplication of data, we excluded primary studies if they were also included in a systematic review captured by our search. The only exception to this was if the primary study also addressed a relevant question that was outside the scope of the included systematic review. Before exclusion, data from the primary studies that we originally captured were abstracted into the evidence tables and reviewed. We also excluded systematic reviews that analyzed primary studies that were fully captured in a more recent systematic review. The only exception to this was if the older systematic review also addressed a relevant question that was outside the scope of the newer systematic review. To ensure that all relevant studies were captured in the search, the bibliography was vetted by a panel of clinical experts.\n# Grading of Evidence\nFirst, the quality of each study was assessed using scales adapted from existing methodology checklists, and scores were recorded in the evidence tables. Appendix 3 (https://www.cdc.gov/infectioncontrol/guidelines/pdf/cauti-guidelines-appendix.pdf) includes the sets of questions we used to assess the quality of each of the major study designs. Next, the quality of the evidence base was assessed using methods adapted from the GRADE Working Group. 32 Briefly, GRADE tables were developed for each of the interventions or questions addressed within the evidence tables. Included in the GRADE tables were the intervention of interest, any outcomes listed in the evidence tables that were judged to be clinically important, the quantity and type of evidence for each outcome, the relevant findings, and the GRADE of evidence for each outcome, as well as an overall GRADE of the evidence base for the given intervention or question. The initial GRADE of evidence for each outcome was deemed high if the evidence base included a randomized controlled trial (RCT) or a systematic review of RCTs, low if the evidence base included only observational studies, or very low if the evidence base consisted only of uncontrolled studies. The initial GRADE could then be modified by eight criteria. 34 Criteria which could decrease the GRADE of an evidence base included quality, consistency, directness, precision, and publication bias. Criteria that could increase the GRADE included a large magnitude of effect, a dose-response gradient, or inclusion of unmeasured confounders that would increase the magnitude of effect (Table 3). GRADE definitions are as follows:\n1. High -further research is very unlikely to change confidence in the estimate of effect 2. Moderate -further research is likely to affect confidence in the estimate of effect and may change the estimate 3. Low -further research is very likely to affect confidence in the estimate of effect and is likely to change the estimate 4. Very low -any estimate of effect is very uncertain After determining the GRADE of the evidence base for each outcome of a given intervention or question, we calculated the overall GRADE of the evidence base for that intervention or question. The overall GRADE was based on the lowest GRADE for the outcomes deemed critical to making a recommendation.\n# Table 3. Rating the Quality of Evidence Using the GRADE Approach\nThe format of this section was changed to improve readability and accessibility. The content is unchanged. \n# Rating the\n\n# Formulating Recommendations\nNarrative evidence summaries were then drafted by the working group using the evidence and GRADE tables. One summary was written for each theme that emerged under each key question. The working group then used the narrative evidence summaries to develop guideline recommendations. Factors determining the strength of a recommendation included 1. the values and preferences used to determine which outcomes were \"critical,\" 2. the harms and benefits that result from weighing the \"critical\" outcomes, and 3. the overall GRADE of the evidence base for the given intervention or question (Table 4). 33 If weighing the \"critical outcomes\" for a given intervention or question resulted in a \"net benefit\" or a \"net harm,\" then a \"Category I Recommendation\" was formulated to strongly recommend for or against the given intervention respectively. If weighing the \"critical outcomes\" for a given intervention or question resulted in a \"trade off\" between benefits and harms, then a \"Category II Recommendation\" was formulated to recommend that providers or institutions consider the intervention when deemed appropriate. If weighing the \"critical outcomes\" for a given intervention or question resulted in an \"uncertain trade off\" between benefits and harms, then a \"No Recommendation\" was formulated to reflect this uncertainty. No recommendation/ Unresolved issue for which there is low to very low quality evidence with unresolved issue uncertain trade offs between benefits and harms.\nCategory I recommendations are defined as strong recommendations with the following implications: 1. For patients: Most people in the patient's situation would want the recommended course of action and only a small proportion would not; request discussion if the intervention is not offered. 2. For clinicians: Most patients should receive the recommended course of action. 3. For policymakers: The recommendation may be adopted as a policy.\nCategory II recommendations are defined as weak recommendations with the following implications:\n1. For patients: Most people in the patient's situation would want the recommended course of action, but many would not. 2. For clinicians: Different choices will be appropriate for different patients, and clinicians must help each patient to arrive at a management decision consistent with her or his values and preferences. 3. For policymakers: Policy making will require substantial debate and involvement of many stakeholders.\nIt should be noted that Category II recommendations are discretionary for the individual institution and are not intended to be enforced.\nThe wording of each recommendation was carefully selected to reflect the recommendation's strength. In most cases, we used the active voice when writing Category I recommendationsthe strong recommendations. Phrases like \"do\" or \"do not\" and verbs without auxiliaries or conditionals were used to convey certainty. We used a more passive voice when writing Category II recommendations -the weak recommendations. Words like \"consider\" and phrases like \"is preferable,\" \"is suggested,\" \"is not suggested,\" or \"is not recommended\" were chosen to reflect the lesser certainty of the Category II recommendations. Rather than a simple statement of fact, each recommendation is actionable, describing precisely a proposed action to take.\nThe category \"No recommendation/unresolved issue\" was most commonly applied to situations where either 1. the overall quality of the evidence base for a given intervention was low to very low and there was no consensus on the benefit of the intervention or 2. there was no published evidence on outcomes deemed critical to weighing the risks and benefits of a given intervention. If the latter was the case, those critical outcomes will be noted at the end of the relevant evidence summary.\nOur evidence-based recommendations were cross-checked with those from guidelines identified in our original systematic search. Recommendations from previous guidelines for topics not directly addressed by our systematic review of the evidence were included in our \"Summary of Recommendations\" if they were deemed critical to the target users of this guideline. Unlike recommendations informed by our literature search, these recommendations are not linked to a key question. These recommendations were agreed upon by expert consensus and are designated either IB if they represent a strong recommendation based on accepted practices (e.g., aseptic technique) or II if they are a suggestion based on a probable net benefit despite limited evidence.\nAll recommendations were approved by HICPAC. Recommendations focused only on efficacy, effectiveness, and safety. The optimal use of these guidelines should include a consideration of the costs relevant to the local setting of guideline users.\n# Reviewing and Finalizing the Guideline\nAfter a draft of the tables, narrative summaries, and recommendations was completed, the working group shared the draft with the expert panel for in-depth review. While the expert panel was reviewing this draft, the working group completed the remaining sections of the guideline, including the executive summary, background, scope and purpose, methods, summary of recommendations, and recommendations for guideline implementation, audit, and further research. The working group then made revisions to the draft based on feedback from members of the expert panel and presented the entire draft guideline to HICPAC for review. The guideline was then posted on the Federal Register for public comment. After a period of public comment, the guideline was revised accordingly, and the changes were reviewed and voted on by HICPAC. The final guideline was cleared internally by CDC and published and posted on the HICPAC website.\n# Updating the Guideline\nFuture revisions to this guideline will be dictated by new research and technological advancements for preventing CAUTI and will occur at the request of HICPAC.\n# VIII. Evidence Review\n\n# Q1. Who should receive urinary catheters?\nTo answer this question, we focused on three subquestions: A. When is urinary catheterization necessary? B. What are the risk factors for CAUTI? and C. What populations are at highest risk of mortality from urinary catheters?\n# Q1A. When is urinary catheterization necessary?\nThe available data examined five main populations. In all populations, we considered CAUTI outcomes as well as other outcomes we deemed critical to weighing the risks and benefits of catheterization. The evidence for this question consists of 1 systematic review, 37 9 RCTs, [38][39][40][41][42][43][44][45][46] and 12 observational studies. [47][48][49][50][51][52][53][54][55][56][57][58] The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1A.\nFor operative patients, low-quality evidence suggested a benefit of avoiding urinary catheterization. [37][38][39][40][41][42][43][44][47][48][49] This was based on a decreased risk of bacteriuria/unspecified UTI, no effect on bladder injury, and increased risk of urinary retention in patients without catheters. Urinary retention in patients without catheters was specifically seen following urogenital surgeries. The most common surgeries studied were urogenital, gynecological, laparoscopic, and orthopedic surgeries. Our search did not reveal data on the impact of catheterization on peri-operative hemodynamic management.\nFor incontinent patients, low-quality evidence suggested a benefit of avoiding urinary catheterization. 45,[50][51][52] This was based on a decreased risk of both SUTI and bacteriuria/unspecified UTI in male nursing home residents without urinary catheters compared to those with continuous condom catheters. We found no difference in the risk of UTI between having a condom catheter only at night and having no catheter. Our search did not reveal data on the impact of catheterization on skin breakdown.\nFor patients with bladder outlet obstruction, very low-quality evidence suggested a benefit of a urethral stent over an indwelling catheter. 53 This was based on a reduced risk of bacteriuria in those receiving a urethral stent. Our search did not reveal data on the impact of catheterization versus stent placement on urinary complications.\nFor patients with spinal cord injury, very low-quality evidence suggested a benefit of avoiding indwelling urinary catheters. 54,56 This was based on a decreased risk of SUTI and bacteriuria in those without indwelling catheters (including patients managed with spontaneous voiding, clean intermittent catheterization [CIC], and external striated sphincterotomy with condom catheter drainage), as well as a lower risk of urinary complications, including hematuria, stones, and urethral injury (fistula, erosion, stricture).\nFor children with myelomeningocele and neurogenic bladder, very low-quality evidence suggested a benefit of CIC compared to urinary diversion or self voiding. 46,57,58 This was based on a decreased risk of bacteriuria/unspecified UTI in patients receiving CIC compared to urinary diversion, and a lower risk of urinary tract deterioration (defined by febrile urinary tract infection, vesicoureteral reflux, hydronephrosis, or increases in BUN or serum creatinine) compared to self-voiding and in those receiving CIC early (< 1 year of age) versus late (> 3 years of age).\n# Evidence Review Table 1A. When is urinary catheterization necessary?\n1A.1. Use urinary catheters in operative patients only as necessary, rather than routinely.\n( \n# Q1B. What are the risk factors for CAUTI?\nTo answer this question, we reviewed the quality of evidence for those risk factors examined in more than one study. We considered the critical outcomes for decision-making to be SUTI and bacteriuria. The evidence for this question consists of 11 RCTs 59-69 and 37 observational studies. 9,50,54, The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1B.\nFor SUTI, 50,54,61,62,74,75,79,83,102,103 \n# Q1C. What populations are at highest risk of mortality from urinary catheters?\nTo answer this question, we reviewed the quality of evidence for those risk factors examined in more than one study. The evidence for this question consists of 2 observational studies. 7,74 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 1C.\nLow-quality evidence suggested that older age, higher severity of illness, and being on an internal medicine service compared to a surgical service were independent risk factors for mortality in patients with indwelling urinary catheters. Both studies evaluating these risk factors found the highest risk of mortality in patients over 70 years of age. Low-quality evidence also suggested that CAUTI was a risk factor for mortality in patients with catheters.\nEvidence Review Table 1C. What populations are at highest risk of mortality from catheters?\n1C.1. Minimize urinary catheter use and duration in all patients, particularly those who may be at higher risk for mortality due to catheterization, such as the elderly and patients with severe illness. (Category IB)\n# Q2. For those who may require urinary catheters, what are the best practices?\nTo answer this question, we focused on four subquestions: A. What are the risks and benefits associated with different approaches to catheterization? B. What are the risks and benefits associated with different types of catheters or collecting systems? C. What are the risks and benefits associated with different catheter management techniques D. What are the risks and benefits associated with different systems interventions?\n# Q2A. What are the risks and benefits associated with different approaches to catheterization?\nThe available data examined the following comparisons of different catheterization approaches:\n1. External versus indwelling urethral 2. Intermittent versus indwelling urethral 3. Intermittent versus suprapubic 4. Suprapubic versus indwelling urethral 5. Clean intermittent versus sterile intermittent For all comparisons, we considered SUTI, bacteriuria/unspecified UTI, or combinations of these outcomes depending on availability, as well as other outcomes critical to weighing the risks and benefits of different catheterization approaches. The evidence for this question consists of 6 systematic reviews, 37,[104][105][106][107][108] 16 RCTs, 62,63,[109][110][111][112][113][114][115][116][117][118][119][120][121][122] and 18 observational studies. 54,73,81,84,[123][124][125][126][127][128][129][130][131][132][133][134][135][136] The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2A\n# Q2A.1. External versus indwelling urethral\nLow-quality evidence suggested a benefit of using external catheters over indwelling urethral catheters in male patients who require a urinary collection device but do not have an indication for an indwelling catheter such as urinary retention or bladder outlet obstruction. 81,109,123 This was based on a decreased risk of a composite outcome of SUTI, bacteriuria, or death as well as increased patient satisfaction with condom catheters. Differences were most pronounced in men without dementia. Statistically significant differences were not found or reported for the individual CAUTI outcomes or death. Our search did not reveal data on differences in local complications such as skin maceration or phimosis.\n# Q2A.2. Intermittent versus indwelling urethral\nLow-quality evidence suggested a benefit of using intermittent catheterization over indwelling urethral catheters in selected populations. 84,[104][105][106][110][111][112][113][114][124][125][126]135,136 This was based on a decreased risk of SUTI and bacteriuria/unspecified UTI but an increased risk of urinary retention in postoperative patients with intermittent catheterization. In one study, urinary retention and bladder distension were avoided by performing catheterization at regular intervals (every 6-8 hrs) until return of voiding. Studies of patients with neurogenic bladder most consistently found a decreased risk of CAUTI with intermittent catheterization. Studies in operative patients whose catheters were removed within 24 hrs of surgery found no differences in bacteriuria with intermittent vs. indwelling catheterization, while studies where catheters were left in for longer durations had mixed results. Our search did not reveal data on differences in patient satisfaction.\n# Q2A.3. Intermittent versus suprapubic\nVery low-quality evidence suggested a benefit of intermittent over suprapubic catheterization in selected populations 115,116,[134][135][136] based on increased patient acceptability and decreased risk of urinary complications (bladder calculi, vesicoureteral reflux, and upper tract abnormalities). Although we found a decreased risk of bacteriuria/unspecified UTI with suprapubic catheterization, there were no differences in SUTI. The populations studied included women undergoing urogynecologic surgery and spinal cord injury patients.\n# Q2A.4. Suprapubic versus indwelling urethral\nLow-quality evidence suggested a benefit of suprapubic catheters over indwelling urethral catheters in selected populations. 37,62,104,107,108,[128][129][130][131][132][133]135,136 This was based on a decreased risk of bacteriuria/unspecified UTI, recatheterization, and urethral stricture, and increased patient comfort and satisfaction. However, there were no differences in SUTI and an increased risk of longer duration of catheterization with suprapubic catheters. Studies involved primarily postoperative and spinal cord injury patients. Our search did not reveal data on differences in complications related to catheter insertion or the catheter site.\n# Q2A.5. Clean intermittent versus sterile intermittent\nModerate-quality evidence suggested no benefit of using sterile over clean technique for intermittent catheterization. 63,73,105,[117][118][119][120][121][122] No differences were found in the risk of SUTI or bacteriuria/unspecified UTI. Study populations included nursing home residents and adults and children with neurogenic bladder/spinal cord injury. \n# Q2B. What are the risks and benefits associated with different catheters or collecting systems?\nThe available data examined the following comparisons between different types of catheters and drainage systems:\n1. Antimicrobial/antiseptic catheters vs. standard catheters a. Silver-coated catheters vs. standard catheters b. Nitrofurazone-impregnated catheters vs. standard catheters 2. Hydrophilic catheters vs. standard catheters 3. Closed vs. open drainage systems 4. Complex vs. simple drainage systems 5. Preconnected/sealed junction catheters vs. standard catheters 6. Catheter valves vs. catheter bags For all comparisons, we considered CAUTI outcomes as well as other outcomes critical to weighing the risks and benefits of different types of catheters or collecting systems. The evidence for this question consists of 5 systematic reviews, 37,[137][138][139][140] 17 RCTs, 64,[143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158] 23 observational studies, 82,86,89,97,[159][160][161][162][163][165][166][167][168][169][170][171][172][173][174][175][176][177][178] and 3 economic analyses. 179180,181 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2B.\n# Q2B.1.a. Silver-coated catheters vs. standard catheters\nLow-quality evidence suggested a benefit of silver-coated catheters over standard latex catheters. 37,82,86,137-139,143,159-163, 165,166 This was based on a decreased risk of bacteriuria/unspecified UTI with silver-coated catheters and no evidence of increased urethral irritation or antimicrobial resistance in studies that reported data on microbiological outcomes. Differences were significant for silver alloy-coated catheters but not silver oxide-coated catheters. In a meta-analysis of randomized controlled trials (see Appendix), silver alloy-coated catheters reduced the risk of asymptomatic bacteriuria compared to standard latex catheters (control latex catheters were either uncoated or coated with hydrogel, Teflon®, or silicone), whereas there were no differences when compared to standard, all silicone catheters. The effect of silver alloy catheters compared to latex catheters was more pronounced when used in patients catheterized <1 week. The results were robust to inclusion or exclusion of non peerreviewed studies. Only one observational study found a decrease in SUTI with silver alloycoated catheters. 166 The setting was a burn referral center, where the control catheters were latex, and patients in the intervention group had new catheters placed on admission, whereas the control group did not. Recent observational studies in hospitalized patients found mixed results for bacteriuria/unspecified UTI.\n# Q2B.1.b. Nitrofurazone-impregnated catheters vs. standard catheters\nLow-quality evidence suggested a benefit of nitrofurazone-impregnated catheters in patients catheterized for short periods of time. 137,138 This was based on a decreased risk of bacteriuria and no evidence of increased antimicrobial resistance in studies that reported microbiological outcomes. Differences were significant in a meta-analysis of three studies examining nitrofurazone-impregnated catheters (only one individual study significant) when duration of catheterization was <1 week. No differences were seen when duration of catheterization was >1 week, although the meta-analysis was borderline significant.\n# Q2B.2. Hydrophilic catheters vs. standard catheters\nVery low-quality evidence suggested a benefit of hydrophilic catheters over standard nonhydrophilic catheters in specific populations undergoing clean intermittent catheterization. 137,[144][145][146][147][148]169 This was based on a decreased risk of SUTI, bacteriuria, hematuria, and pain during insertion, and increased patient satisfaction. Differences in CAUTI outcomes were limited to one study of spinal cord injury patients and one study of patients receiving intravesical immunochemoprophylaxis for bladder cancer, while multiple other studies found no significant differences.\n# Q2B.3. Closed vs. open drainage systems\nVery low-quality evidence suggested a benefit of using a closed rather than open urinary drainage system. 89,171 This was based on a decreased risk of bacteriuria with a closed drainage system. One study also found a suggestion of a decreased risk of SUTI, bacteremia, and UTIrelated mortality associated with closed drainage systems, but differences were not statistically significant. Sterile, continuously closed drainage systems became the standard of care based on an uncontrolled study published in 1966 demonstrating a dramatic reduction in the risk of infection in short-term catheterized patients with the use of a closed system. 23 Recent data also include the finding that disconnection of the drainage system is a risk factor for bacteriuria (Q1B).\n# Q2B.4. Complex vs. simple drainage systems\nLow-quality evidence suggested no benefit of complex closed urinary drainage systems over simple closed urinary drainage systems. [150][151][152]154,172,176,177 Although there was a decreased risk of bacteriuria with the complex systems, differences were found only in studies published before 1990, and not in more recent studies. The complex drainage systems studied included various mechanisms for reducing bacterial entry, such as antiseptic-releasing cartridges at the drain port of the urine collection bag; see evidence table for systems evaluated.\n# Q2B.5. Preconnected/sealed junction catheters vs. standard catheters\nLow-quality evidence suggested a benefit of using preconnected catheters with junction seals over catheters with unsealed junctions to reduce the risk of disconnections. 64,153,156,175 This was based on a decreased risk of SUTI and bacteriuria with preconnected sealed catheters. Studies that found differences had higher rates of CAUTI in the control group than studies that did not find an effect.\n# Q2B.6. Catheter valves vs. drainage bags\nModerate-quality evidence suggested a benefit of catheter valves over drainage bags in selected patients with indwelling urinary catheters. 140 Catheter valves led to greater patient satisfaction but no differences in bacteriuria/unspecified UTI or pain/bladder spasms. Details regarding the setting for recruitment and follow-up of the patients in the studies were unclear, and the majority of subjects were men. Our search did not reveal data on the effect of catheter valves on bladder function, bladder/urethral trauma, or catheter blockage. \n# Q2C. What are the risks and benefits associated with different catheter management techniques?\nThe available data examined the following catheter management techniques: For all comparisons, we considered CAUTI outcomes as well as other outcomes critical to weighing the risks and benefits of different catheter management techniques. The evidence for this question consists of 6 systematic reviews, 37,105,106,[182][183][184] 56 RCTs, 60,61,[65][66][67][68][69]143,158,158, 34 observational studies, 83,85,88,90,96,102,133,167,178, and 1 economic analysis. 180 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2C.\n# Q2C.1. Antimicrobial prophylaxis\nLow-quality evidence suggested no benefit of antimicrobial prophylaxis in patients undergoing short-term catheterization. 37,60,61,83,85,133,158,178,182,185,186,[189][190][191][232][233][234] This was based on heterogeneous results for SUTI and bacteriuria/unspecified UTI and no adverse events related to antimicrobials. Lack of consistency in specific factors, such as patient population, antimicrobial agents, timing of administration, and duration of follow-up, did not allow for a summary of evidence of the effect of antimicrobial prophylaxis on CAUTI in patients undergoing short term catheterization. Only two studies evaluated adverse events related to antimicrobials. Our search did not reveal data on antimicrobial resistance or Clostridium difficile infection.\nLow-quality evidence suggested no benefit of antimicrobial prophylaxis in patients undergoing long-term catheterization (indwelling and clean intermittent catheterization). 106,183,192,194,235,238 This was based on a decreased risk of bacteriuria, heterogeneous results for SUTI, and no differences reported for catheter encrustation or adverse events, although data were sparse. One systematic review suggested an increase in antimicrobial resistance with antimicrobial use.\n# Q2C.2. Urinary antiseptics\nLow-quality evidence suggested a benefit of methenamine for short-term catheterized patients. 196,197 This was based on a reduced risk of SUTI and bacteriuria and no differences in adverse events. Evidence was limited to two studies of patients following gynecological surgery in Norway and Sweden.\nVery low-quality evidence suggested a benefit of methanamine for long-term catheterized patients. 106,[236][237][238][239] This was based on a reduced risk of encrustation but no differences in risk of SUTI or bacteriuria. Data on encrustation was limited to one study. Studies involved primarily elderly and spinal cord injury patients with chronic indwelling catheters\n# Q2C.3. Bladder irrigation\nLow-quality evidence suggested no benefit of bladder irrigation in patients with indwelling or intermittent catheters. 66,69,[199][200][201][202][203][204][205][206][240][241][242] This was based on no differences in SUTI and heterogeneous findings for bacteriuria.\n# Q2C.4. Antiseptic instillation in the drainage bag\nLow-quality evidence suggested no benefit of antiseptic instillation in urinary drainage bags. 90,[207][208][209][210][211][243][244][245] This was based on no differences in SUTI and heterogeneous results for bacteriuria.\n# Q2C.5. Periurethral care\nLow-quality evidence suggested no benefit of antiseptic meatal cleaning regimens before or during catheterization to prevent CAUTI. 65,67,68,88,158,[212][213][214][215][216]246,247 This was based on no difference in the risk of bacteriuria in patients receiving periurethral care regimens compared to those not receiving them. One study found a higher risk of bacteriuria with cleaning of the urethral meatus-catheter junction (either twice daily application of povidine-iodine or once daily cleaning with a non-antiseptic solution of green soap and water) in a subgroup of women with positive meatal cultures and in patients not receiving antimicrobials. Periurethral cleaning with chlorhexidine before catheter insertion did not have an effect in two studies.\n# Q2C.6. Routine catheter or bag change\nLow-quality evidence suggested no benefit of routine catheter or drainage bag changes to prevent CAUTI. 102,[217][218][219]248,249 This was based on no difference or an increased risk of SUTI and no difference in bacteriuria with routine compared to as-needed changes or with more frequent changing intervals. One study in nursing home residents found no differences in SUTI with routine monthly catheter changes compared to changing only for obstruction or infection, but the study was underpowered to detect a difference. Another study in home care patients found an increased risk of SUTI when catheters were changed more frequently than monthly.\n# Q2C.7. Catheter lubricants\nVery low-quality evidence suggested a benefit of using lubricants for catheter insertion. 167,[220][221][222][223][250][251][252][253][254] This was based on a decreased risk of SUTI and bacteriuria with the use of a prelubricated catheter compared to a catheter lubricated by the patient and a decreased risk of bacteriuria with use of a lubricant versus no lubricant. Studies were heterogeneous both in the interventions and outcomes studied. Several studies comparing antiseptic lubricants to nonantiseptic lubricants found no significant differences.\n# Q2C.8. Securing devices\nLow-quality evidence suggested no benefit of using catheter securing devices to prevent CAUTI. 224 This was based on no significant difference in the risk of SUTI or meatal erosion. The only study in this category looked at one particular product.\n# Q2C.9. Bacterial interference\nModerate-quality evidence suggested a benefit of using bacterial interference in catheterized patients. 225 In the one study evaluating this intervention, urinary colonization with a nonpathogenic Escherichia coli was associated with a decreased risk of SUTI in adults with spinal cord injury and a history of frequent CAUTI.\n# Q2C.10. Catheter cleansing\nVery low-quality evidence suggested a benefit of wet versus dry storage procedures for catheters used in clean intermittent catheterization. 255 This was based on a decreased risk of SUTI with a wet storage procedure in one study of spinal cord injury patients undergoing clean intermittent catheterization compared to a dry storage procedure where the catheter was left to air dry after washing. In the wet procedure, the catheter was stored in a dilute povidone-iodine solution after washing with soap and water.\n# Q2C.11. Catheter removal strategies a. Clamping vs. free drainage prior to removal\nLow-quality evidence suggested no benefit of clamping versus free drainage before catheter removal. 37,184 This was based on no difference in risk of bacteriuria, urinary retention, or recatheterization between the two strategies. One study comparing a clamp and release strategy to free drainage over 72 hours found a greater risk of bacteriuria in the clamping group.\n# b. Postoperative duration of catheterization\nModerate-quality evidence suggested a benefit of shorter versus longer postoperative durations of catheterization. 37,184,227,228 This was based on a decreased risk of bacteriuria/unspecified UTI, decreased time to ambulation and length of stay, no differences in urinary retention and SUTI, and increased risk of recatheterization. Significant decreases in bacteriuria/unspecified UTI were found specifically for comparisons of 1 day versus 3 or 5 days of postoperative catheterization. Recatheterization risk was greater in only one study comparing immediate removal to removal 6 or 12 hours after hysterectomy.\n# Q2C.12. Assessment of urine volumes\nLow-quality evidence suggested a benefit of using portable ultrasound to assess urine volume in patients undergoing intermittent catheterization. 229,230 This was based on fewer catheterizations but no reported differences in risk of unspecified UTI. Patients studied were adults with neurogenic bladder in inpatient rehabilitation centers. Our search did not reveal data on the use of ultrasound in catheterized patients in other settings. We considered CAUTI outcomes, duration of catheterization, recatheterization, and transmission of pathogens when weighing the risks and benefits of different systems interventions. The evidence for this question consists of 1 RCT 259 and 19 observational studies. 3,25,[260][261][262][263][264][265][266][267][268][269][270][271][272][273][274][275][276] The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 2D.\n# Q2D.1. Multifaceted infection control/quality improvement programs\nLow-quality evidence suggested a benefit of multifaceted infection control/quality improvement programs to reduce the risk of CAUTI. 3,[260][261][262][263][264][265][266][267] This was based on a decreased risk of SUTI, bacteriuria/unspecified UTI, and duration of catheter use with implementation of such programs. Studies evaluated various multifaceted interventions. The studies with significant findings included:\n1. education and performance feedback regarding compliance with catheter care, emphasizing hand hygiene, and maintaining unobstructed urine flow;\n2. computerized alerts to physicians, nurse-driven protocols to remove catheters, and use of handheld bladder scanners to assess for urinary retention;\n3. guidelines and education focusing on perioperative catheter management; and 4. a multifaceted infection control program including guidelines for catheter insertion and maintenance. A program using a checklist and algorithm for appropriate catheter use also suggested a decrease in unspecified UTI and catheter duration, but statistical differences were not reported.\n# Q2D.2. Reminders\nVery low-quality evidence suggested a benefit of using urinary catheter reminders to prevent CAUTI. [268][269][270] This was based on a decreased risk of bacteriuria and duration of catheterization and no differences in recatheterization or SUTI when reminders were used. Reminders to physicians included both computerized and non-computerized alerts about the presence of urinary catheters and the need to remove unnecessary catheters.\n# Q2D.3. Bacteriologic monitoring\nVery low-quality evidence suggested no benefit of bacteriologic monitoring to prevent CAUTI. 25,271 Although one study found a decreased risk of bacteriuria during a period of bacteriologic monitoring and feedback, only 2% of SUTI episodes were considered potentially preventable with the use of bacteriologic monitoring.\n# Q2D.4. Hand hygiene\nVery low-quality evidence suggested a benefit of using alcohol hand sanitizer in reducing CAUTI. This was based on one study in a rehabilitation facility that found a decrease in unspecified UTI, although no statistical differences were reported. 272 A separate multifaceted study that included education and performance feedback on compliance with catheter care and hand hygiene showed a decrease in risk of SUTI. 265\n# Q2D.5. Patient placement\nVery low-quality evidence suggested a benefit of spatially separating patients to prevent transmission of urinary pathogens. 273 This was based on a decreased risk of transmission of urinary bacterial pathogens in nursing home residents in separate rooms compared to residents in the same rooms.\n# Q2D.6. Catheter team versus self-catheterization\nVery low-quality evidence suggested no benefit of a catheter team to prevent CAUTI among patients requiring intermittent catheterization. 274 This was based on one study showing no difference in unspecified UTI between use of a catheter care team and self-catheterization for intermittent catheterization in paraplegic patients.\n# Q2D.7. Feedback\nVery low-quality evidence suggested a benefit of using nursing feedback to prevent CAUTI. 275 This was based on a decreased risk of unspecified UTI during an intervention where nursing staff were provided with regular reports of unit-specific rates of CAUTI.\n# Q2D.8. Nurse-directed catheter removal\nVery low-quality evidence suggested a benefit of a nurse-directed catheter removal program to prevent CAUTI. 276 This was based on a decreased risk of unspecified UTI during an intervention where criteria were developed that allowed a registered nurse to remove a catheter without a physician's order when no longer medically necessary. Of the three intensive care units where the intervention was implemented, differences were significant only in the coronary intensive care unit.\nEvidence Review Table 2D \n# Q3: What are the best practices for preventing UTI associated with obstructed urinary catheters?\nThe available data examined the following practices:\n1. Methods to prevent/reduce encrustations or blockage 2. Catheter materials preventing blockage For this question, available relevant outcomes included blockage/encrustation. We did not find data on the outcomes of CAUTI. The evidence for this question consists of 1 systematic review, 277 2 RCTs, 278,279 and 2 observational studies. 280,281 The findings of the evidence review and the grades for all important outcomes are shown in Evidence Review Table 3.\n# Q3.1. Methods to prevent/reduce encrustations or blockage\nLow-quality evidence suggested a benefit of acidifying solutions or oral acetohydroxamic acid in preventing or reducing catheter encrustations and blockage in long-term catheterized patients. 277,278,280,281 No differences were seen with daily catheter irrigation with normal saline.\n# Q3.2. Catheter materials preventing blockage\nLow-quality evidence suggested a benefit of silicone over latex or Teflon-coated catheters in prevention or reducing catheter encrustations in long-term catheterized patients who were prone to blockage. No differences were seen with different materials in patients considered \"nonblockers.\" 279 Evidence Review Table 3. What are the best practices for preventing UTI associated with obstructed urinary catheters? \n# Abbreviations Abbreviation\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":270,"cells":{"id":{"kind":"string","value":"41bdd01b73d09b39429d99c6b8132c36aefc7879"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Fetal alcohol syndrome (FAS) results from maternal alcohol use during pregnancy and carries lifelong consequences. Early recognition of FAS can result in better outcomes for persons who receive a diagnosis. Although FAS was first identified in 1973, persons with this condition often do not receive a diagnosis. In 2002, Congress directed CDC to update and refine diagnostic and referral criteria for FAS, incorporating recent scientific and clinical evidence. In 2002, CDC convened a scientific working group (SWG) of persons with expertise in FAS research, diagnosis, and treatment to draft criteria for diagnosing FAS. This report summarizes the diagnostic guidelines drafted by the SWG, provides recommendations for when and how to refer a person suspected of having problems related to prenatal alcohol exposure, and assesses existing practices for creating supportive environments that might prevent long-term adverse consequences associated with FAS. The guidelines were created on the basis of a review of scientific evidence, clinical expertise, and the experiences of families affected by FAS regarding the physical and neuropsychologic features of FAS and the medical, educational, and social services needed by persons with FAS and their families. The guidelines are intended to facilitate early identification of persons affected by prenatal exposure to alcohol so they and their families can receive services that enable them to achieve healthy lives and reach their full potential. This report also includes recommendations to enhance identification of and intervention for women at risk for alcohol-exposed pregnancies. Additional data are needed to develop diagnostic criteria for other related disorders (e.g., alcohol-related neurodevelopmental disorder).# Introduction\nPrenatal exposure to alcohol during pregnancy damages the developing fetus and is a leading preventable cause of birth defects and developmental disabilities (1)(2)(3). Children exposed to alcohol during fetal development can suffer multiple negative effects, including physical and cognitive deficits. Although the number and severity of negative effects can range from subtle to serious, they are always lifelong.\nReferral and diagnosis for fetal alcohol syndrome (FAS) can be made throughout the lifespan. However, the majority of persons with FAS are referred and receive a diagnosis during childhood. Thus, the terms \"child\" or \"children\" as used in these guidelines are not intended to preclude referral, assessment, and diagnosis of older persons.\n\n# Background\nThe effects of prenatal exposure to alcohol and basic diagnostic features of FAS were first described in 1973 (4)(5)(6)(7)(8). In 1981, the U.S. Surgeon General issued a public health advisory warning that alcohol use during pregnancy could cause birth defects (9); this warning was reissued in 2004 (10). In 1989, Congress mandated that language warning of the consequences of drinking during pregnancy be included on alcohol product labels (11).\nDespite the known adverse effects of prenatal exposure to alcohol (4,5), children who experience these effects often do not receive a correct diagnosis or referral for diagnostic evaluation because of the absence of uniformly accepted diagnostic criteria and guidelines for referral. Early identification and diagnosis of FAS in affected persons are essential components to providing health, education, and social services that promote optimal well-being. In 2002, Congress directed CDC to 1) develop guidelines for diagnosing FAS and other negative birth outcomes resulting from prenatal exposure to alcohol, 2) incorporate these guidelines into curricula for medical and allied health students and practitioners, and 3) disseminate curricula concerning these guidelines to facilitate training of medical and allied health students and practitioners.\nThese guidelines represent a consensus of opinion from persons with expertise in relevant scientific and clinical fields, with input from service professionals and families affected by FAS. Information that served as the basis for the development of these guidelines was obtained from published scientific literature, clinical knowledge of participants, and the experience of families affected by FAS.\nCDC staff initially identified reports and other documents that were used as the scientific basis for creating diagnostic guidelines. On the basis of this information, and in coordination with the National Taskforce on Fetal Alcohol Syndrome and Fetal Alcohol Effect (NTFFAS/FAE), other federally funded FAS programs, and nongovernment organizations concerned with FAS, CDC formed a scientific working group (SWG) of persons with expertise in research and clinical practice regarding prenatal exposure to alcohol to develop diagnostic guidelines for FAS.\nGuidelines were formulated on the basis of consensus among SWG members and NTFFAS/FAE. To assist in defining the dysmorphologic features most useful for identifying persons with FAS, SWG members assembled a matrix of the major and associated dysmorphic features of non-FAS syndromes that had one or more features in common with FAS. This matrix was used to determine a combination of dysmorphic features most discriminative for FAS. To assist deliberations concerning central nervous system (CNS) abnormalities associated with FAS, persons with expertise in the science, assessment, and treatment of psychological aspects of FAS were asked to identify the CNS abnormalities and other neurobehavioral domains most common among persons affected by prenatal alcohol exposure. These responses formed the basis for discussion and the resulting guidelines for CNS abnormalities for persons with FAS.\nThis report summarizes the guidelines drafted as a result of the SWG's deliberations, provides recommendations for when and how to refer a person suspected of having problems related to prenatal alcohol exposure, and assesses existing practices for creating supportive environments that might prevent long-term adverse consequences associated with FAS.\n\n# Prevalence\nVaried FAS prevalences (range: 0.2-1.5 cases per 1,000 live births) have been reported worldwide (12)(13)(14)(15). Other studies that used different ascertainment methodologies have produced different estimates (range: 0.5-2.0 cases per 1,000 live births) (16)(17)(18)(19)(20)(21)(22). These rates are comparable with or higher than rates for other common developmental disabilities (e.g., Down syndrome or spina bifida) (23). On the basis of these prevalence estimates, approximately 4 million infants are born each year with prenatal alcohol exposure, and an estimated 1,000-6,000 are born with FAS.\nStudies have reported consistently that >50% of all U.S. women of childbearing age report alcohol consumption during the previous month (1,(24)(25)(26)(27)(28). The majority of these women drank only occasionally, but >13% could have been classified as moderate or heavy drinkers. In addition, 12% of women reported binge drinking (i.e., consuming five or more drinks on one occasion) during the preceding month (1,25,27,28). Approximately half of all U.S. pregnancies are unintended, and millions of women of childbearing age are sexually active while not using adequate contraception (24)(25)(26)(27)(28). Recent data from the Behavioral Risk Factors Surveillance System indicate that an estimated 12%-13% of U.S. women aged 18-44 years are sexually active, do not use contraception effectively, and drink alcohol frequently or binge drink, thereby putting them at risk for an alcohol-exposed pregnancy (24). Because data are available for all subpopulations, prevalences might be greater than these data indicate.\n\n# Fetal Alcohol Spectrum Disorder\nMultiple terms are used to describe the continuum of effects that result from prenatal exposure to alcohol, including fetal alcohol effects, alcohol-related birth defects (ARBD), alcohol-related neurodevelopment disorder (ARND), and, most recently, fetal alcohol spectrum disorders (FASDs) (29). In April 2004, the National Organization on Fetal Alcohol Syndrome (NOFAS) convened a meeting of representatives from three federal agencies (the National Institutes of Health , CDC, and the Substance Abuse and Mental Health Services Administration ) and persons with expertise in the field to develop a consensus definition of FASDs. The resulting definition, which is used in this report, defined FASDs as the range of effects that can occur in a person whose mother drank alcohol during pregnancy, including physical, mental, behavior, and learning disabilities, with possible lifelong implications. As this definition indicates, multiple diagnostic categories (e.g., FAS, ARND, and ARBD) are subsumed under the term FASDs. However, FASDs is not a diagnostic category and should be used only when referring to the collection of diagnostic terms resulting from prenatal exposure to alcohol.\n\n# Recommendations Diagnostic Criteria\nFor the majority of health-care providers, the key indicator of FAS is the set of characteristic facial features first described in 1973 (4). Alcohol is a teratogen that results in dysmorphia, growth problems, and abnormalities of the central nervous system in multiple ways (30,31).\nConfirmation and documentation of prenatal alcohol exposure can be difficult to establish. For birth mothers, admission of alcohol use during pregnancy can be stigmatizing. The situation can be further complicated if the woman continues to use alcohol, especially at high consumption rates. Clinicians might need to obtain information regarding alcohol use from other reliable informants, such as a relative.\nClinicians often have to evaluate a child or adult for FAS without definitive information regarding the mother's use of alcohol during pregnancy. This situation occurs frequently for children in foster and adoptive homes. In such cases, every effort should be made to obtain the necessary information, but lack of confirmation of alcohol use during pregnancy should not preclude a diagnosis of FAS if all other criteria are present. In rare instances, absence of exposure will be confirmed. Documentation that the birth mother did not drink any amount of alcohol from conception through birth would indicate that a FAS diagnosis is not appropriate. This finding typically implies either that the birth mother knew the date of conception (e.g., a planned pregnancy) and did not consume alcohol from that day forward or that she was prevented from drinking for a certain reason (e.g., incarceration).\nBecause of the imprecise nature of exposure information, the following two qualifying terms are suggested for a finding of prenatal alcohol exposure:\n- FAS with confirmed prenatal alcohol exposure requires documentation of the alcohol consumption patterns of the birth mother during the index pregnancy on the basis of clinical observation; self-reports; reports of heavy alcohol use during pregnancy by a reliable informant; medical records documenting positive blood alcohol levels or alcohol treatment; or other social, legal, or medical problems related to drinking during the index pregnancy. - FAS with unknown prenatal alcohol exposure indicates neither a confirmed presence nor a confirmed absence of exposure. Examples include situations in which the child is adopted, and any prenatal exposure is unknown; the birth mother is an alcoholic, but confirmed evidence of exposure during pregnancy does not exist; or conflicting reports regarding exposure exist that cannot be reliably resolved. Prenatal exposure to alcohol alone is not sufficient to warrant a diagnosis of FAS. Despite the heterogeneity of expression for features related to prenatal exposure to alcohol, a diagnosis of FAS requires documentation of three findings: 1) three specific facial abnormalities; 2) growth deficit; and 3) CNS abnormalities (Appendix) (30,31) (Box).\n\n# BOX. Characteristics for diagnosing fetal alcohol syndrome\n\n# Facial dysmorphia\nOn the basis of racial norms (i.e., those appropriate for a person's race), the person exhibits all three of the following characteristic facial features: - smooth philtrum (University of Washington Lip-Philtrum Guide- rank 4 or 5*), - thin vermillion border (University of Washington Lip-Philtrum Guide rank 4 or 5), and - small palpebral fissures (<10th percentile).\n\n# Growth problems\nConfirmed, documented prenatal or postnatal height, weight, or both <10th percentile, adjusted for age, sex, gestational age, and race or ethnicity\nCentral\n\n# Considerations When Diagnosing FAS\nBecause FAS is a syndrome rather than a specific disease, additional features can be present. For example, in addition to the key facial dymorphic features, maxillary hypoplasia is often noted for persons with FAS (3). Features often change with age or development. After puberty, the characteristic facial features associated with FAS can become more difficult to detect (32). However, the key features remain constant for the majority of persons with FAS (33,34).\nChanges in growth pattern across development also lead to variability in presentation. For certain affected persons, growth problems might occur at a younger age but not be present at the time of the diagnostic evaluation. This is particularly important when considering prenatal growth retardation or early growth problems caused by failure to thrive. Because multiple treatments exist for growth problems (e.g., use of feeding tubes or hormone therapy), any history of growth retardation, including prenatal growth deficiencies, is consistent with the criteria for diagnosing FAS (35). The clinician should be certain that the child was not nutritionally deprived at the single point in time when the growth deficit was present. The adopted threshold for growth (<10th percentile) represents an attempt to maximize sensitivity, even though it reduces specificity.\n\n# CNS Abnormalities\nThe diagnostic criteria for CNS abnormality require documentation of one of three types of deficits or abnormalities (i.e., structural, neurologic, and functional). A person might have more than one CNS abnormality (36). Identifying CNS abnormalities resulting from prenatal alcohol exposure can be the most difficult aspect of a FAS diagnosis because of the heterogeneity of expression for these deficits across persons (Appendix).\nApproximately one fourth of persons who receive a diagnosis of FAS perform at two standard deviations below the mean (which approaches substantial impairment ) on standardized measures of cognition (37). To capture the full spectrum of effects adequately, two levels of functional deficits are consistent with the criteria for a CNS abnormality: 1) performance below the third percentile (i.e., two standard deviations below the mean) on a measure of global cognitive functioning or 2) performance <16th percentile (i.e., one standard deviation below the mean) on standardized measures of three functional domains. Thus, persons scoring below the normal range on a global measure of intelligence or development and persons scoring in the belowaverage range on standardized measures of three specific functional domains would be consistent with the criteria for functional CNS abnormality for diagnostic purposes.\nBecause of the importance of documenting CNS abnormalities and the variability in functional deficits, the diagnostic process should include a thorough neuropsychologic evaluation that assesses multiple domains. Extensive standardized testing might not be readily available in all diagnostic settings. Clinicians are encouraged to supplement their observations by obtaining standardized testing through early intervention programs, public schools, and psychologists in private practice. Such testing will facilitate the development of appropriate personalized treatment plans for persons who receive a diagnosis of FAS. These guidelines recommend that functional domains be assessed by using norm-referenced standardized measures. Assessments should be conducted by professionals using reliable and validated instruments.\n\n# Differential Diagnosis\nIndividual dysmorphic features are not unique to any particular syndrome. Even rare defects or certain clusters of dysmorphic features can appear in multiple syndromes. Therefore, a process of differential diagnosis is essential in making an accurate FAS diagnosis. Features that discriminate these disorders from FAS have been described (38). Certain syndromes have single overlapping features with FAS. With the exception of toluene embryopathy, no other known syndrome has the full constellation of small palpebral fissures, thin vermillion border, and smooth philtrum. However, for certain syndromes (e.g., Williams syndrome, Dubowitz syndrome, or fetal dilantin syndrome), the overall constellation of features (primary, occasional features, or both) is similar to FAS, and these syndromes should be considered in particular when completing the differential diagnosis.\nGrowth retardation and deficiencies occur among children, adolescents, and adults for multiple reasons. Insufficient nutrition could be a particular problem for infants with poor sucking responses who fail to thrive. In addition, certain genetic disorders result in specific growth deficiencies (e.g., dwarfism). Prenatal growth retardation can result from multiple factors, including maternal smoking or other behaviors leading to hypoxia, poor maternal nutrition, or genetic disorders unrelated to maternal alcohol consumption. Both environmental and genetic bases for growth retardation should be considered for differential diagnosis when considering a FAS diagnosis. Finally, because a threshold of <10th percentile (rather than the lower threshold of the third percentile commonly used to denote growth retardation) was adopted, certain children will be classified as being consistent with this criterion for reasons other than prenatal exposure to alcohol (e.g., parents having short stature). However, because the diagnosis of FAS is made only when facial dysmorphia and CNS abnormalities also are present, the increased sensitivity achieved with the 10th percentile was selected.\nDifferential diagnosis of CNS abnormities involves not only ruling out other disorders but also specifying simultaneously occurring disorders. CNS deficits associated with FAS (especially functional deficits) can be produced by multiple factors in addition to prenatal alcohol exposure. Observed functional deficits should be determined not to be better explained by other causes. In addition to other organic syndromes that produce deficits in one or more of the previously cited domains (e.g., Williams syndrome and Down syndrome), disrupted home environments or other external factors can produce functional deficits in multiple domains that overlap those affected by FAS. In making a differential diagnosis of FAS, the clinician should evaluate CNS abnormalities in conjunction with dysmorphia and laboratory findings. CNS abnormalities resulting from environmental influences (e.g., abuse or neglect, disruptive homes, and lack of opportunities) are harder to differentiate. To assist with differential diagnosis between FAS and environmental causes for CNS abnormalities, clinicians should obtain a complete, detailed history for the person and family members.\nIn addition to ruling out other causes for CNS abnormalities, a complete diagnosis should identify and specify other disorders that can coexist with FAS (e.g., autism, conduct disorder, or oppositional defiant disorder). A particular person might have a conduct disorder in addition to FAS; however, not all persons with FAS have conduct disorders, and not all persons with conduct disorders have FAS. Certain functional deficits might lead to additional behavior problems. For example, a child with an attention problem also could have conduct disorder. Clinicians should consider organic causes, environmental contributions, and comorbidity for both inclusive and exclusive purposes when evaluating a person for a FAS diagnosis (32,39). Because differential diagnosis for CNS abnormalities within a FAS diagnosis is difficult, the evaluation should be conducted by professionals trained in both the features of FAS and those of a broad array of birth defects and developmental disabilities.\n\n# Conditions Consistent with a Subset of Diagnostic Criteria for FAS\nThe majority of persons with deficits resulting from prenatal exposure to alcohol do not express all the features necessary for a FAS diagnosis (36). Sufficient scientific evidence is not available to define diagnostic criteria for any prenatal alcohol-related condition other than FAS. Persons who have the neurodevelopment deficits required for a FAS diagnosis but who do not have all three facial features or growth deficits might not receive a diagnosis and so not be provided with services. Ongoing funding has been provided by the National Institute on Alcohol Abuse and Alcoholism to conduct research that might lead to evidence-based diagnostic criteria for persons with other conditions caused by prenatal alcohol use. CDC is using a collaborative database of neurodevelopment data from five intervention studies to explore the nature of persons who could be considered in the diagnostic category of alcohol related neurodevelopment disorder, as well as data from a prospective cohort study in Denmark of children aged 5 years. FAS is the only diagnostic category with scientific evidence to support clinical criteria at this time. As future data become available, these guidelines can be refined and expanded to delineate other conditions resulting from prenatal alcohol exposure.\n\n# Mental Health Problems and Other Lifelong Consequences\nFAS has lifelong consequences. Common FAS-related mental health conditions (excluding attention problems) reported include conduct disorders, oppositional defiant disorders, anxiety disorders, adjustment disorders, sleep disorders, and depression (37,(40)(41)(42)(43)(44). Although attention problems can be classified as a mental health issue or psychiatric condition, in these guidelines, they are treated as a primary deficit resulting from alcohol-related CNS damage rather than a secondary mental health concern (45). Decreased adaptive skills and increased problems with daily living abilities have been documented (e.g., dependent living conditions, disrupted school experiences, poor employment records, and encounters with law enforcement, including incarceration) among persons with FAS (37). These mental health-related consequences should not be used for diagnosis. However, they are prevalent among persons with FAS and are likely to result in referral and comprehensive diagnostic evaluation.\n\n# Referral Considerations\nProviders of medical, educational, and social services often must decide whether to refer a child, person, or family to a specialist for a full FAS diagnostic evaluation. This decision can be difficult. For biologically related family members, social stigma might be associated with any evaluation concerning prenatal alcohol exposure. In adoptive or foster families, alcohol use during pregnancy might be suspected, but direct information might not be available.\n\n# MMWR October 28, 2005\nThe following guidelines were developed to assist service providers in making referral decisions. Each case should be evaluated individually. When in doubt, providers should refer persons for a full evaluation by a multidisciplinary team with experience in evaluating prenatal alcohol exposure.\nThe following circumstances should prompt a diagnostic referral:\n- When prenatal alcohol exposure is known, a child should be referred for full FAS evaluation when substantial prenatal alcohol use (i.e., seven or more drinks per week, three or more drinks on multiple occasions, or both) has been confirmed. If substantial prenatal alcohol exposure is known, in the absence of any other positive criteria (i.e., dysmorphia, growth deficits, or CNS abnormalities), the primary health-care provider should document this exposure and monitor the child's ongoing growth and development closely. - When information regarding prenatal alcohol exposure is unknown, a child should be referred for full FAS evaluation for any one of the following:\n-any report of concern by a parent or caregiver (e.g., foster or adoptive parent) that a child has or might have FAS; -presence of all three facial features (i.e., smooth philtrum, thin vermillion border, and small palpebral fissures); -presence of one or more of these facial features, with growth deficits in height, weight, or both; -presence of one or more facial features, with one or more CNS abnormalities; or -presence of one or more facial features, with growth deficits and one or more CNS abnormalities. In addition to specific features associated with a FAS diagnosis, certain social and family history factors have been associated with prenatal alcohol exposure (46). The possibility of prenatal alcohol exposure should be considered fully for persons who are experiencing or have experienced one or more of the following:\n- premature maternal death related to alcohol use (either disease or trauma), - living with an alcoholic parent, - current or previous abuse or neglect, - current or previous involvement with child protective services agencies (PSAs), - a history of transient caregiving situations, or - foster or adoptive placements (including kinship care). Although such situations might have a negative impact on the development of any child, evidence exists that children with FAS or a related disorder are particularly likely to expe-rience negative situations that involve a dysfunctional family unit (46), especially if the biologic mother abuses alcohol.\n\n# Services for Persons with FAS\nFor persons with developmental disabilities and their families, diagnosis is never an endpoint. This is particularly true for persons with FAS, their families, and their communities. The diagnostic process (especially the neuropsychologic assessment) should be part of a continuum of care that identifies and facilitates appropriate health-care, education, and community services. Early diagnosis and a stable, nurturing home environment have been identified as strong protective factors for persons with FAS (46). Limited information is available regarding strategies for interventions specific to persons with FAS. Information available has been gathered primarily from the experience of persons with other disabilities and from that of parents gained through trial and error and shared through informal networks. Treatments currently employed to reduce the risk for adverse effects of FAS have not been evaluated systematically or scientifically. In 2001, CDC provided the first federal funding to develop and test systematic, scientifically developed interventions specific to FAS (e.g., a modified mathematics curriculum or a program to develop peer friendship skills). These projects are in their final stages, and findings will be published.\nThe learning and life skills affected by prenatal alcohol exposure vary among persons, depending on the amount, timing, and pattern of exposure and on each person's current and past environment (47,48). As a result, services needed for persons with FAS and their families vary according to the parts of the brain affected, the person's age or level of maturation, the health or functioning of the family, and the person's overall living environment. Thus, the service needs of affected persons and their families should be individualized (49). Certain general areas of service and specific services have been identified as helpful to persons with FAS and their families (32).\nInterventions should include strategies that stabilize home placement and improve parent-child interaction (47). One means of accomplishing this goal is to increase the understanding of the disorder among parents, teachers, law enforcement personnel, and other professionals who might become involved with the affected person. Children with FAS often need specialized parenting techniques because of their difficulty with cause-and-effect reasoning and other executive functioning skills (47). Caregiver education should highlight and explain differences in the thought processes of children with FAS compared with typically developing children and children with other developmental disabilities. This knowl-edge would enable parents to avoid potentially difficult situations (e.g., overly stimulating environments) and better manage problems when they do arise. Overall, a better functioning family that results from caregiver education promotes the stable, nurturing home that has been demonstrated to be a protective factor for children with FAS (50).\nProfessionals who work with persons affected by FAS could benefit from better understanding of the disorder and services available for affected persons and their families (39). These professionals can help link families with needed community resources and ensure that affected children receive maximum benefit from services provided. Interacting with social and educational service agencies can be overwhelming and confusing, and each agency typically uses a specialized vocabulary (i.e., jargon) that is difficult for nonspecialists to understand. In addition to being able to diagnose FAS, clinicians should help parents and caregivers identify available services, determine which ones are effective for their children, and understand how to work productively with service providers (32).\nPrenatally exposed infants and children often enter the foster or adoptive care system at an early age. The prevalence of children with FAS or a related disorder in the foster care system is estimated to be 10 times that of the general population (51). Although PSAs might have information regarding a child's prenatal history, PSA staff generally do not know about FAS, understand how FAS affects the child, or communicate with other service systems regarding the child's FAS status (51). As a result, foster and adoptive families typically are not educated regarding the long-term effects of FAS and are unprepared to meet their children's needs.\nThe majority of PSAs require foster parents to take a specified number of educational courses annually. These courses should include education regarding the effects and developmental needs of children with FAS because the majority of foster parents will encounter at least one child with FAS or a related disorder during their time as a foster parent (51). Projects funded by CDC have developed FAS curricula for parents, educators, and juvenile justice systems; information regarding these curricula is available at / ncbddd/fas/awareness.htm.\nThe assessment process is integral to both the FAS diagnosis and the development of an effective treatment plan. Such a treatment plan minimizes risk factors for lifelong negative consequences and promotes protective factors that maximize developmental potential. Clinicians and service providers must ensure that assessments include communication and social skills, emotional maturity, verbal and comprehension abilities, language usage, and, if appropriate, referral for medication assessments. Finally, the health and development of children with disabilities, including children with FAS, can be promoted by public support for programs that provide access to school, recreational, and social activities.\n\n# Alcohol Use During Pregnancy\nBecause no safe threshold of alcohol use during pregnancy has been established, CDC and NTFFAS/FAE recommend that women who are pregnant, planning a pregnancy, or at risk for pregnancy should not drink alcohol. Women of childbearing age who are not pregnant should drink no more than seven drinks per week and no more than three drinks on any one occasion.\nFederal, state, and local agencies; clinicians and researchers; educational and social service professionals; and families should work together to educate women of childbearing age and communities countrywide regarding the risks of drinking alcohol during pregnancy. Women who have had at least one child with FAS are at especially high risk for giving birth to a second affected child (2,52). Universal screening for alcohol use among all women of childbearing age might help identify women who drink above recommended levels as well as those who drink and might become pregnant. Screening can be performed in clinicians' offices or in community health settings. Screening techniques that include measures of quantity, frequency, and heavy episodic drinking, as well as behavioral manifestations of risk drinking, have proven to be most beneficial; simple questionnaires have been developed to screen for problematic alcohol use among adults in multiple populations and settings (53).\nEffective prevention programs frequently employ a multicomponent approach that combines cognitive-behavioral techniques with norms clarification, education, and motivational enhancement interventions. For women who screen positive for hazardous alcohol use or abuse, brief interventions that use time-limited, self-help, and preventative strategies to promote reductions in alcohol use in nondependent persons and that facilitate referral of dependent persons to specialized treatment programs are low-cost, effective treatment alternatives (54)(55)(56)(57). The acronym FRAMES is used to encompass six key elements of the majority of successful brief interventions as follows: 1) feedback of personal risk, 2) responsibility for personal control, 3) advice to change, 4) menu of ways to reduce or stop drinking, 5) empathetic counseling style, and 6) self-efficacy or optimism regarding reducing or stopping drinking (58). Preconception counseling of women of childbearing age who are at risk for an alcohol-exposed pregnancy and who are not using effective contraception has been demonstrated as a promising method of prevention (59). Project CHOICES, funded by CDC, is an example of a brief intervention that has been effective. Information regarding this project and other federally sponsored studies of prenatal alcohol screening and intervention programs is available at , , , and services.ahrq.gov.\n\n# Summary of Recommendations\nOn the basis of a review of current scientific and clinical evidence, the following recommendations are made concerning referral of children and diagnosis of FAS:\n\n# Diagnosis of FAS\n- A diagnosis of FAS should be made if documentation exists of 1) all three dysmorphic facial features (i.e., smooth philtrum, thin vermillion border, and small palpebral fissures), 2) prenatal or postnatal growth deficit in height or weight, and 3) CNS abnormality. - The diagnosis should be classified on the basis of available history as confirmed prenatal alcohol exposure or unknown prenatal alcohol exposure. - CNS abnormality may be documented as structural, neurologic, or functional (Box).\n\n# Referral\n- If prenatal alcohol exposure is known, a child or person should be referred for full FAS evaluation when alcohol abuse (defined as seven or more alcohol drinks per week or three or more alcohol drinks on multiple occasions, or both) is confirmed. - If prenatal alcohol exposure is unknown, a child or person should be referred for full FAS evaluation when: -a parent or caregiver (foster or adoptive parent) reports that a child has or might have FAS; -all three facial features (i.e., smooth philtrum, thin vermillion border, and small palpebral fissures) are present; -one or more facial features are present in addition to growth deficits in height, weight, or both; one or more facial features are present and one or more CNS abnormalities; or -one or more facial features are present, with growth deficits and one or more CNS abnormalities. - In addition to specific features associated with the FAS diagnosis, the following social and family history factors associated with prenatal exposures to alcohol might indicate a need for referral:\n-premature maternal death related to alcohol use (either disease or trauma), -living with an alcoholic parent, -current or previous abuse or neglect, -current or previous involvement with child PSAs, -a history of transient caregiving situations, or -having been in foster or adoptive care (including kinship care).\n\n# Services\n- The FAS diagnosis and the diagnostic process (especially the neuropsychologic assessment) should be considered as part of a continuum of care that identifies and facilitates appropriate health-care, education, and community services. - General areas of service needs for persons with FAS and their families should include strategies that stabilize home placement, improve parent-child interaction through caregiver education, advocate for access to services, and educate service professionals involved with affected persons and their families regarding FAS and its consequences. - Specific intervention services should be tailored to a person's individual needs and deficits. These might include communication and social skills; emotional development; verbal and comprehension abilities; language usage; and, if appropriate, referral for medication assessments. - The needs of children in adoptive or foster placements should receive particular attention in the diagnostic and referral process.\n\n# Prevention\n- Federal, state, and local agencies; clinicians and researchers; educational and social service professionals; and families should work together to educate women of childbearing age and communities countrywide regarding the risks of drinking alcohol during pregnancy. - Universal screening by health-care providers for alcohol use is recommended for all women of childbearing age. - For women drinking at risk levels and not effectively using contraception, brief interventions have proven effective in reducing the risk for an alcohol-exposed pregnancy. - Because no safe threshold of alcohol use during pregnancy has been established, women who are pregnant, planning a pregnancy, or at risk for pregnancy should be advised not to drink alcohol. Women who are not pregnant, not planning a pregnancy, or not at risk for unintended preg-nancy should be advised to drink no more than seven drinks per week and no more than three drinks on any one occasion. - Additional information regarding these guidelines has been published (60).\n\n# MMWR October 28, 2005\ning on the amount, timing, and pattern of alcohol exposure (e.g., chronic exposure versus binge episodes). Despite this inherent variation in effects, areas of functional vulnerability have been observed consistently by clinicians and researchers with particular damage to corresponding structures reported (e.g., corpus callosum, cerebellum, or basal ganglia). For functional deficits, multiple locations in the brain (and corresponding functional capability) are generally accepted to be affected by prenatal exposure to alcohol. Functional deficits consistent with CNS abnormality criteria can be identified in two ways: 1) global cognitive deficit (e.g., decreased IQ) or substantial developmental delay in children too young for an IQ assessment or 2) deficits in three or more specific functional domains. These two ways of assessing functional CNS abnormality were adopted because of the composite nature of cognitive, intellectual, and developmental measures (15,16). Decreased performance on a standardized measure of cognition, intelligence, and development assumes deficits in multiple domains. In the absence of such a measure, multiple domains should be assessed individually to determine that multiple functional domains have been affected. For each domain, other agents and environmental factors can produce deficits or outcomes similar to prenatal alcohol exposure, making differential diagnosis essential.\nThe specific domains most often cited as areas of deficit or concern for persons with FAS are described below. These descriptions are intended to be suggestive and are examples of likely and possible problems a clinician might encounter and need to assess by using psychometric instruments. The examples are not intended to be exhaustive or to present a list of behaviors to be used as a checklist without reliable and valid assessment.\n- Cognitive deficits or significant developmental discrepancies. Global deficits or delays can leave the child scoring in the normal range of development but below what would be expected for the child's environment and background (17)(18)(19)(20)(21)(22). In addition to formal testing (either through records or current testing), behaviors that might be observed or reported in the clinical setting that suggest cognitive deficits or developmental delays that should be assessed by standardized testing include but are not limited to specific learning disabilities (especially mathematic or visual-spatial deficits), uneven profile of (22,(36)(37)(38).\nBehaviors that can be observed or reported in the clinical setting that indicate motor problems that should be assessed by standardized testing include but are not limited to delayed motor milestones, difficulty with writing or drawing, clumsiness, balance problems, tremors, and poor dexterity. For infants, a poor suck is often observed (17,(38)(39)(40). - Attention and hyperactivity problems. Attention problems are often noted for children with FAS, with children frequently receiving a diagnosis of attention-deficit hyperactivity disorder (ADHD) (41). Although such a diagnosis can be applied, attention problems for children with FAS do not appear to be consistent with the classic pattern of ADHD. Persons with FAS tend to have difficulty with the encoding of information and flexibility (shifting) aspects of attention, whereas children with ADHD typically display problems with focus and sustaining attention (42,43). Persons with FAS also can appear to display hyperactivity because their impulsivity might lead to increased activity levels. Behaviors that might be observed or reported in the clinical setting that suggest attention problems related to FAS that should be assessed by standardized testing include but are not limited to being described by adults as \"busy,\" inattentive, easily distracted, difficulty calming down, being overly active, difficulty completing tasks, and/or trouble with transitions.\nParents might report inconsistency in attention from day to day (e.g., \"on\" days and \"off\" days) (44-50).\n- Social skills problems. The executive, attention, and developmental problems described previously often lead to clinically significant difficulty for persons with FAS when interacting with peers and others. Because of the mental representation problems, persons with FAS often have social perception or social communication problems that make it difficult for them to grasp the more subtle aspects of human interactions (51,52). Consistent difficulty understanding the consequence of behavior or inappropriate behavior frequently is described for persons with FAS (53,54). Behaviors that can be observed or reported in the clinical setting that indicate these types of social difficulties that should be assessed by standardized testing include but are not limited to lack of fear of strangers, naiveté and gullibility, being taken advantage of easily, inappropriate choice of friends, preferring younger friends, immaturity, superficial interactions, adaptive skills significantly below cognitive potential, inappropriate sexual behaviors, difficulty understanding the perspective of others, poor social cognition, and clinically significant inappropriate initiations or interactions (55)(56)(57). Standardized assessment of social problems can be difficult; social functioning is a multifaceted domain that can require multiple areas of assessment. - Other potential domains that can be affected. In addition to these five most-often-cited problem areas, deficits and problems to be assessed by standardized testing can present in several other areas, including sensory problems (e.g., tactile defensiveness and oral sensitivity), pragmatic language problems (e.g., difficulty reading facial expression, and poor ability to understand the perspectives of others), memory deficits (e.g., forgetting welllearned material, and needing many trials to remember), and difficulty responding appropriately to common parenting practices (e.g., not understanding cause-andeffect discipline). Although abnormalities in these areas have been reported for persons with FAS, deficits in these areas are reported at a lower frequency than are those in the other five specific domains (53).\n\n# INSTRUCTIONS ACCREDITATION Continuing Medical Education (CME).\nCDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.25 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training. CDC will award 0.1 CEUs to participants who successfully complete this activity.\n\n# Continuing Nursing Education (CNE).\nThis activity for 1.3 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation.\n\n# What percentage of sexually active women of childbearing age do not use contraception effectively and drink alcohol frequently or binge drink, putting them at risk for an alcohol-exposed pregnancy?\nA. 1%-2%. B. 12%-13%. C. 20%-40%. D. 50%-75%.\n\n# The diagnosis of FAS includes which of the following criteria?\nA. Documentation of all three facial abnormalities (i.e., smooth philtrum, thin vermillion, and small palpebral fissures). B. Documentation of growth deficits.\nC. Documentation of central nervous system abnormalities. D. Documentation of mental retardation. E. A, B, and C. F. A and D.\n\n# Which of the following statements is true?\nA. One of the diagnostic criteria for FAS is mental retardation. B. Persons who have been exposed to alcohol prenatally but whose physical condition is not consistent with the criteria for FAS might have substantial cognitive deficits. C. All persons with FAS have attention deficit hyperactivity disorder. D. Persons with FAS are likely to have speech and language impairments but not fine motor deficits.\n\n# A person should be referred for a complete multidisciplinary diagnostic evaluation when…\nA. all three facial features are present. B. any concern is reported by a parent or caregiver that a child has or might possibly have been exposed to alcohol prenatally. C. a child is living with an alcoholic parent, or the biological mother died as a result of alcohol-related disease or trauma. D. all of the above.\n\n# Goal and Objectives\nThis report provides updated criteria for diagnosis of fetal alcohol syndrome (FAS) among persons affected by prenatal alcohol exposure. The goal of this report is to provide guidance for health-care providers in determining which persons might need referral for a complete multidisciplinary diagnostic evaluation and information regarding medical, educational, social, and family services appropriate for affected persons. Upon completion of this educational activity, the reader should be able to 1) describe the negative outcomes associated with prenatal exposure to alcohol, 2) list the specific criteria that constitute a diagnosis of FAS, 3) identify persons who should receive a referral for a multidisciplinary evaluation for FAS, 4) list services appropriate for a person receiving a FAS diagnosis, and 5) list instruments appropriate for screening women of childbearing age for alcohol use or abuse.\nTo receive continuing education credit, please answer all of the following questions."},"raw_text":{"kind":"string","value":"Fetal alcohol syndrome (FAS) results from maternal alcohol use during pregnancy and carries lifelong consequences. Early recognition of FAS can result in better outcomes for persons who receive a diagnosis. Although FAS was first identified in 1973, persons with this condition often do not receive a diagnosis. In 2002, Congress directed CDC to update and refine diagnostic and referral criteria for FAS, incorporating recent scientific and clinical evidence. In 2002, CDC convened a scientific working group (SWG) of persons with expertise in FAS research, diagnosis, and treatment to draft criteria for diagnosing FAS. This report summarizes the diagnostic guidelines drafted by the SWG, provides recommendations for when and how to refer a person suspected of having problems related to prenatal alcohol exposure, and assesses existing practices for creating supportive environments that might prevent long-term adverse consequences associated with FAS. The guidelines were created on the basis of a review of scientific evidence, clinical expertise, and the experiences of families affected by FAS regarding the physical and neuropsychologic features of FAS and the medical, educational, and social services needed by persons with FAS and their families. The guidelines are intended to facilitate early identification of persons affected by prenatal exposure to alcohol so they and their families can receive services that enable them to achieve healthy lives and reach their full potential. This report also includes recommendations to enhance identification of and intervention for women at risk for alcohol-exposed pregnancies. Additional data are needed to develop diagnostic criteria for other related disorders (e.g., alcohol-related neurodevelopmental disorder).# Introduction\nPrenatal exposure to alcohol during pregnancy damages the developing fetus and is a leading preventable cause of birth defects and developmental disabilities (1)(2)(3). Children exposed to alcohol during fetal development can suffer multiple negative effects, including physical and cognitive deficits. Although the number and severity of negative effects can range from subtle to serious, they are always lifelong.\nReferral and diagnosis for fetal alcohol syndrome (FAS) can be made throughout the lifespan. However, the majority of persons with FAS are referred and receive a diagnosis during childhood. Thus, the terms \"child\" or \"children\" as used in these guidelines are not intended to preclude referral, assessment, and diagnosis of older persons.\n# Background\nThe effects of prenatal exposure to alcohol and basic diagnostic features of FAS were first described in 1973 (4)(5)(6)(7)(8). In 1981, the U.S. Surgeon General issued a public health advisory warning that alcohol use during pregnancy could cause birth defects (9); this warning was reissued in 2004 (10). In 1989, Congress mandated that language warning of the consequences of drinking during pregnancy be included on alcohol product labels (11).\nDespite the known adverse effects of prenatal exposure to alcohol (4,5), children who experience these effects often do not receive a correct diagnosis or referral for diagnostic evaluation because of the absence of uniformly accepted diagnostic criteria and guidelines for referral. Early identification and diagnosis of FAS in affected persons are essential components to providing health, education, and social services that promote optimal well-being. In 2002, Congress directed CDC to 1) develop guidelines for diagnosing FAS and other negative birth outcomes resulting from prenatal exposure to alcohol, 2) incorporate these guidelines into curricula for medical and allied health students and practitioners, and 3) disseminate curricula concerning these guidelines to facilitate training of medical and allied health students and practitioners.\nThese guidelines represent a consensus of opinion from persons with expertise in relevant scientific and clinical fields, with input from service professionals and families affected by FAS. Information that served as the basis for the development of these guidelines was obtained from published scientific literature, clinical knowledge of participants, and the experience of families affected by FAS.\nCDC staff initially identified reports and other documents that were used as the scientific basis for creating diagnostic guidelines. On the basis of this information, and in coordination with the National Taskforce on Fetal Alcohol Syndrome and Fetal Alcohol Effect (NTFFAS/FAE), other federally funded FAS programs, and nongovernment organizations concerned with FAS, CDC formed a scientific working group (SWG) of persons with expertise in research and clinical practice regarding prenatal exposure to alcohol to develop diagnostic guidelines for FAS.\nGuidelines were formulated on the basis of consensus among SWG members and NTFFAS/FAE. To assist in defining the dysmorphologic features most useful for identifying persons with FAS, SWG members assembled a matrix of the major and associated dysmorphic features of non-FAS syndromes that had one or more features in common with FAS. This matrix was used to determine a combination of dysmorphic features most discriminative for FAS. To assist deliberations concerning central nervous system (CNS) abnormalities associated with FAS, persons with expertise in the science, assessment, and treatment of psychological aspects of FAS were asked to identify the CNS abnormalities and other neurobehavioral domains most common among persons affected by prenatal alcohol exposure. These responses formed the basis for discussion and the resulting guidelines for CNS abnormalities for persons with FAS.\nThis report summarizes the guidelines drafted as a result of the SWG's deliberations, provides recommendations for when and how to refer a person suspected of having problems related to prenatal alcohol exposure, and assesses existing practices for creating supportive environments that might prevent long-term adverse consequences associated with FAS.\n# Prevalence\nVaried FAS prevalences (range: 0.2-1.5 cases per 1,000 live births) have been reported worldwide (12)(13)(14)(15). Other studies that used different ascertainment methodologies have produced different estimates (range: 0.5-2.0 cases per 1,000 live births) (16)(17)(18)(19)(20)(21)(22). These rates are comparable with or higher than rates for other common developmental disabilities (e.g., Down syndrome or spina bifida) (23). On the basis of these prevalence estimates, approximately 4 million infants are born each year with prenatal alcohol exposure, and an estimated 1,000-6,000 are born with FAS.\nStudies have reported consistently that >50% of all U.S. women of childbearing age report alcohol consumption during the previous month (1,(24)(25)(26)(27)(28). The majority of these women drank only occasionally, but >13% could have been classified as moderate or heavy drinkers. In addition, 12% of women reported binge drinking (i.e., consuming five or more drinks on one occasion) during the preceding month (1,25,27,28). Approximately half of all U.S. pregnancies are unintended, and millions of women of childbearing age are sexually active while not using adequate contraception (24)(25)(26)(27)(28). Recent data from the Behavioral Risk Factors Surveillance System indicate that an estimated 12%-13% of U.S. women aged 18-44 years are sexually active, do not use contraception effectively, and drink alcohol frequently or binge drink, thereby putting them at risk for an alcohol-exposed pregnancy (24). Because data are available for all subpopulations, prevalences might be greater than these data indicate.\n# Fetal Alcohol Spectrum Disorder\nMultiple terms are used to describe the continuum of effects that result from prenatal exposure to alcohol, including fetal alcohol effects, alcohol-related birth defects (ARBD), alcohol-related neurodevelopment disorder (ARND), and, most recently, fetal alcohol spectrum disorders (FASDs) (29). In April 2004, the National Organization on Fetal Alcohol Syndrome (NOFAS) convened a meeting of representatives from three federal agencies (the National Institutes of Health [NIH], CDC, and the Substance Abuse and Mental Health Services Administration [SAMHSA]) and persons with expertise in the field to develop a consensus definition of FASDs. The resulting definition, which is used in this report, defined FASDs as the range of effects that can occur in a person whose mother drank alcohol during pregnancy, including physical, mental, behavior, and learning disabilities, with possible lifelong implications. As this definition indicates, multiple diagnostic categories (e.g., FAS, ARND, and ARBD) are subsumed under the term FASDs. However, FASDs is not a diagnostic category and should be used only when referring to the collection of diagnostic terms resulting from prenatal exposure to alcohol.\n# Recommendations Diagnostic Criteria\nFor the majority of health-care providers, the key indicator of FAS is the set of characteristic facial features first described in 1973 (4). Alcohol is a teratogen that results in dysmorphia, growth problems, and abnormalities of the central nervous system in multiple ways (30,31).\nConfirmation and documentation of prenatal alcohol exposure can be difficult to establish. For birth mothers, admission of alcohol use during pregnancy can be stigmatizing. The situation can be further complicated if the woman continues to use alcohol, especially at high consumption rates. Clinicians might need to obtain information regarding alcohol use from other reliable informants, such as a relative.\nClinicians often have to evaluate a child or adult for FAS without definitive information regarding the mother's use of alcohol during pregnancy. This situation occurs frequently for children in foster and adoptive homes. In such cases, every effort should be made to obtain the necessary information, but lack of confirmation of alcohol use during pregnancy should not preclude a diagnosis of FAS if all other criteria are present. In rare instances, absence of exposure will be confirmed. Documentation that the birth mother did not drink any amount of alcohol from conception through birth would indicate that a FAS diagnosis is not appropriate. This finding typically implies either that the birth mother knew the date of conception (e.g., a planned pregnancy) and did not consume alcohol from that day forward or that she was prevented from drinking for a certain reason (e.g., incarceration).\nBecause of the imprecise nature of exposure information, the following two qualifying terms are suggested for a finding of prenatal alcohol exposure:\n• FAS with confirmed prenatal alcohol exposure requires documentation of the alcohol consumption patterns of the birth mother during the index pregnancy on the basis of clinical observation; self-reports; reports of heavy alcohol use during pregnancy by a reliable informant; medical records documenting positive blood alcohol levels or alcohol treatment; or other social, legal, or medical problems related to drinking during the index pregnancy. • FAS with unknown prenatal alcohol exposure indicates neither a confirmed presence nor a confirmed absence of exposure. Examples include situations in which the child is adopted, and any prenatal exposure is unknown; the birth mother is an alcoholic, but confirmed evidence of exposure during pregnancy does not exist; or conflicting reports regarding exposure exist that cannot be reliably resolved. Prenatal exposure to alcohol alone is not sufficient to warrant a diagnosis of FAS. Despite the heterogeneity of expression for features related to prenatal exposure to alcohol, a diagnosis of FAS requires documentation of three findings: 1) three specific facial abnormalities; 2) growth deficit; and 3) CNS abnormalities (Appendix) (30,31) (Box).\n# BOX. Characteristics for diagnosing fetal alcohol syndrome\n\n# Facial dysmorphia\nOn the basis of racial norms (i.e., those appropriate for a person's race), the person exhibits all three of the following characteristic facial features: • smooth philtrum (University of Washington Lip-Philtrum Guide* rank 4 or 5*), • thin vermillion border (University of Washington Lip-Philtrum Guide rank 4 or 5), and • small palpebral fissures (<10th percentile).\n# Growth problems\nConfirmed, documented prenatal or postnatal height, weight, or both <10th percentile, adjusted for age, sex, gestational age, and race or ethnicity \nCentral\n# Considerations When Diagnosing FAS\nBecause FAS is a syndrome rather than a specific disease, additional features can be present. For example, in addition to the key facial dymorphic features, maxillary hypoplasia is often noted for persons with FAS (3). Features often change with age or development. After puberty, the characteristic facial features associated with FAS can become more difficult to detect (32). However, the key features remain constant for the majority of persons with FAS (33,34).\nChanges in growth pattern across development also lead to variability in presentation. For certain affected persons, growth problems might occur at a younger age but not be present at the time of the diagnostic evaluation. This is particularly important when considering prenatal growth retardation or early growth problems caused by failure to thrive. Because multiple treatments exist for growth problems (e.g., use of feeding tubes or hormone therapy), any history of growth retardation, including prenatal growth deficiencies, is consistent with the criteria for diagnosing FAS (35). The clinician should be certain that the child was not nutritionally deprived at the single point in time when the growth deficit was present. The adopted threshold for growth (<10th percentile) represents an attempt to maximize sensitivity, even though it reduces specificity.\n# CNS Abnormalities\nThe diagnostic criteria for CNS abnormality require documentation of one of three types of deficits or abnormalities (i.e., structural, neurologic, and functional). A person might have more than one CNS abnormality (36). Identifying CNS abnormalities resulting from prenatal alcohol exposure can be the most difficult aspect of a FAS diagnosis because of the heterogeneity of expression for these deficits across persons (Appendix).\nApproximately one fourth of persons who receive a diagnosis of FAS perform at two standard deviations below the mean (which approaches substantial impairment [i.e., mental retardation]) on standardized measures of cognition (37). To capture the full spectrum of effects adequately, two levels of functional deficits are consistent with the criteria for a CNS abnormality: 1) performance below the third percentile (i.e., two standard deviations below the mean) on a measure of global cognitive functioning or 2) performance <16th percentile (i.e., one standard deviation below the mean) on standardized measures of three functional domains. Thus, persons scoring below the normal range on a global measure of intelligence or development and persons scoring in the belowaverage range on standardized measures of three specific functional domains would be consistent with the criteria for functional CNS abnormality for diagnostic purposes.\nBecause of the importance of documenting CNS abnormalities and the variability in functional deficits, the diagnostic process should include a thorough neuropsychologic evaluation that assesses multiple domains. Extensive standardized testing might not be readily available in all diagnostic settings. Clinicians are encouraged to supplement their observations by obtaining standardized testing through early intervention programs, public schools, and psychologists in private practice. Such testing will facilitate the development of appropriate personalized treatment plans for persons who receive a diagnosis of FAS. These guidelines recommend that functional domains be assessed by using norm-referenced standardized measures. Assessments should be conducted by professionals using reliable and validated instruments.\n# Differential Diagnosis\nIndividual dysmorphic features are not unique to any particular syndrome. Even rare defects or certain clusters of dysmorphic features can appear in multiple syndromes. Therefore, a process of differential diagnosis is essential in making an accurate FAS diagnosis. Features that discriminate these disorders from FAS have been described (38). Certain syndromes have single overlapping features with FAS. With the exception of toluene embryopathy, no other known syndrome has the full constellation of small palpebral fissures, thin vermillion border, and smooth philtrum. However, for certain syndromes (e.g., Williams syndrome, Dubowitz syndrome, or fetal dilantin syndrome), the overall constellation of features (primary, occasional features, or both) is similar to FAS, and these syndromes should be considered in particular when completing the differential diagnosis.\nGrowth retardation and deficiencies occur among children, adolescents, and adults for multiple reasons. Insufficient nutrition could be a particular problem for infants with poor sucking responses who fail to thrive. In addition, certain genetic disorders result in specific growth deficiencies (e.g., dwarfism). Prenatal growth retardation can result from multiple factors, including maternal smoking or other behaviors leading to hypoxia, poor maternal nutrition, or genetic disorders unrelated to maternal alcohol consumption. Both environmental and genetic bases for growth retardation should be considered for differential diagnosis when considering a FAS diagnosis. Finally, because a threshold of <10th percentile (rather than the lower threshold of the third percentile commonly used to denote growth retardation) was adopted, certain children will be classified as being consistent with this criterion for reasons other than prenatal exposure to alcohol (e.g., parents having short stature). However, because the diagnosis of FAS is made only when facial dysmorphia and CNS abnormalities also are present, the increased sensitivity achieved with the 10th percentile was selected.\nDifferential diagnosis of CNS abnormities involves not only ruling out other disorders but also specifying simultaneously occurring disorders. CNS deficits associated with FAS (especially functional deficits) can be produced by multiple factors in addition to prenatal alcohol exposure. Observed functional deficits should be determined not to be better explained by other causes. In addition to other organic syndromes that produce deficits in one or more of the previously cited domains (e.g., Williams syndrome and Down syndrome), disrupted home environments or other external factors can produce functional deficits in multiple domains that overlap those affected by FAS. In making a differential diagnosis of FAS, the clinician should evaluate CNS abnormalities in conjunction with dysmorphia and laboratory findings. CNS abnormalities resulting from environmental influences (e.g., abuse or neglect, disruptive homes, and lack of opportunities) are harder to differentiate. To assist with differential diagnosis between FAS and environmental causes for CNS abnormalities, clinicians should obtain a complete, detailed history for the person and family members.\nIn addition to ruling out other causes for CNS abnormalities, a complete diagnosis should identify and specify other disorders that can coexist with FAS (e.g., autism, conduct disorder, or oppositional defiant disorder). A particular person might have a conduct disorder in addition to FAS; however, not all persons with FAS have conduct disorders, and not all persons with conduct disorders have FAS. Certain functional deficits might lead to additional behavior problems. For example, a child with an attention problem also could have conduct disorder. Clinicians should consider organic causes, environmental contributions, and comorbidity for both inclusive and exclusive purposes when evaluating a person for a FAS diagnosis (32,39). Because differential diagnosis for CNS abnormalities within a FAS diagnosis is difficult, the evaluation should be conducted by professionals trained in both the features of FAS and those of a broad array of birth defects and developmental disabilities.\n# Conditions Consistent with a Subset of Diagnostic Criteria for FAS\nThe majority of persons with deficits resulting from prenatal exposure to alcohol do not express all the features necessary for a FAS diagnosis (36). Sufficient scientific evidence is not available to define diagnostic criteria for any prenatal alcohol-related condition other than FAS. Persons who have the neurodevelopment deficits required for a FAS diagnosis but who do not have all three facial features or growth deficits might not receive a diagnosis and so not be provided with services. Ongoing funding has been provided by the National Institute on Alcohol Abuse and Alcoholism to conduct research that might lead to evidence-based diagnostic criteria for persons with other conditions caused by prenatal alcohol use. CDC is using a collaborative database of neurodevelopment data from five intervention studies to explore the nature of persons who could be considered in the diagnostic category of alcohol related neurodevelopment disorder, as well as data from a prospective cohort study in Denmark of children aged 5 years. FAS is the only diagnostic category with scientific evidence to support clinical criteria at this time. As future data become available, these guidelines can be refined and expanded to delineate other conditions resulting from prenatal alcohol exposure.\n# Mental Health Problems and Other Lifelong Consequences\nFAS has lifelong consequences. Common FAS-related mental health conditions (excluding attention problems) reported include conduct disorders, oppositional defiant disorders, anxiety disorders, adjustment disorders, sleep disorders, and depression (37,(40)(41)(42)(43)(44). Although attention problems can be classified as a mental health issue or psychiatric condition, in these guidelines, they are treated as a primary deficit resulting from alcohol-related CNS damage rather than a secondary mental health concern (45). Decreased adaptive skills and increased problems with daily living abilities have been documented (e.g., dependent living conditions, disrupted school experiences, poor employment records, and encounters with law enforcement, including incarceration) among persons with FAS (37). These mental health-related consequences should not be used for diagnosis. However, they are prevalent among persons with FAS and are likely to result in referral and comprehensive diagnostic evaluation.\n# Referral Considerations\nProviders of medical, educational, and social services often must decide whether to refer a child, person, or family to a specialist for a full FAS diagnostic evaluation. This decision can be difficult. For biologically related family members, social stigma might be associated with any evaluation concerning prenatal alcohol exposure. In adoptive or foster families, alcohol use during pregnancy might be suspected, but direct information might not be available.\n# MMWR October 28, 2005\nThe following guidelines were developed to assist service providers in making referral decisions. Each case should be evaluated individually. When in doubt, providers should refer persons for a full evaluation by a multidisciplinary team with experience in evaluating prenatal alcohol exposure.\nThe following circumstances should prompt a diagnostic referral:\n• When prenatal alcohol exposure is known, a child should be referred for full FAS evaluation when substantial prenatal alcohol use (i.e., seven or more drinks per week, three or more drinks on multiple occasions, or both) has been confirmed. If substantial prenatal alcohol exposure is known, in the absence of any other positive criteria (i.e., dysmorphia, growth deficits, or CNS abnormalities), the primary health-care provider should document this exposure and monitor the child's ongoing growth and development closely. • When information regarding prenatal alcohol exposure is unknown, a child should be referred for full FAS evaluation for any one of the following:\n-any report of concern by a parent or caregiver (e.g., foster or adoptive parent) that a child has or might have FAS; -presence of all three facial features (i.e., smooth philtrum, thin vermillion border, and small palpebral fissures); -presence of one or more of these facial features, with growth deficits in height, weight, or both; -presence of one or more facial features, with one or more CNS abnormalities; or -presence of one or more facial features, with growth deficits and one or more CNS abnormalities. In addition to specific features associated with a FAS diagnosis, certain social and family history factors have been associated with prenatal alcohol exposure (46). The possibility of prenatal alcohol exposure should be considered fully for persons who are experiencing or have experienced one or more of the following:\n• premature maternal death related to alcohol use (either disease or trauma), • living with an alcoholic parent, • current or previous abuse or neglect, • current or previous involvement with child protective services agencies (PSAs), • a history of transient caregiving situations, or • foster or adoptive placements (including kinship care). Although such situations might have a negative impact on the development of any child, evidence exists that children with FAS or a related disorder are particularly likely to expe-rience negative situations that involve a dysfunctional family unit (46), especially if the biologic mother abuses alcohol.\n# Services for Persons with FAS\nFor persons with developmental disabilities and their families, diagnosis is never an endpoint. This is particularly true for persons with FAS, their families, and their communities. The diagnostic process (especially the neuropsychologic assessment) should be part of a continuum of care that identifies and facilitates appropriate health-care, education, and community services. Early diagnosis and a stable, nurturing home environment have been identified as strong protective factors for persons with FAS (46). Limited information is available regarding strategies for interventions specific to persons with FAS. Information available has been gathered primarily from the experience of persons with other disabilities and from that of parents gained through trial and error and shared through informal networks. Treatments currently employed to reduce the risk for adverse effects of FAS have not been evaluated systematically or scientifically. In 2001, CDC provided the first federal funding to develop and test systematic, scientifically developed interventions specific to FAS (e.g., a modified mathematics curriculum or a program to develop peer friendship skills). These projects are in their final stages, and findings will be published.\nThe learning and life skills affected by prenatal alcohol exposure vary among persons, depending on the amount, timing, and pattern of exposure and on each person's current and past environment (47,48). As a result, services needed for persons with FAS and their families vary according to the parts of the brain affected, the person's age or level of maturation, the health or functioning of the family, and the person's overall living environment. Thus, the service needs of affected persons and their families should be individualized (49). Certain general areas of service and specific services have been identified as helpful to persons with FAS and their families (32).\nInterventions should include strategies that stabilize home placement and improve parent-child interaction (47). One means of accomplishing this goal is to increase the understanding of the disorder among parents, teachers, law enforcement personnel, and other professionals who might become involved with the affected person. Children with FAS often need specialized parenting techniques because of their difficulty with cause-and-effect reasoning and other executive functioning skills (47). Caregiver education should highlight and explain differences in the thought processes of children with FAS compared with typically developing children and children with other developmental disabilities. This knowl-edge would enable parents to avoid potentially difficult situations (e.g., overly stimulating environments) and better manage problems when they do arise. Overall, a better functioning family that results from caregiver education promotes the stable, nurturing home that has been demonstrated to be a protective factor for children with FAS (50).\nProfessionals who work with persons affected by FAS could benefit from better understanding of the disorder and services available for affected persons and their families (39). These professionals can help link families with needed community resources and ensure that affected children receive maximum benefit from services provided. Interacting with social and educational service agencies can be overwhelming and confusing, and each agency typically uses a specialized vocabulary (i.e., jargon) that is difficult for nonspecialists to understand. In addition to being able to diagnose FAS, clinicians should help parents and caregivers identify available services, determine which ones are effective for their children, and understand how to work productively with service providers (32).\nPrenatally exposed infants and children often enter the foster or adoptive care system at an early age. The prevalence of children with FAS or a related disorder in the foster care system is estimated to be 10 times that of the general population (51). Although PSAs might have information regarding a child's prenatal history, PSA staff generally do not know about FAS, understand how FAS affects the child, or communicate with other service systems regarding the child's FAS status (51). As a result, foster and adoptive families typically are not educated regarding the long-term effects of FAS and are unprepared to meet their children's needs.\nThe majority of PSAs require foster parents to take a specified number of educational courses annually. These courses should include education regarding the effects and developmental needs of children with FAS because the majority of foster parents will encounter at least one child with FAS or a related disorder during their time as a foster parent (51). Projects funded by CDC have developed FAS curricula for parents, educators, and juvenile justice systems; information regarding these curricula is available at http://www.cdc.gov/ ncbddd/fas/awareness.htm.\nThe assessment process is integral to both the FAS diagnosis and the development of an effective treatment plan. Such a treatment plan minimizes risk factors for lifelong negative consequences and promotes protective factors that maximize developmental potential. Clinicians and service providers must ensure that assessments include communication and social skills, emotional maturity, verbal and comprehension abilities, language usage, and, if appropriate, referral for medication assessments. Finally, the health and development of children with disabilities, including children with FAS, can be promoted by public support for programs that provide access to school, recreational, and social activities.\n# Alcohol Use During Pregnancy\nBecause no safe threshold of alcohol use during pregnancy has been established, CDC and NTFFAS/FAE recommend that women who are pregnant, planning a pregnancy, or at risk for pregnancy should not drink alcohol. Women of childbearing age who are not pregnant should drink no more than seven drinks per week and no more than three drinks on any one occasion.\nFederal, state, and local agencies; clinicians and researchers; educational and social service professionals; and families should work together to educate women of childbearing age and communities countrywide regarding the risks of drinking alcohol during pregnancy. Women who have had at least one child with FAS are at especially high risk for giving birth to a second affected child (2,52). Universal screening for alcohol use among all women of childbearing age might help identify women who drink above recommended levels as well as those who drink and might become pregnant. Screening can be performed in clinicians' offices or in community health settings. Screening techniques that include measures of quantity, frequency, and heavy episodic drinking, as well as behavioral manifestations of risk drinking, have proven to be most beneficial; simple questionnaires have been developed to screen for problematic alcohol use among adults in multiple populations and settings (53).\nEffective prevention programs frequently employ a multicomponent approach that combines cognitive-behavioral techniques with norms clarification, education, and motivational enhancement interventions. For women who screen positive for hazardous alcohol use or abuse, brief interventions that use time-limited, self-help, and preventative strategies to promote reductions in alcohol use in nondependent persons and that facilitate referral of dependent persons to specialized treatment programs are low-cost, effective treatment alternatives (54)(55)(56)(57). The acronym FRAMES is used to encompass six key elements of the majority of successful brief interventions as follows: 1) feedback of personal risk, 2) responsibility for personal control, 3) advice to change, 4) menu of ways to reduce or stop drinking, 5) empathetic counseling style, and 6) self-efficacy or optimism regarding reducing or stopping drinking (58). Preconception counseling of women of childbearing age who are at risk for an alcohol-exposed pregnancy and who are not using effective contraception has been demonstrated as a promising method of prevention (59). Project CHOICES, funded by CDC, is an example of a brief intervention that has been effective. Information regarding this project and other federally sponsored studies of prenatal alcohol screening and intervention programs is available at http://www.cdc.gov/ncbddd/fas, http://www.niaaa.nih.gov, http://www.fascenter.samhsa.gov, and http://www.preventive services.ahrq.gov.\n# Summary of Recommendations\nOn the basis of a review of current scientific and clinical evidence, the following recommendations are made concerning referral of children and diagnosis of FAS:\n# Diagnosis of FAS\n• A diagnosis of FAS should be made if documentation exists of 1) all three dysmorphic facial features (i.e., smooth philtrum, thin vermillion border, and small palpebral fissures), 2) prenatal or postnatal growth deficit in height or weight, and 3) CNS abnormality. • The diagnosis should be classified on the basis of available history as confirmed prenatal alcohol exposure or unknown prenatal alcohol exposure. • CNS abnormality may be documented as structural, neurologic, or functional (Box).\n# Referral\n• If prenatal alcohol exposure is known, a child or person should be referred for full FAS evaluation when alcohol abuse (defined as seven or more alcohol drinks per week or three or more alcohol drinks on multiple occasions, or both) is confirmed. • If prenatal alcohol exposure is unknown, a child or person should be referred for full FAS evaluation when: -a parent or caregiver (foster or adoptive parent) reports that a child has or might have FAS; -all three facial features (i.e., smooth philtrum, thin vermillion border, and small palpebral fissures) are present; -one or more facial features are present in addition to growth deficits in height, weight, or both; one or more facial features are present and one or more CNS abnormalities; or -one or more facial features are present, with growth deficits and one or more CNS abnormalities. • In addition to specific features associated with the FAS diagnosis, the following social and family history factors associated with prenatal exposures to alcohol might indicate a need for referral:\n-premature maternal death related to alcohol use (either disease or trauma), -living with an alcoholic parent, -current or previous abuse or neglect, -current or previous involvement with child PSAs, -a history of transient caregiving situations, or -having been in foster or adoptive care (including kinship care).\n# Services\n• The FAS diagnosis and the diagnostic process (especially the neuropsychologic assessment) should be considered as part of a continuum of care that identifies and facilitates appropriate health-care, education, and community services. • General areas of service needs for persons with FAS and their families should include strategies that stabilize home placement, improve parent-child interaction through caregiver education, advocate for access to services, and educate service professionals involved with affected persons and their families regarding FAS and its consequences. • Specific intervention services should be tailored to a person's individual needs and deficits. These might include communication and social skills; emotional development; verbal and comprehension abilities; language usage; and, if appropriate, referral for medication assessments. • The needs of children in adoptive or foster placements should receive particular attention in the diagnostic and referral process.\n# Prevention\n• Federal, state, and local agencies; clinicians and researchers; educational and social service professionals; and families should work together to educate women of childbearing age and communities countrywide regarding the risks of drinking alcohol during pregnancy. • Universal screening by health-care providers for alcohol use is recommended for all women of childbearing age. • For women drinking at risk levels and not effectively using contraception, brief interventions have proven effective in reducing the risk for an alcohol-exposed pregnancy. • Because no safe threshold of alcohol use during pregnancy has been established, women who are pregnant, planning a pregnancy, or at risk for pregnancy should be advised not to drink alcohol. Women who are not pregnant, not planning a pregnancy, or not at risk for unintended preg-nancy should be advised to drink no more than seven drinks per week and no more than three drinks on any one occasion. • Additional information regarding these guidelines has been published (60).\n# MMWR October 28, 2005\ning on the amount, timing, and pattern of alcohol exposure (e.g., chronic exposure versus binge episodes). Despite this inherent variation in effects, areas of functional vulnerability have been observed consistently by clinicians and researchers with particular damage to corresponding structures reported (e.g., corpus callosum, cerebellum, or basal ganglia). For functional deficits, multiple locations in the brain (and corresponding functional capability) are generally accepted to be affected by prenatal exposure to alcohol. Functional deficits consistent with CNS abnormality criteria can be identified in two ways: 1) global cognitive deficit (e.g., decreased IQ) or substantial developmental delay in children too young for an IQ assessment or 2) deficits in three or more specific functional domains. These two ways of assessing functional CNS abnormality were adopted because of the composite nature of cognitive, intellectual, and developmental measures (15,16). Decreased performance on a standardized measure of cognition, intelligence, and development assumes deficits in multiple domains. In the absence of such a measure, multiple domains should be assessed individually to determine that multiple functional domains have been affected. For each domain, other agents and environmental factors can produce deficits or outcomes similar to prenatal alcohol exposure, making differential diagnosis essential.\nThe specific domains most often cited as areas of deficit or concern for persons with FAS are described below. These descriptions are intended to be suggestive and are examples of likely and possible problems a clinician might encounter and need to assess by using psychometric instruments. The examples are not intended to be exhaustive or to present a list of behaviors to be used as a checklist without reliable and valid assessment.\n• Cognitive deficits or significant developmental discrepancies. Global deficits or delays can leave the child scoring in the normal range of development but below what would be expected for the child's environment and background (17)(18)(19)(20)(21)(22). In addition to formal testing (either through records or current testing), behaviors that might be observed or reported in the clinical setting that suggest cognitive deficits or developmental delays that should be assessed by standardized testing include but are not limited to specific learning disabilities (especially mathematic or visual-spatial deficits), uneven profile of (22,(36)(37)(38).\nBehaviors that can be observed or reported in the clinical setting that indicate motor problems that should be assessed by standardized testing include but are not limited to delayed motor milestones, difficulty with writing or drawing, clumsiness, balance problems, tremors, and poor dexterity. For infants, a poor suck is often observed (17,(38)(39)(40). • Attention and hyperactivity problems. Attention problems are often noted for children with FAS, with children frequently receiving a diagnosis of attention-deficit hyperactivity disorder (ADHD) (41). Although such a diagnosis can be applied, attention problems for children with FAS do not appear to be consistent with the classic pattern of ADHD. Persons with FAS tend to have difficulty with the encoding of information and flexibility (shifting) aspects of attention, whereas children with ADHD typically display problems with focus and sustaining attention (42,43). Persons with FAS also can appear to display hyperactivity because their impulsivity might lead to increased activity levels. Behaviors that might be observed or reported in the clinical setting that suggest attention problems related to FAS that should be assessed by standardized testing include but are not limited to being described by adults as \"busy,\" inattentive, easily distracted, difficulty calming down, being overly active, difficulty completing tasks, and/or trouble with transitions.\nParents might report inconsistency in attention from day to day (e.g., \"on\" days and \"off\" days) (44-50).\n• Social skills problems. The executive, attention, and developmental problems described previously often lead to clinically significant difficulty for persons with FAS when interacting with peers and others. Because of the mental representation problems, persons with FAS often have social perception or social communication problems that make it difficult for them to grasp the more subtle aspects of human interactions (51,52). Consistent difficulty understanding the consequence of behavior or inappropriate behavior frequently is described for persons with FAS (53,54). Behaviors that can be observed or reported in the clinical setting that indicate these types of social difficulties that should be assessed by standardized testing include but are not limited to lack of fear of strangers, naiveté and gullibility, being taken advantage of easily, inappropriate choice of friends, preferring younger friends, immaturity, superficial interactions, adaptive skills significantly below cognitive potential, inappropriate sexual behaviors, difficulty understanding the perspective of others, poor social cognition, and clinically significant inappropriate initiations or interactions (55)(56)(57). Standardized assessment of social problems can be difficult; social functioning is a multifaceted domain that can require multiple areas of assessment. • Other potential domains that can be affected. In addition to these five most-often-cited problem areas, deficits and problems to be assessed by standardized testing can present in several other areas, including sensory problems (e.g., tactile defensiveness and oral sensitivity), pragmatic language problems (e.g., difficulty reading facial expression, and poor ability to understand the perspectives of others), memory deficits (e.g., forgetting welllearned material, and needing many trials to remember), and difficulty responding appropriately to common parenting practices (e.g., not understanding cause-andeffect discipline). Although abnormalities in these areas have been reported for persons with FAS, deficits in these areas are reported at a lower frequency than are those in the other five specific domains (53).\n# INSTRUCTIONS ACCREDITATION Continuing Medical Education (CME).\nCDC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CDC designates this educational activity for a maximum of 1.25 hours in category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Continuing Education Unit (CEU). CDC has been approved as an authorized provider of continuing education and training programs by the International Association for Continuing Education and Training. CDC will award 0.1 CEUs to participants who successfully complete this activity.\n# Continuing Nursing Education (CNE).\nThis activity for 1.3 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center's Commission on Accreditation. \n# What percentage of sexually active women of childbearing age do not use contraception effectively and drink alcohol frequently or binge drink, putting them at risk for an alcohol-exposed pregnancy?\nA. 1%-2%. B. 12%-13%. C. 20%-40%. D. 50%-75%.\n# The diagnosis of FAS includes which of the following criteria?\nA. Documentation of all three facial abnormalities (i.e., smooth philtrum, thin vermillion, and small palpebral fissures). B. Documentation of growth deficits.\nC. Documentation of central nervous system abnormalities. D. Documentation of mental retardation. E. A, B, and C. F. A and D.\n# Which of the following statements is true?\nA. One of the diagnostic criteria for FAS is mental retardation. B. Persons who have been exposed to alcohol prenatally but whose physical condition is not consistent with the criteria for FAS might have substantial cognitive deficits. C. All persons with FAS have attention deficit hyperactivity disorder. D. Persons with FAS are likely to have speech and language impairments but not fine motor deficits.\n# A person should be referred for a complete multidisciplinary diagnostic evaluation when…\nA. all three facial features are present. B. any concern is reported by a parent or caregiver that a child has or might possibly have been exposed to alcohol prenatally. C. a child is living with an alcoholic parent, or the biological mother died as a result of alcohol-related disease or trauma. D. all of the above. \n# Goal and Objectives\nThis report provides updated criteria for diagnosis of fetal alcohol syndrome (FAS) among persons affected by prenatal alcohol exposure. The goal of this report is to provide guidance for health-care providers in determining which persons might need referral for a complete multidisciplinary diagnostic evaluation and information regarding medical, educational, social, and family services appropriate for affected persons. Upon completion of this educational activity, the reader should be able to 1) describe the negative outcomes associated with prenatal exposure to alcohol, 2) list the specific criteria that constitute a diagnosis of FAS, 3) identify persons who should receive a referral for a multidisciplinary evaluation for FAS, 4) list services appropriate for a person receiving a FAS diagnosis, and 5) list instruments appropriate for screening women of childbearing age for alcohol use or abuse.\nTo receive continuing education credit, please answer all of the following questions. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":271,"cells":{"id":{"kind":"string","value":"8735edab7c82a8d3649d03ae67a6167cdebb0ed7"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"# CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR CARBON MONOXIDE\nrecommends that employee exposure to carbon monoxide (CO) at the workplace be controlled by requiring compliance with the standard set forth in the following eight sections.\nControl of employee exposure to CO at his place of employment at the limits stated will (1) prevent acute CO poisoning, (2) protect the employee from deleterious myocardial alterations associated with levels of carboxyhemoglobin (COHb) in excess of 5 percent and (3) provide the employee protection from adverse behavioral manifestations resulting from exposure to low levels of CO.\nThe recommended standard is measurable by techniques that are valid, reproducible and currently available to industry and governmental agencies and is attainable with existing technology. The recommended standard is designed to protect the safety and health of workers who are performing a normal 8-hour per day, 40-hour per week work assignment. It is not designed for the population-at-large and any extrapolation beyond the general worker population is unwarranted. Because of the well-defined relationship between smoking and the concomitant exposure to CO in inhaled smoke the recommended standard may not provide the same degree of protection to those workers who smoke as it will to nonsmokers. Likewise, under conditions of reduced ambient oxygen concentration, such as would be encountered by workers at very high altitudes (e.g., 5,000 -8,000 feet above sea level), the permissible exposure stated in the recommended standard should be appropriately lowered to compensate for loss in the oxygen-carrying capacity of the blood. In 1-1 addition, workers with physical impairments that interfere with normal oxygen delivery to the tissues (e.g., emphysema, anemia, coronary heart disease) will not be provided the same degree of protection as the healthy worker population. The criteria and the standard recommended in this docu ment will be reviewed and revised as necessary.\n\n# 1-2 (a) Concentration\n(1) Occupational exposure to carbon monoxide shall be controlled so that no worker shall be exposed at a concentration greater than 35 ppm determined as a time-weighted average (TWA) exposure for an 8-hour workday, as measured with a portable, direct reading, hopcalite-type carbon monoxide meter calibrated against known concentrations of CO, or with gas detector tube units certified under Title 42 of the Code of Federal Regulations, Part 84.\n(2) No level of carbon monoxide to which workers are exposed shall exceed a ceiling concentration of 200 ppm.\n\n# (b) Calibration, Sampling and Analysis\nProcedures for calibration of equipment, sampling and analysis of CO samples shall be followed as provided in Appendix I.\n\n# Section 1 -Work Environment 1-3\nBecause employees with overt cardiovascular disease may not be protected by an occupational exposure to 35 ppm of CO, a medical program should be instituted consisting of preplacement and periodic examinations with special attention to the cardiovascular system and to medical con ditions which could be exacerbated by exposure to CO. Such a medical program could also provide the opportunity for conducting antismoking programs for high-risk employees. Areas where significant exposure to carbon monoxide is likely to occur shall be posted with a sign stating:\n\n# CARBON MONOXIDE (CO) DANGER High concentrations may be fatal\nProvide adequate ventilation High concentrations in air may be explosive\nSeek immediate medical attention if you experience any of the below symptoms:\n1 -Severe Headache 2 -Dizziness 3 -Nausea and vomiting Gas masks are located: (Specific location to be filled in by employer) For purposes of this section the term \"significant exposure to carbon monoxide\" refers to eight-hour TWA exposures exceeding 25 ppm but excludes such exposure as may be self-administered through smoking.\nIn the event of an emergency or when a variance has been allowed and the use of respiratory protective equipment authorized by the Secretary of Labor, the employer shall provide and insure that the employee wears, as appropriate, one of the following respiratory protective devices approved by NIOSH or the Bureau of Mines as provided in Part 11 of Title 30, Code of Federal Regulations: (a) Type N Gas Mask (Emergency Situation):\nFor entry into or escape from an environment containing not over 20,000 ppm, which is not deficient in oxygen, for a total exposure period of not more than 30 minutes. Areas in which large amounts of CO are stored, used or emitted, or areas within the workplace through which large amounts of CO are trans ported, shall be provided with sufficient respiratory protective devices of the types specified in Section 4 and shall be readily accessible to persons who may be located in the area to assure a timely, orderly evacuation of the area by all persons in the event of accidental, massive release of CO.\nAn automatic visual and audible alarm that is set to be activated when the CO concentration reaches 500 ppm should be employed in such areas. Employees working in such areas shall be informed of the hazards and symptoms of acute CO poisoning (see Section 6) and shall be trained to implement an emergency evacuation plan designed for such an occurrence. Periodic drills, held not less frequently than every six months, shall be conducted to assure that such plans are adequate and effective in case of an emergency situation.\n(c) Fire Hazards Adequate fire extinguishing agents shall be readily available in the areas outlined in paragraph (b) of this section since CO will burn when mixed with air and may be explosive when concentrations of between 12.5 percent to 74.2 percent are reached.\nSection 5 -Emergency Procedures 1-7 (a) Each employee who receives significant exposure to carbon monoxide shall be apprised of all hazards, relevant symptoms, appropriate emergency procedures, and proper conditions and precautions for the safe use of CO or safe exposure to CO and shall be instructed as to the location of such information, which shall be kept on file as prescribed in paragraph (b) of this section and shall be readily accessible to all employees at each establishment where CO is involved in industrial processes and operations. (a) Each container in which CO is stored shall be examined for leaks upon its arrival at the establishment or upon filling and shall be reexamined periodically at least every three months.\n(b) Prior to transferring CO from a storage container, an inspection shall be conducted to detect any gas leaks in the transport system (e.g., cylinder seal with gas regulator, regulator apparatus, regulator seal with transport conduits, conduit system, etc.). (1) Personal exposure (\"breathing zone\") samples- shall be collected in accordance with procedures specified in Appendix I in all workplaces where employees are significantly exposed to CO , Samples will be collected and evaluated as both TWA and ceiling concentration values.\n(2) Frequency of monitoring should be at least annually. It is recognized that more frequent monitoring may be indicated in certain circum stances depending upon the nature of the process, the rate of production, the effectiveness of control measurements, the time of day and seasonal variation, however, more frequent monitoring requirements cannot be recommended until there are extensive studies of specific operations in industry.\n(3) Blood analysis for COHb, as specified in Appendix II, shall be performed on all persons employed in work areas when, in the judgment of the OSHA Industrial Hygienist, biologic standards are needed to evaluate borderline exposure to CO (see Chapter V). and experiments and any other information available to him which will assure insofar as practicable that no employee will suffer diminished health, functional capacity, or life expectancy as a result of his work experience.\nThe National Institute for Occupational Safety and Health (NIOSH), after a review of data and consultations with others, formalized a system for the development of criteria upon which standards can be established to protect the health of employees from exposure to hazardous chemical and physical agents. It should be emphasized that any criteria documentation for a recommended standard should enable management and labor to develop better engineering controls and more healthful work practices and should not be accepted as a final goal in itself.\n1 In evaluating occupational hazards and setting priorities, it was determined that the potential for exposure of employees at the workplace to CO was greater than that for any other chemical or physical agent.\nThe significance of the CO dose-response relationship in man is attested furthermore by numerous research studies which have been documented in II-l the scientific literature. In a recent conference on the biological effects of CO sponsored by the New York Academy of Sciences, the findings and views of scientists from the United States, Australia, England, France, and 2 Denmark were presented.\nBackground information for this report was obtained from many sources, including those directly cited and listed in the references. In addition 3 there is a bibliography of nearly 1,000 references and abstracts on CO The criteria contained in this document were developed to assure that the recommended standard based thereon would (1) protect employees against both acute and chronic CO exposure, (2) be measurable by techniques that are valid, reproducible and available to industry and governmental agencies and (3) be attainable with existing technology.\n\n# II-2\nIn 1969 the Committee on Effects of Atmospheric Contaminants on Human Health and Welfare, appointed by the Environmental Studies Board of the National Academy of Sciences, reported on the evaluation of current knowledge concerning the effects of CO on man.^ While this report deals primarily with the effects on man of exposure to CO from air pollution sources, it is pertinent to note the following statement in the Introduction: \"...Today, the two main sources of carbon monoxide appear to be cigarette smoke and the internal combustion engine. And the subject of concern has changed from the acute effects of short-term exposure...to the lasting effects of long-term, low-level exposure, of a duration anywhere from a month to a lifetime, and in the range of CO concentrations that would produce 0.5-10% COHb.\" Thus, in the case of occupational exposures to CO, a worker's smoking habits must be taken into consideration when evaluating the environment. This factor has not been generally considered until the past few years.\nIt should be emphasized that the above report raised many questions concerning the effects of low-level exposures to CO, and that Committee recommended many additional research studies in this area.\nAlthough important evidence exists which indicates that subtle aber rations may occur in the central nervous system (CNS) during exposure to levels of CO lower than those of the recommended standard, the significance of these changes and their translation to effects upon employee safety and health is not entirely clear. The diversity of opinions and the conflicting experimental evidence existing in this area does not permit the clear-cut assessment of the scientific merit of such data or its extrapolation to the normal working population at this time. If reliable data become available which clearly demonstrate significant impairment of employee II-3 behavior during exposure to very low levels of CO (producing less than 5 percent COHb), then the criteria for the recommended standard will be reassessed on the basis of the additional evidence.\n\n# II-4 III. BIOLOGIC EFFECTS OF EXPOSURE TO CARBON MONOXIDE\nCarbon monoxide (CO) is an odorless, colorless, tasteless gas which is an active reducing agent for chemicals at elevated temperatures, but is principally encountered as a waste product of incomplete combustion of carbonaceous material. A summary of the physical properties is presented in Table I. The best understood biologic effect of CO is its combination with hemoglobin (Hb) to form carboxyhemoglobin (COIIb) , thereby rendering the hemoglobin molecule less able to bind with oxygen. This action of CO results in more persons succumbing each year to acute CO poisoning than to any other single toxic agent, except alcohol.6\n\n# Extent of Exposure\nWith the single exception of carbon dioxide (CO2X total emissions of CO each year exceed those of all other atmospheric pollutants combined.\nIn 1968 it was estimated that 102 million tons of CO were released into the atmosphere by the major sources of emission.^ Over one-half of this amount (58 percent) was produced by the gasoline-powered internal combustion engine. Specified industrial processes accounted for approximately 10 percent of the total. A summation of CO emission estimates for 1968 by specific industrial processes is presented in Table II.\nFrom Table II it can be observed that large amounts of CO are emitted from petroleum refineries, iron foundries, kraft pulp mills, sintering mills, lampblack plants and formaldehyde manufacturers. Major sources of CO production within the first four industries have been identified as the cupola in the iron foundry, the catalytic cracking units in the petroleum refineries, the lime kilns and the kraft recovery furnaces in the kraft paper mills, and the sintering of blast furnace feed in sintering plants.\n\n# III-l\nAside from the above major industrial processes which produce large quantities of CO, there are numerous operations (arc welding, automobile repair, traffic control, tunnel construction, etc.) where the occupational exposure for a worker to CO can be considerable. In fact any industrial process or operation where incomplete combustion of carbonaceous material occurs may easily be of consequence as concerns occupational exposure to CO.\n\n# Historical Reports and Theoretical Considerations\nMan's intimate association with carbon monoxide as a true environmental hazard began with his discovery of fire. Since that time his technological history has been one of advancement by means of incomplete combustion. The seriousness of exposure to high concentration of CO has been realized since the earliest medical writings. The Greeks and Romans used exposure to CO 7 as a means of execution of criminals and committing suicide.\nPriestly discovered the chemical composition of CO in the late 18th within the range, 220 to 290 and later investigations have generally confirmed this range, although at a slightly lower level, under conditions of complete hemoglobin saturation by oxygen and CO.^ ^ Briefly, the affinity constant may be expressed as the number of moles of oxygen which must be present with each mole of CO in order to maintain an equal saturation of hemoglobin. While CO actually combines less rapidly with reduced hemo globin than does oxygen, the tenacity of the binding between CO and hemo globin is some 200 to 300 times that of oxygen. This saturation of hemoglobin by either oxygen or CO occurs in four steps involving intermediates with four equilibrium constants:\nk' k' Hb4 + X ^ XHb4 KX = k '2 XHb . + X (X) 0Hb . K9 = ; --- 4 k.2 2 4 ^ k-2 ill k,3 (X)2Hb4 + X £ = ? <X)3Hb4 K3-Rj- k '4 k 'i (X)3Hb4 + X ^ (X)4Hb4 K4 -Î\nn the above equations, X represents either oxygen or CO with a different equilibrium constant for each equation. It has been determined that in both cases is much higher (18 to 50 times higher) than K-^, K2 , or K3 because k'^ is much greater than Under these circumstances the last ligand to bind to hemoglobin (K^ equation) dissociates much more 15 readily than it binds.\nThe differences between the four constants depend on intra-molecular forces occurring as a result of the interactions of each III-3 ligand with the others, or with other portions of the hemoglobin molecule.\nHence, the effect is an allosteric one resulting in conformational changes in the hemoglobin molecule. These differences in reaction rates affect the dissociation of oxygen or CO from hemoglobin such that, as can be observed in Figure 1, the shapes of the respective dissociation curves are sigmoidal rather than parabolic, as is the case with myoglobin, which possesses only 16 one heme group with a single dissociation constant.\nLikewise\n\n# III-4\nThe difference in the partial pressure of oxygen (Pq^) between freshly oxygenated arterial blood (P = 100 mm Hg) and mixed venous blood°2 (P = 40 mm Hg) represents a release to the tissues of approximately Oo 16 5 milliliters 0^/100 milliliters blood.\nA shift of the steep portion of the oxyhemoglobin dissociation curve to the left would tend to change the release of oxygen to the tissues appreciably.\nWhile the dissociation curve shifts to the right, allowing for a more efficient dissociation of oxygen to the peripheral tissues under conditions of reduced ambient oxygen tension (hypoxic hypoxia), just the opposite 4,16,19,21 situation occurs during exposure to CO (anemic hypoxia).\nThe leftward shift during CO exposure occurs because of the much greater affinity of CO for hemoglobin and in spite of the fact that the amount of oxygen in 4 physical solution in the blood remains near normal.\nThe oxygen content of the blood is not only lowered during exposure to CO, but the shift of the oxyhemoglobin dissociation curve to the left decreases the amount of remaining oxygen that is made available to the tissues. As mentioned earlier in this report it has been confirmed that an 51 52 endogenous source of CO exists as a product of heme catabolism. '\n\n# III-8\nWhen an ct-methylene bridge in the heme portion of hemoglobin is broken during 51 the catabolic process, a molecule of CO is released.\nIt has been estimated that this production amounts to approximately 0.3 to 1.0 milliliter(ml)/hour with an additional 0.1 milliliter(ml)/hour resulting from a similar catabolic process involving other heme-containing compounds (e.g., myoglobin and cyto-6,53 chrome and catalase enzymes).\nThis endogenous production of CO, which gives rise to approximately 0.5 to 0.8 percent COHb, would not be expected to be of important physiologic consequence per se since the hypothesized mechanism has evolved with man, but its removal would merit due consideration in a closed system such as a submarine or a space capsule. Also, in the determination of total CO exposure this quantity must be included as \"base line\" COHb.\n\n# Cardiovascular Effects of CO\nThe critical importance of cardiovascular involvement during exposure 6,28,49-6*0 to CO is becoming increasingly evident.\nWhile the brain has a higher requirement for oxygen than the heart, in contrast to the cerebral circulation the coronary circulation must supply an even increased amount of oxygen during periods of generalized tissue hypoxia; since under these circumstances the heart is forced to increase both its rate and its output 49 in order to meet the normal oxygen demands of the body.\nThis increase in myocardial activity demands an increased oxygen supply to the myocardium which must be met by the coronary circulation. Under hypoxic conditions increased oxygen supply to the peripheral tissues can be accommodated by increased blood flow (via vascular dilatation) and/or increased oxygen extraction by the tissues. As mentioned earlier the peculiar dissociation characteristics of O^Hb permits an oxygen reserve which is used at reduced III-9\nP . The myocardium under these circumstances appears only to increase 2 the flow of blood rather than to extract an additional amount of oxygen from the coronary circulation. While the peripheral tissues normally extract only 25 percent of the oxygen content of the perfusing arterial blood during resting conditions, the myocardium extracts 75 percent, thus leaving the mixed venous blood only 25 percent saturated. This mechanism has the overall effect of maintaining the myocardial oxygen tension at a higher level than would be present in other muscle tissue and thus insures a continual aerobic metabolism, even under hypoxic duress. In terms of oxygen tension, the mixed venous blood of the peripheral tissues is approximately 40 mm Hg while the mixed venous blood of the coronary circulation is only 20 mm Hg. In the presence of COHb (and the shift to the left of the oxyhemoglobin dissociation curve), however, the arterio-venous difference can only be maintained by an increased flow in the coronary circulation.\nIn an individual with diminished coronary circulation because of coronary heart disease, however, this situation may result in a decrease in the mixed venous oxygen tension of the myocardium precipitated by an inability to maintain the normal arterio-venous gradient. This hypoxic effect is further enhanced, as mentioned above, by an increase in cardiac rate and output as a general response to peripheral tissue hypoxemia. A person with diminished coronary circulation caused by coronary heart disease, consequently, may be constantly near the point of myocardial tissue hypoxia. This exposure to CO increased the COHb slightly less than 1 percent per minute. It appears that the canine may be able to tolerate a much higher level of COHb than is the human before significant myocardial changes occur.\n\n# Jaffe\nhas emphasized the relationship between CO poisoning and an elevated titer of serum lactic dehydrogenase as an indicator of myocardial damage. He speculated that \"...even 'normal' amounts of carbon monoxide may operate as the last straw in precipitating coronary attacks.\" Mien rats 65 were exposed to 500 ppm CO for four hours Lassiter, Coleman, and Lawrence observed a statistically significant aberration in the plasma lactic dehydrogenase isoenzyme distribution which was considered to be highly indica tive of myocardial damage. The COHb level in the animals at termination of exposure was <40 percent.\nThe relationship between chronic cigarette smoking and increased risk of 66 coronary heart disease (CHD) is undeniable, as is the fact that cigarette smoking causes increased exposure to CO. A CO concentration of 4 percent (40,000 ppm) in cigarette smoke, which will cause an alveolar concentration of 0.04 to 0.05 percent (400 to 500 ppm) will produce a COHb concentration 6,67-69 70 3 to 10 percent.\nGoldsmith estimated that the cigarette smoker is exposed to 475 ppm of CO for approximately six minutes per cigarette.\nIn a review article on CO and human health} Goldsmith and Landaw stated that the COHb level in the one-pack-a-day cigarette smoker is 5.9 percent, which they say is a sufficient concentration to impose a serious health threat to persons with underlying vascular insufficiency.\nIn another paper these two investigators used a regression analysis of expired air samples from 3,311 longshoremen and found a COHb of 6.8 percent in two-pack-a-day smokers and 1.2 percent COHb in nonsmokers. They believed that the high level in the nonsmokers, above the 0.5 to 0.8 percent normally present as a result of endogenous production, was accounted for by occupa tional exposure.\nIn a study by Kjeldsen\"^ COHb levels of both smokers and nonsmokers were compared from 934 'tHD-free\"persons. The mean COHb was 0.4 percent for nonsmokers and 7.3 percent for cigarette smokers who inhaled. In addition, the mean level of COHb for all 416 smokers in the study, regard less of inhalation habits or number of cigarettes smoked, was 4.0 percent.\nA similar study is presently being conducted to determine the range 72 of COHb in the American public by Stewart and Peterson. The presently available data, from Milwaukee, has demonstrated that the mean COHb levels for nonsmokers is 1.33 ±0.85 percent and for smokers is 4.47 ±2.52 percent. In an epidemiologic survey involving approximately 4,000 middle-aged males, who were kept under medical surveillance for 8 to 10 years, Doyle 74 and co-workers found that one-pack-a-day smokers had about a three-fold greater risk of myocardial infarction than did nonsmokers, or former smokers.\nThe finding that death rates for ex-smokers were no higher than for 16 nonsmokers prompted Bartlett to state that the effect of cigarette smoking on this particular pattern is completely reversible when an individual ceases to smoke. He concluded that smoking caused a myocardial hypoxemia by some acute, reversible process, which was probably unrelated to the formation of hard, irreversible, atherosclerotic lesions and that CO would fit such an epidemiologic pattern very well. He further stated, however, that other components of cigarette smoke, including nicotine, may be responsible for this pattern and that the question, in his estimation, remained unsolved.\nAstrup, Kjeldsen, and Wanstrup,^ reporting on an investigation in progress in 19 70 in which 1,000 randomly chosen individuals were examined for evidence of arteriosclerotic disease, demonstrated a clear relationship between this disease and high COHb levels after smoking. They further stated that it is very likely \"...that it is the inhalation of CO in tobacco smoke that is, in part, responsible for the much higher risk of smokers to develop coronary heart disease and other obliterating arterial diseases in comparison to that of nonsmokers.\" pain in the patients exposed to 50 ppm for four hours. The same level of significance was also found for the patients exposed to 100 ppm although the differences of results between the two regimes were not significantly different. The other parameter measured, duration of pain, was statisti cally significant (p <0.05) only for the patients exposed to 100 ppm CO.\nAgain the differences of results between the lower and higher exposures were not significant. Knelson concluded, using this particular protocol of exposure, that patients with angina pectoris who were exposed to CO and then exercised experienced pain earlier and pain lasted longer, than when these same patients were exposed to ambient air.\nAn interesting set of data has been produced recently by Horvat and 7Q co-workers ' concerning the effect of oxygen breathing on the threshold of angina pain in patients with confirmed coronary heart disease. The investigators first determined the angina threshold while the patients breathed air by increasing the heart rate via right atrial pacing. Patients were then, unknowingly, switched to 100 percent oxygen and the heart paced to the previously determined angina threshold. Angina pain did not occur in nine of eleven patients. Associated with this improvement was increased lactate extraction from an average of -17 ±15 to +18 ±10 percent (p <0.025).\nIn four of six patients lactate production turned to lactate extraction, in six of seven patients S-T abnormalities in the EKG were improved as well as improvement in pulsus alternans in three of five patients. These data present significant evidence that oxygen breathing permits the heart to do more work before coronary insufficiency develops. They also indicate the validity of the approach used by Knelson in determining Lloyd and co-workers noted that while certain areas (e.g., janitors) had an excess of deaths due to heart disease, other areas had a deficit in this specific cause of mortality.\nIn attempting to determine why an apparent selection for health should have been more likely among steelworkers dying from heart disease, it was\nsuggested that such persons may have been more likely to migrate between work areas. Thus, employees exhibiting symptoms of cardiac insufficiency (e.g., shortness of breath) may move to less physically demanding jobs on their own. Similarly, employees with CHD who return to work following an attack are often returned to less physically demanding jobs (e.g., janitors and mechanical maintenance). As a result the investigators indicate that selection for health may have been more important than environmental factors in explaining the excess in mortality from heart disease among janitors and mechanical maintenance personnel. If this suggestion is correct, then the work areas from which those employees dying from heart disease migrated would not be expected to show similar increases in deaths from heart disease. For example, if these employees migrated from the areas aforementioned that produce significant exposure to CO, then those areas would be expected to have a lower SMR for heart disease. Although this rate for those areas was not published in the paper, because of statistical insignificance, the SMR for all deaths in those areas, as mentioned, did not demonstrate trends which were statistically significant.\nBased upon this study, then, it would not seem possible either to infer or to deny that occupational exposure to CO at the three work places in question resulted in an excess of deaths due to heart disease.\nMore information is needed concerning daily exposure of workers, engaged in various levels of activity, to specific sources of CO within their working environment and the correlation of such information to both smoking habits and to nonoccupational exposure.\n\n# III-32\nRegardless of CO source, however, the rate of CO excretion from the blood is dependent upon the concentration in the ambient air, and for smokers with elevated COHb levels who are occupationally exposed to CO, their excretion of CO will be proportionally delayed.\nBecause the recommended standard for occupational exposure to CO is designed to protect employees with CHD, it is necessary to characterize the extent of this disease among the general worker population.\nFriedberg has defined CHD to represent clinical heart disease due to lesions of the coronary arteries. However, the term, CHD, is generally used to refer to the process of atherosclerosis of the coronary arteries leading to disturbances in the myocardial blood supply. It is in this latter context that the term applies in the criteria document.\nIt is an established fact that each year more persons in the U.S. die 103 from CHD than from any other disease.\nCoronary atherosclerotic heart 104 disease is the most common form of cardiac disease in adults in the U.S.\nDuring the Korean War autopsies performed on young soldiers, with an average age of twenty-two years, revealed that 77.3 percent had gross pathologic 104 , 105 \" evidence of CHD.\nA study of autopsies in a stabilized population of 30,000 revealed that CHD was the cause of death in 40 percent of the males.\n\n# Friedberg states:\n\"The diagnosis of coronary (atherosclerotic) heart disease refers to clinical manifestations and not to the mere presence of atherosclerotic lesions. Extensive pathologic lesions may be present but cannot be diagnosed unless they produce overt clinical manifestations or are revealed by coronary angiography.\"\nIn most cases the first clinical manifestation of CHD is expressed''\"ê ither as the angina pectoris syndrome or as frank myocardial infarction.\n\n# III-33\nAccording to the Framingham, Massachusetts, study conducted by the USPHS, CHD was first manifested in one-sixth of the cases of CHD as sudden death. produced in the myocardium of patients with coronary artery disease during acute exposure to concentrations of CO sufficient to produce a COHb content of less than 9 percent provides metabolic evidence of myocardial hypoxia occurring under this regime. His finding that in patients with coronary artery disease the coronary blood flow did not increase at this level of COHb saturation, although it did increase in controls, serves to further underscore the possible consequences for an individual with coronary heart disease (CHD) who is carrying less than 9 percent COHb. Furthermore, it 111-35 must be emphasized that these coronary patients were at rest and were not subjected to exercise. The consequences of this additional stress were 7 8 documented earlier in the study by Knelson. His discovery that the time to onset of pain was diminished in cigarette smokers with angina pectoris during exercise immediately following exposure to 50 ppm of CO for four hours (average COHb of 3.0 percent), provides considerable evidence that workers with CHD, and particularly those with CHD who smoke, should not be exposed to concentrations of CO which will produce a level of COHb in excess of 5 percent.\nSimilarly, the effects of CO on behavior are not in complete agreement.\nAs mentioned previously, several mechanisms have been suggested to possibly account for the differing results. These suggestions can be summarized by noting that no one study has completely replicated the experimental design of any previous study that indicated a behavioral impairment due to CO Because the emission of CO is on so large a scale it becomes difficult to single out, identify and rank individual sources in order of importance as concerns occupational exposure. Indeed, as emphasized earlier in this report, the smoking habits of the worker have a tremendous bearing on his actual daily exposure to CO. The CO pollution from traffic to and from the place of employment likewise will affect his total daily exposure.\nSeveral studies concerning occupational exposure to CO are presented below. The investigators commented on the results of the study by saying:\nV-6\nto recognize the effect that the level of activity has upon the uptake of CO and to judiciously evaluate the exposure of his employees and limit their activity accordingly. The data in Appendix IV have been included specifically for this purpose. In addition, the employer must give special consideration to limiting the activity of employees exposed to CO at high altitudes in order to compensate for the dual loss in oxygen-carrying capacity of the blood.\nV-7\n\n# VI. COMPATIBILITY WITH AIR QUALITY STANDARDS\nThe Environmental Protection Agency (EPA), under provisions of the Clean Air Act (PL 91-604), promulgated national primary and secondary air quality 123 standards on April 30, 1971.\nThe primary and secondary standards for \"in the comments, serious questions were raised about the soundness of this evidence. Extensive consideration was given to this matter. The conclusions reached were that the evidence regarding impaired time-interval discrimination had not been refuted and that a less restrictive national standard for CO would therefore not provide the margin of safety which may be needed to protect the health of persons especially sensitive to the effects of elevated carboxy hemoglobin levels. The only change made in the national standards for CO was a modification of the 1-hour value. The revised standard affords protection from the same low levels of blood carboxyhemoglobin as a result of short-term exposure. The national standards for carbon monoxide, as set forth below, are intended to protect against the occurrence of carboxyhemoglobin levels above 2 percent. It is the Administrator's judgment that attainment of the national standards for carbon monoxide will provide an adequate safety margin for protection of public health and will protect against known and anticipated adverse effects on public welfare.\"\n\n# VI-1\nThe air quality standard is designed to protect the population-at-large and takes into consideration 24-hour per day exposure of the very young, the very old, and the seriously ill. The evidence presented in this (NIOSH) criteria documentation supports the concept of the necessity of providing protection for that portion of the general worker population with coronary heart disease (CHD), who are especially sensitive to elevated levels of COHb.\nAlthough the Administrator of EPA has stated above that the evidence concerning the impairment of time-interval discrimination at low levels of COHb, presumably as low as 2 percent, has not been refuted, neither has such evidence been confirmed.\nVI-2\n\n# VII. APPENDIX I SAMPLING AND ANALYSIS OF CARBON MONOXIDE (CO)\nWorker exposure to CO shall be measured with a portable, direct reading, hopcalite-type carbon monoxide meter calibrated against known concentrations of CO, or with gas detector tube units certified under Title 42 of the Code of Federal Regulations, Part 84. Samples shall be collected from the worker's breathing zone and a sufficient number shall be collected at random intervals throughout the workday so that a statistically accurate determination of compliance may be made as outlined in the following section.\n\n# Principles for Air Sampling for Carbon Monoxide (CO)\nThe characteristic manner in which CO proceeds from the pulmonary alveolar spaces, through the blood capillary membrane \"barrier,\" into the plasma, through the red blood cell membrane, ultimately to combine with hemoglobin imposes certain requirements for air sampling if proper deter mination of compliance with the recommended standard is to be made. The rate of CO diffusion from the lung to hemoglobin depends upon the partition coefficient for CO between alveolar air and pulmonary blood. The magnitude of this coefficient is such as to delay transfer of CO to the circulating hemoglobin (Hb). This time delay makes it essential in any estimation of the carboxyhemoglobin level to know how long the exposure was experienced as well as the CO concentration during the exposure. Reference to Figure 2 shows that a continuous exposure of over eight hours' duration is required to attain maximum combination of CO with hemoglobin at the recommended standard of 35 ppm.\n\n# Air Sampling Methods\n\n# VIII-1\nThe sampling and analytical procedures recommended below will provide the necessary data to determine compliance with the recommended standard.\nThe methodology and equipment utilized to collect and analyze samples to determine concentrations of CO in the air or concentration of COHb in the exposed worker shall be subjected to a proficiency and/or calibration test program conducted by NIOSH or by another agency of the federal govern ment under agreement with NIOSH for certification for such determinations.\n\n# Determination of Compliance\nThe following procedure shall be used to determine compliance with the eight-hour, time-weighted average standard based on a small number of instantaneous (grab) samples collected at random intervals during the workday.\nGiven: the results of r i samples with a mean m and a range (difference between least and greatest) jr. If, for from 3 to 10 samples, m is greater than the total of: An extensive review of the methodology covering the determination of 12 4 carbon monoxide has been prepared by Maehly. In an updating review of Because carboxyhemoglobin constitutes the toxic product formed during carbon monoxide intoxication, and because the carboxyhemoglobin formed is quite stable, the analyst is presented with the opportunity of directly evaluating the toxic agent. In so doing, two facts are established:\n(1) proof that an exposure has occurred, and (2) quantitative proof the exposure has produced a particular toxic concentration in the body.\nDiffusion, chromatographic and gasometric methods all involve liberation of carbon monoxide from hemoglobin and either gasometric transfer operations or secondary titrations which are technically difficult for the microliter gas volumes involved. This limitation is even more critical when the effects of temperature and pressure on gas volumes are considered. Careful evaluation of the methods for direct measurement of carboxyhemoglobin has been reviewed in detail. Of these methods, three are considered to be feasible for con sideration as the recommended method.\n\n# (a)\nThe colorimetric method of Amenta uses small blood samples and measures the absorbance of an ammonia-hemolyzed sample at three wave-length\n\n# Analytical Methodology\nIX-1 settings on the spectrophotometer: 560, 575, and 498 nm. In calculating the results, the absorbance of the mixture at 498 nm (an isosbestic point) is the denominator in the equation for oxyhemoglobin, carboxyhemoglobin, and the unknown. This mathematical manipulation gives a value corrected for the total hemoglobin concentration (i.e., the R factor). The values (IL = 1.097, R = 0.057) are then used for calculating percentage COHb by 2 the ratio R^ -R^/R^^-R^q XIOO = percentage COHb. The relatively small absorbance difference observed with this method reduces its precision and accuracy, especially in the low COHb range (ca. 10 percent).\n\n# (b) The method of Harper\ninvolves hemolyssis of blood by distilled water, addition of a buffer (pH 7.2) and reduction of oxyhemoglobin by sodium hydrosulfite. The reduced hemoglobin is then converted to methemoglobin by the addition of potassium ferricyanide. The carboxyhemoglobin is converted to methemoglobin at a slower rate than reduced hemoglobin; therefore, the carboxyhemoglobin can be measured before appreciable conversion to methemoglobin takes place. The method requires a careful control of timed manipulations to obtain reproducible results.\n\n# Range and Sensitivity\nFor 1 ml of oxalated blood the range is 0 to 100 percent saturation COHb. Sensitivity is 0.5 percent saturation.\n\n# Interferences\nHemolyzed blood contains pigments arising from the breakdown of hemoglobin and will cause interference in the method. Bile pigments may also interfere.\n\n# Precision and Accuracy\nThe difference in concentrations obtained by this procedure and compared to results obtained on the same samples analyzed by the Van Slyke method are not significant at the 5 percent level [t-Value = 1.81 (14 deg. (A) Chemical stability, incompatibility, hazardous decomposition products, and hazardous polymerization.\nX-2 (A) Detailed procedures to be followed with emphasis on precautions to be taken in cleaning up and safe disposal of materials leaked or spilled.\nThis includes proper labeling and disposal of containers containing residues, contaminated absorbants, etc.\n(ix) Section VIII. Special Protection Information.\n(A) Requirements for personal protective equipment, such as respirators, eye protection and protective clothing, and ventilation, such as local exhaust (at site of product use or application), general, or other special types.\n(x) Section IX. Special Precautions.\n(A) Any other general precautionary information, such as personal protective equipment for exposure to the thermal decomposition products listed in Section VI, and to particulates formed by abrading a dry coating, such as by a power sanding disc.\n(xi) Hie signature of the responsible person filling out the data sheet, his address, and the date on which it is filled out.\n(xii) The NFPA 704M numerical hazard ratings as defined in Section (c) (5) following. The entry shall be made immediately to the right of the heading, \"Material Safety Data Sheet\" at the top of the page and within a diamond symbol preprinted on the forms.\nN i in O ir - -1 - - - - - - - - - - - - - - - - - - - - (M ao r» < NO »o m < r\"\n< u e O o O O O o o o O o ' J o O O O O o O 0 0 - - - - - - - - - - - - - - - - - - - - o o O O o *»? o o o c o o CJ o o O í j O o o H\nO o © O o o o o o o o O O O © © O o © O - - - - - - - - - - - - - - - - - - - - © o © © © © © © o o © © © o o © c © o o C M ro 4- tn o O' <\\l i f s co «4 4-f-o rr. 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The recommended standard is designed to protect the safety and health of workers who are performing a normal 8-hour per day, 40-hour per week work assignment. It is not designed for the population-at-large and any extrapolation beyond the general worker population is unwarranted. Because of the well-defined relationship between smoking and the concomitant exposure to CO in inhaled smoke the recommended standard may not provide the same degree of protection to those workers who smoke as it will to nonsmokers. Likewise, under conditions of reduced ambient oxygen concentration, such as would be encountered by workers at very high altitudes (e.g., 5,000 -8,000 feet above sea level), the permissible exposure stated in the recommended standard should be appropriately lowered to compensate for loss in the oxygen-carrying capacity of the blood. In 1-1 addition, workers with physical impairments that interfere with normal oxygen delivery to the tissues (e.g., emphysema, anemia, coronary heart disease) will not be provided the same degree of protection as the healthy worker population. The criteria and the standard recommended in this docu ment will be reviewed and revised as necessary.\n# 1-2 (a) Concentration\n(1) Occupational exposure to carbon monoxide shall be controlled so that no worker shall be exposed at a concentration greater than 35 ppm determined as a time-weighted average (TWA) exposure for an 8-hour workday, as measured with a portable, direct reading, hopcalite-type carbon monoxide meter calibrated against known concentrations of CO, or with gas detector tube units certified under Title 42 of the Code of Federal Regulations, Part 84.\n(2) No level of carbon monoxide to which workers are exposed shall exceed a ceiling concentration of 200 ppm.\n# (b) Calibration, Sampling and Analysis\nProcedures for calibration of equipment, sampling and analysis of CO samples shall be followed as provided in Appendix I.\n# Section 1 -Work Environment 1-3\nBecause employees with overt cardiovascular disease may not be protected by an occupational exposure to 35 ppm of CO, a medical program should be instituted consisting of preplacement and periodic examinations with special attention to the cardiovascular system and to medical con ditions which could be exacerbated by exposure to CO. Such a medical program could also provide the opportunity for conducting antismoking programs for high-risk employees. Areas where significant exposure to carbon monoxide is likely to occur shall be posted with a sign stating:\n# CARBON MONOXIDE (CO) DANGER High concentrations may be fatal\nProvide adequate ventilation High concentrations in air may be explosive\nSeek immediate medical attention if you experience any of the below symptoms:\n1 -Severe Headache 2 -Dizziness 3 -Nausea and vomiting Gas masks are located: (Specific location to be filled in by employer) For purposes of this section the term \"significant exposure to carbon monoxide\" refers to eight-hour TWA exposures exceeding 25 ppm but excludes such exposure as may be self-administered through smoking.\n# 1-5\nIn the event of an emergency or when a variance has been allowed and the use of respiratory protective equipment authorized by the Secretary of Labor, the employer shall provide and insure that the employee wears, as appropriate, one of the following respiratory protective devices approved by NIOSH or the Bureau of Mines as provided in Part 11 of Title 30, Code of Federal Regulations: (a) Type N Gas Mask (Emergency Situation):\nFor entry into or escape from an environment containing not over 20,000 ppm, which is not deficient in oxygen, for a total exposure period of not more than 30 minutes. Areas in which large amounts of CO are stored, used or emitted, or areas within the workplace through which large amounts of CO are trans ported, shall be provided with sufficient respiratory protective devices of the types specified in Section 4 and shall be readily accessible to persons who may be located in the area to assure a timely, orderly evacuation of the area by all persons in the event of accidental, massive release of CO.\nAn automatic visual and audible alarm that is set to be activated when the CO concentration reaches 500 ppm should be employed in such areas. Employees working in such areas shall be informed of the hazards and symptoms of acute CO poisoning (see Section 6) and shall be trained to implement an emergency evacuation plan designed for such an occurrence. Periodic drills, held not less frequently than every six months, shall be conducted to assure that such plans are adequate and effective in case of an emergency situation.\n(c) Fire Hazards Adequate fire extinguishing agents shall be readily available in the areas outlined in paragraph (b) of this section since CO will burn when mixed with air and may be explosive when concentrations of between 12.5 percent to 74.2 percent are reached.\nSection 5 -Emergency Procedures 1-7 (a) Each employee who receives significant exposure to carbon monoxide [see Section 3(b)] shall be apprised of all hazards, relevant symptoms, appropriate emergency procedures, and proper conditions and precautions for the safe use of CO or safe exposure to CO and shall be instructed as to the location of such information, which shall be kept on file as prescribed in paragraph (b) of this section and shall be readily accessible to all employees at each establishment where CO is involved in industrial processes and operations. (a) Each container in which CO is stored shall be examined for leaks upon its arrival at the establishment or upon filling and shall be reexamined periodically at least every three months.\n(b) Prior to transferring CO from a storage container, an inspection shall be conducted to detect any gas leaks in the transport system (e.g., cylinder seal with gas regulator, regulator apparatus, regulator seal with transport conduits, conduit system, etc.). (1) Personal exposure (\"breathing zone\") samples* shall be collected in accordance with procedures specified in Appendix I in all workplaces where employees are significantly exposed to CO [see Section 3(b)], Samples will be collected and evaluated as both TWA and ceiling concentration values.\n(2) Frequency of monitoring should be at least annually. It is recognized that more frequent monitoring may be indicated in certain circum stances depending upon the nature of the process, the rate of production, the effectiveness of control measurements, the time of day and seasonal variation, however, more frequent monitoring requirements cannot be recommended until there are extensive studies of specific operations in industry.\n(3) Blood analysis for COHb, as specified in Appendix II, shall be performed on all persons employed in work areas when, in the judgment of the OSHA Industrial Hygienist, biologic standards are needed to evaluate borderline exposure to CO (see Chapter V). and experiments and any other information available to him which will assure insofar as practicable that no employee will suffer diminished health, functional capacity, or life expectancy as a result of his work experience.\nThe National Institute for Occupational Safety and Health (NIOSH), after a review of data and consultations with others, formalized a system for the development of criteria upon which standards can be established to protect the health of employees from exposure to hazardous chemical and physical agents. It should be emphasized that any criteria documentation for a recommended standard should enable management and labor to develop better engineering controls and more healthful work practices and should not be accepted as a final goal in itself.\n1 In evaluating occupational hazards and setting priorities, it was determined that the potential for exposure of employees at the workplace to CO was greater than that for any other chemical or physical agent.\nThe significance of the CO dose-response relationship in man is attested furthermore by numerous research studies which have been documented in II-l the scientific literature. In a recent conference on the biological effects of CO sponsored by the New York Academy of Sciences, the findings and views of scientists from the United States, Australia, England, France, and 2 Denmark were presented.\nBackground information for this report was obtained from many sources, including those directly cited and listed in the references. In addition 3 there is a bibliography of nearly 1,000 references and abstracts on CO The criteria contained in this document were developed to assure that the recommended standard based thereon would (1) protect employees against both acute and chronic CO exposure, (2) be measurable by techniques that are valid, reproducible and available to industry and governmental agencies and (3) be attainable with existing technology.\n# II-2\nIn 1969 the Committee on Effects of Atmospheric Contaminants on Human Health and Welfare, appointed by the Environmental Studies Board of the National Academy of Sciences, reported on the evaluation of current knowledge concerning the effects of CO on man.^ While this report deals primarily with the effects on man of exposure to CO from air pollution sources, it is pertinent to note the following statement in the Introduction: \"...Today, the two main sources of carbon monoxide appear to be cigarette smoke and the internal combustion engine. And the subject of concern has changed from the acute effects of short-term exposure...to the lasting effects of long-term, low-level exposure, of a duration anywhere from a month to a lifetime, and in the range of CO concentrations that would produce 0.5-10% COHb.\" Thus, in the case of occupational exposures to CO, a worker's smoking habits must be taken into consideration when evaluating the environment. This factor has not been generally considered until the past few years.\nIt should be emphasized that the above report raised many questions concerning the effects of low-level exposures to CO, and that Committee recommended many additional research studies in this area.\nAlthough important evidence exists which indicates that subtle aber rations may occur in the central nervous system (CNS) during exposure to levels of CO lower than those of the recommended standard, the significance of these changes and their translation to effects upon employee safety and health is not entirely clear. The diversity of opinions and the conflicting experimental evidence existing in this area does not permit the clear-cut assessment of the scientific merit of such data or its extrapolation to the normal working population at this time. If reliable data become available which clearly demonstrate significant impairment of employee II-3 behavior during exposure to very low levels of CO (producing less than 5 percent COHb), then the criteria for the recommended standard will be reassessed on the basis of the additional evidence.\n# II-4 III. BIOLOGIC EFFECTS OF EXPOSURE TO CARBON MONOXIDE\nCarbon monoxide (CO) is an odorless, colorless, tasteless gas which is an active reducing agent for chemicals at elevated temperatures, but is principally encountered as a waste product of incomplete combustion of carbonaceous material. A summary of the physical properties is presented in Table I. The best understood biologic effect of CO is its combination with hemoglobin (Hb) to form carboxyhemoglobin (COIIb) , thereby rendering the hemoglobin molecule less able to bind with oxygen. This action of CO results in more persons succumbing each year to acute CO poisoning than to any other single toxic agent, except alcohol.6\n# Extent of Exposure\nWith the single exception of carbon dioxide (CO2X total emissions of CO each year exceed those of all other atmospheric pollutants combined.\nIn 1968 it was estimated that 102 million tons of CO were released into the atmosphere by the major sources of emission.^ Over one-half of this amount (58 percent) was produced by the gasoline-powered internal combustion engine. Specified industrial processes accounted for approximately 10 percent of the total. A summation of CO emission estimates for 1968 by specific industrial processes is presented in Table II.\nFrom Table II it can be observed that large amounts of CO are emitted from petroleum refineries, iron foundries, kraft pulp mills, sintering mills, lampblack plants and formaldehyde manufacturers. Major sources of CO production within the first four industries have been identified as the cupola in the iron foundry, the catalytic cracking units in the petroleum refineries, the lime kilns and the kraft recovery furnaces in the kraft paper mills, and the sintering of blast furnace feed in sintering plants.\n# III-l\nAside from the above major industrial processes which produce large quantities of CO, there are numerous operations (arc welding, automobile repair, traffic control, tunnel construction, etc.) where the occupational exposure for a worker to CO can be considerable. In fact any industrial process or operation where incomplete combustion of carbonaceous material occurs may easily be of consequence as concerns occupational exposure to CO.\n# Historical Reports and Theoretical Considerations\nMan's intimate association with carbon monoxide as a true environmental hazard began with his discovery of fire. Since that time his technological history has been one of advancement by means of incomplete combustion. The seriousness of exposure to high concentration of CO has been realized since the earliest medical writings. The Greeks and Romans used exposure to CO 7 as a means of execution of criminals and committing suicide.\nPriestly discovered the chemical composition of CO in the late 18th within the range, 220 to 290 and later investigations have generally confirmed this range, although at a slightly lower level, under conditions of complete hemoglobin saturation by oxygen and CO.^ ^ Briefly, the affinity constant may be expressed as the number of moles of oxygen which must be present with each mole of CO in order to maintain an equal saturation of hemoglobin. While CO actually combines less rapidly with reduced hemo globin than does oxygen, the tenacity of the binding between CO and hemo globin is some 200 to 300 times that of oxygen. This saturation of hemoglobin by either oxygen or CO occurs in four steps involving intermediates with four equilibrium constants:\nk' k' Hb4 + X ^ XHb4 KX = k '2 XHb . + X (X) 0Hb . K9 = ; --- 4 k.2 2 4 ^ k-2 ill k,3 (X)2Hb4 + X £ = ? <X)3Hb4 K3-Rj- k '4 k 'i (X)3Hb4 + X ^ (X)4Hb4 K4 -Î\nn the above equations, X represents either oxygen or CO with a different equilibrium constant for each equation. It has been determined that in both cases is much higher (18 to 50 times higher) than K-^, K2 , or K3 because k'^ is much greater than Under these circumstances the last ligand to bind to hemoglobin (K^ equation) dissociates much more 15 readily than it binds.\nThe differences between the four constants depend on intra-molecular forces occurring as a result of the interactions of each III-3 ligand with the others, or with other portions of the hemoglobin molecule.\nHence, the effect is an allosteric one resulting in conformational changes in the hemoglobin molecule. These differences in reaction rates affect the dissociation of oxygen or CO from hemoglobin such that, as can be observed in Figure 1, the shapes of the respective dissociation curves are sigmoidal rather than parabolic, as is the case with myoglobin, which possesses only 16 one heme group with a single dissociation constant.\nLikewise \n# III-4\nThe difference in the partial pressure of oxygen (Pq^) between freshly oxygenated arterial blood (P = 100 mm Hg) and mixed venous blood°2 (P = 40 mm Hg) represents a release to the tissues of approximately Oo 16 5 milliliters 0^/100 milliliters blood.\nA shift of the steep portion of the oxyhemoglobin dissociation curve to the left would tend to change the release of oxygen to the tissues appreciably.\nWhile the dissociation curve shifts to the right, allowing for a more efficient dissociation of oxygen to the peripheral tissues under conditions of reduced ambient oxygen tension (hypoxic hypoxia), just the opposite 4,16,19,21 situation occurs during exposure to CO (anemic hypoxia).\nThe leftward shift during CO exposure occurs because of the much greater affinity of CO for hemoglobin and in spite of the fact that the amount of oxygen in 4 physical solution in the blood remains near normal.\nThe oxygen content of the blood is not only lowered during exposure to CO, but the shift of the oxyhemoglobin dissociation curve to the left decreases the amount of remaining oxygen that is made available to the tissues. As mentioned earlier in this report it has been confirmed that an 51 52 endogenous source of CO exists as a product of heme catabolism. '\n# III-8\nWhen an ct-methylene bridge in the heme portion of hemoglobin is broken during 51 the catabolic process, a molecule of CO is released.\nIt has been estimated that this production amounts to approximately 0.3 to 1.0 milliliter(ml)/hour with an additional 0.1 milliliter(ml)/hour resulting from a similar catabolic process involving other heme-containing compounds (e.g., myoglobin and cyto-6,53 chrome and catalase enzymes).\nThis endogenous production of CO, which gives rise to approximately 0.5 to 0.8 percent COHb, would not be expected to be of important physiologic consequence per se since the hypothesized mechanism has evolved with man, but its removal would merit due consideration in a closed system such as a submarine or a space capsule. Also, in the determination of total CO exposure this quantity must be included as \"base line\" COHb.\n# Cardiovascular Effects of CO\nThe critical importance of cardiovascular involvement during exposure 6,28,49-6*0 to CO is becoming increasingly evident.\nWhile the brain has a higher requirement for oxygen than the heart, in contrast to the cerebral circulation the coronary circulation must supply an even increased amount of oxygen during periods of generalized tissue hypoxia; since under these circumstances the heart is forced to increase both its rate and its output 49 in order to meet the normal oxygen demands of the body.\nThis increase in myocardial activity demands an increased oxygen supply to the myocardium which must be met by the coronary circulation. Under hypoxic conditions increased oxygen supply to the peripheral tissues can be accommodated by increased blood flow (via vascular dilatation) and/or increased oxygen extraction by the tissues. As mentioned earlier the peculiar dissociation characteristics of O^Hb permits an oxygen reserve which is used at reduced III-9\nP . The myocardium under these circumstances appears only to increase 2 the flow of blood rather than to extract an additional amount of oxygen from the coronary circulation. While the peripheral tissues normally extract only 25 percent of the oxygen content of the perfusing arterial blood during resting conditions, the myocardium extracts 75 percent, thus leaving the mixed venous blood only 25 percent saturated. This mechanism has the overall effect of maintaining the myocardial oxygen tension at a higher level than would be present in other muscle tissue and thus insures a continual aerobic metabolism, even under hypoxic duress. In terms of oxygen tension, the mixed venous blood of the peripheral tissues is approximately 40 mm Hg while the mixed venous blood of the coronary circulation is only 20 mm Hg. In the presence of COHb (and the shift to the left of the oxyhemoglobin dissociation curve), however, the arterio-venous difference can only be maintained by an increased flow in the coronary circulation.\nIn an individual with diminished coronary circulation because of coronary heart disease, however, this situation may result in a decrease in the mixed venous oxygen tension of the myocardium precipitated by an inability to maintain the normal arterio-venous gradient. This hypoxic effect is further enhanced, as mentioned above, by an increase in cardiac rate and output as a general response to peripheral tissue hypoxemia. A person with diminished coronary circulation caused by coronary heart disease, consequently, may be constantly near the point of myocardial tissue hypoxia. This exposure to CO increased the COHb slightly less than 1 percent per minute. It appears that the canine may be able to tolerate a much higher level of COHb than is the human before significant myocardial changes occur.\n# Jaffe\nhas emphasized the relationship between CO poisoning and an elevated titer of serum lactic dehydrogenase as an indicator of myocardial damage. He speculated that \"...even 'normal' amounts of carbon monoxide may operate as the last straw in precipitating coronary attacks.\" Mien rats 65 were exposed to 500 ppm CO for four hours Lassiter, Coleman, and Lawrence observed a statistically significant aberration in the plasma lactic dehydrogenase isoenzyme distribution which was considered to be highly indica tive of myocardial damage. The COHb level in the animals at termination of exposure was <40 percent.\nThe relationship between chronic cigarette smoking and increased risk of 66 coronary heart disease (CHD) is undeniable, as is the fact that cigarette smoking causes increased exposure to CO. A CO concentration of 4 percent (40,000 ppm) in cigarette smoke, which will cause an alveolar concentration of 0.04 to 0.05 percent (400 to 500 ppm) will produce a COHb concentration 6,67-69 70 3 to 10 percent.\nGoldsmith estimated that the cigarette smoker is exposed to 475 ppm of CO for approximately six minutes per cigarette.\n# 111-14\nIn a review article on CO and human health} Goldsmith and Landaw stated that the COHb level in the one-pack-a-day cigarette smoker is 5.9 percent, which they say is a sufficient concentration to impose a serious health threat to persons with underlying vascular insufficiency.\nIn another paper these two investigators used a regression analysis of expired air samples from 3,311 longshoremen and found a COHb of 6.8 percent in two-pack-a-day smokers and 1.2 percent COHb in nonsmokers. They believed that the high level in the nonsmokers, above the 0.5 to 0.8 percent normally present as a result of endogenous production, was accounted for by occupa tional exposure.\nIn a study by Kjeldsen\"^ COHb levels of both smokers and nonsmokers were compared from 934 'tHD-free\"persons. The mean COHb was 0.4 percent for nonsmokers and 7.3 percent for cigarette smokers who inhaled. In addition, the mean level of COHb for all 416 smokers in the study, regard less of inhalation habits or number of cigarettes smoked, was 4.0 percent.\nA similar study is presently being conducted to determine the range 72 of COHb in the American public by Stewart and Peterson. The presently available data, from Milwaukee, has demonstrated that the mean COHb levels for nonsmokers is 1.33 ±0.85 percent and for smokers is 4.47 ±2.52 percent. In an epidemiologic survey involving approximately 4,000 middle-aged males, who were kept under medical surveillance for 8 to 10 years, Doyle 74 and co-workers found that one-pack-a-day smokers had about a three-fold greater risk of myocardial infarction than did nonsmokers, or former smokers.\nThe finding that death rates for ex-smokers were no higher than for 16 nonsmokers prompted Bartlett to state that the effect of cigarette smoking on this particular pattern is completely reversible when an individual ceases to smoke. He concluded that smoking caused a myocardial hypoxemia by some acute, reversible process, which was probably unrelated to the formation of hard, irreversible, atherosclerotic lesions and that CO would fit such an epidemiologic pattern very well. He further stated, however, that other components of cigarette smoke, including nicotine, may be responsible for this pattern and that the question, in his estimation, remained unsolved.\nAstrup, Kjeldsen, and Wanstrup,^ reporting on an investigation in progress in 19 70 in which 1,000 randomly chosen individuals were examined for evidence of arteriosclerotic disease, demonstrated a clear relationship between this disease and high COHb levels after smoking. They further stated that it is very likely \"...that it is the inhalation of CO in tobacco smoke that is, in part, responsible for the much higher risk of smokers to develop coronary heart disease and other obliterating arterial diseases in comparison to that of nonsmokers.\" pain in the patients exposed to 50 ppm for four hours. The same level of significance was also found for the patients exposed to 100 ppm although the differences of results between the two regimes were not significantly different. The other parameter measured, duration of pain, was statisti cally significant (p <0.05) only for the patients exposed to 100 ppm CO.\nAgain the differences of results between the lower and higher exposures were not significant. Knelson concluded, using this particular protocol of exposure, that patients with angina pectoris who were exposed to CO and then exercised experienced pain earlier and pain lasted longer, than when these same patients were exposed to ambient air.\nAn interesting set of data has been produced recently by Horvat and 7Q co-workers ' concerning the effect of oxygen breathing on the threshold of angina pain in patients with confirmed coronary heart disease. The investigators first determined the angina threshold while the patients breathed air by increasing the heart rate via right atrial pacing. Patients were then, unknowingly, switched to 100 percent oxygen and the heart paced to the previously determined angina threshold. Angina pain did not occur in nine of eleven patients. Associated with this improvement was increased lactate extraction from an average of -17 ±15 to +18 ±10 percent (p <0.025).\nIn four of six patients lactate production turned to lactate extraction, in six of seven patients S-T abnormalities in the EKG were improved as well as improvement in pulsus alternans in three of five patients. These data present significant evidence that oxygen breathing permits the heart to do more work before coronary insufficiency develops. They also indicate the validity of the approach used by Knelson in determining Lloyd and co-workers noted that while certain areas (e.g., janitors) had an excess of deaths due to heart disease, other areas had a deficit in this specific cause of mortality.\nIn attempting to determine why an apparent selection for health should have been more likely among steelworkers dying from heart disease, it was\n# 111-31\nsuggested that such persons may have been more likely to migrate between work areas. Thus, employees exhibiting symptoms of cardiac insufficiency (e.g., shortness of breath) may move to less physically demanding jobs on their own. Similarly, employees with CHD who return to work following an attack are often returned to less physically demanding jobs (e.g., janitors and mechanical maintenance). As a result the investigators indicate that selection for health may have been more important than environmental factors in explaining the excess in mortality from heart disease among janitors and mechanical maintenance personnel. If this suggestion is correct, then the work areas from which those employees dying from heart disease migrated would not be expected to show similar increases in deaths from heart disease. For example, if these employees migrated from the areas aforementioned that produce significant exposure to CO, then those areas would be expected to have a lower SMR for heart disease. Although this rate for those areas was not published in the paper, because of statistical insignificance, the SMR for all deaths in those areas, as mentioned, did not demonstrate trends which were statistically significant.\nBased upon this study, then, it would not seem possible either to infer or to deny that occupational exposure to CO at the three work places in question resulted in an excess of deaths due to heart disease.\nMore information is needed concerning daily exposure of workers, engaged in various levels of activity, to specific sources of CO within their working environment and the correlation of such information to both smoking habits and to nonoccupational exposure.\n# III-32\nRegardless of CO source, however, the rate of CO excretion from the blood is dependent upon the concentration in the ambient air, and for smokers with elevated COHb levels who are occupationally exposed to CO, their excretion of CO will be proportionally delayed.\nBecause the recommended standard for occupational exposure to CO is designed to protect employees with CHD, it is necessary to characterize the extent of this disease among the general worker population.\n# 102\nFriedberg has defined CHD to represent clinical heart disease due to lesions of the coronary arteries. However, the term, CHD, is generally used to refer to the process of atherosclerosis of the coronary arteries leading to disturbances in the myocardial blood supply. It is in this latter context that the term applies in the criteria document.\nIt is an established fact that each year more persons in the U.S. die 103 from CHD than from any other disease.\nCoronary atherosclerotic heart 104 disease is the most common form of cardiac disease in adults in the U.S.\nDuring the Korean War autopsies performed on young soldiers, with an average age of twenty-two years, revealed that 77.3 percent had gross pathologic 104 , 105 \" evidence of CHD.\nA study of autopsies in a stabilized population of 30,000 revealed that CHD was the cause of death in 40 percent of the males.\n# 102\n\n# Friedberg states:\n\"The diagnosis of coronary (atherosclerotic) heart disease refers to clinical manifestations and not to the mere presence of atherosclerotic lesions. Extensive pathologic lesions may be present but cannot be diagnosed unless they produce overt clinical manifestations or are revealed by coronary angiography.\"\nIn most cases the first clinical manifestation of CHD is expressed''\"ê ither as the angina pectoris syndrome or as frank myocardial infarction.\n# III-33\nAccording to the Framingham, Massachusetts, study conducted by the USPHS, CHD was first manifested in one-sixth of the cases of CHD as sudden death. produced in the myocardium of patients with coronary artery disease during acute exposure to concentrations of CO sufficient to produce a COHb content of less than 9 percent provides metabolic evidence of myocardial hypoxia occurring under this regime. His finding that in patients with coronary artery disease the coronary blood flow did not increase at this level of COHb saturation, although it did increase in controls, serves to further underscore the possible consequences for an individual with coronary heart disease (CHD) who is carrying less than 9 percent COHb. Furthermore, it 111-35 must be emphasized that these coronary patients were at rest and were not subjected to exercise. The consequences of this additional stress were 7 8 documented earlier in the study by Knelson. His discovery that the time to onset of pain was diminished in cigarette smokers with angina pectoris during exercise immediately following exposure to 50 ppm of CO for four hours (average COHb of 3.0 percent), provides considerable evidence that workers with CHD, and particularly those with CHD who smoke, should not be exposed to concentrations of CO which will produce a level of COHb in excess of 5 percent.\nSimilarly, the effects of CO on behavior are not in complete agreement.\nAs mentioned previously, several mechanisms have been suggested to possibly account for the differing results. These suggestions can be summarized by noting that no one study has completely replicated the experimental design of any previous study that indicated a behavioral impairment due to CO Because the emission of CO is on so large a scale it becomes difficult to single out, identify and rank individual sources in order of importance as concerns occupational exposure. Indeed, as emphasized earlier in this report, the smoking habits of the worker have a tremendous bearing on his actual daily exposure to CO. The CO pollution from traffic to and from the place of employment likewise will affect his total daily exposure.\nSeveral studies concerning occupational exposure to CO are presented below. The investigators commented on the results of the study by saying:\nV-6\nto recognize the effect that the level of activity has upon the uptake of CO and to judiciously evaluate the exposure of his employees and limit their activity accordingly. The data in Appendix IV have been included specifically for this purpose. In addition, the employer must give special consideration to limiting the activity of employees exposed to CO at high altitudes in order to compensate for the dual loss in oxygen-carrying capacity of the blood.\nV-7\n# VI. COMPATIBILITY WITH AIR QUALITY STANDARDS\nThe Environmental Protection Agency (EPA), under provisions of the Clean Air Act (PL 91-604), promulgated national primary and secondary air quality 123 standards on April 30, 1971.\nThe primary and secondary standards for \"in the comments, serious questions were raised about the soundness of this evidence. Extensive consideration was given to this matter. The conclusions reached were that the evidence regarding impaired time-interval discrimination had not been refuted and that a less restrictive national standard for CO would therefore not provide the margin of safety which may be needed to protect the health of persons especially sensitive to the effects of elevated carboxy hemoglobin levels. The only change made in the national standards for CO was a modification of the 1-hour value. The revised standard affords protection from the same low levels of blood carboxyhemoglobin as a result of short-term exposure. The national standards for carbon monoxide, as set forth below, are intended to protect against the occurrence of carboxyhemoglobin levels above 2 percent. It is the Administrator's judgment that attainment of the national standards for carbon monoxide will provide an adequate safety margin for protection of public health and will protect against known and anticipated adverse effects on public welfare.\"\n# VI-1\nThe air quality standard is designed to protect the population-at-large and takes into consideration 24-hour per day exposure of the very young, the very old, and the seriously ill. The evidence presented in this (NIOSH) criteria documentation supports the concept of the necessity of providing protection for that portion of the general worker population with coronary heart disease (CHD), who are especially sensitive to elevated levels of COHb.\nAlthough the Administrator of EPA has stated above that the evidence concerning the impairment of time-interval discrimination at low levels of COHb, presumably as low as 2 percent, has not been refuted, neither has such evidence been confirmed.\nVI-2\n# VII. APPENDIX I SAMPLING AND ANALYSIS OF CARBON MONOXIDE (CO)\nWorker exposure to CO shall be measured with a portable, direct reading, hopcalite-type carbon monoxide meter calibrated against known concentrations of CO, or with gas detector tube units certified under Title 42 of the Code of Federal Regulations, Part 84. Samples shall be collected from the worker's breathing zone and a sufficient number shall be collected at random intervals throughout the workday so that a statistically accurate determination of compliance may be made as outlined in the following section.\n# Principles for Air Sampling for Carbon Monoxide (CO)\nThe characteristic manner in which CO proceeds from the pulmonary alveolar spaces, through the blood capillary membrane \"barrier,\" into the plasma, through the red blood cell membrane, ultimately to combine with hemoglobin imposes certain requirements for air sampling if proper deter mination of compliance with the recommended standard is to be made. The rate of CO diffusion from the lung to hemoglobin depends upon the partition coefficient for CO between alveolar air and pulmonary blood. The magnitude of this coefficient is such as to delay transfer of CO to the circulating hemoglobin (Hb). This time delay makes it essential in any estimation of the carboxyhemoglobin level to know how long the exposure was experienced as well as the CO concentration during the exposure. Reference to Figure 2 shows that a continuous exposure of over eight hours' duration is required to attain maximum combination of CO with hemoglobin at the recommended standard of 35 ppm.\n# Air Sampling Methods\n\n# VIII-1\nThe sampling and analytical procedures recommended below will provide the necessary data to determine compliance with the recommended standard.\nThe methodology and equipment utilized to collect and analyze samples to determine concentrations of CO in the air or concentration of COHb in the exposed worker shall be subjected to a proficiency and/or calibration test program conducted by NIOSH or by another agency of the federal govern ment under agreement with NIOSH for certification for such determinations.\n# Determination of Compliance\nThe following procedure shall be used to determine compliance with the eight-hour, time-weighted average standard based on a small number of instantaneous (grab) samples collected at random intervals during the workday.\nGiven: the results of r i samples with a mean m and a range (difference between least and greatest) jr. If, for from 3 to 10 samples, m is greater than the total of: An extensive review of the methodology covering the determination of 12 4 carbon monoxide has been prepared by Maehly. In an updating review of Because carboxyhemoglobin constitutes the toxic product formed during carbon monoxide intoxication, and because the carboxyhemoglobin formed is quite stable, the analyst is presented with the opportunity of directly evaluating the toxic agent. In so doing, two facts are established:\n(1) proof that an exposure has occurred, and (2) quantitative proof the exposure has produced a particular toxic concentration in the body.\nDiffusion, chromatographic and gasometric methods all involve liberation of carbon monoxide from hemoglobin and either gasometric transfer operations or secondary titrations which are technically difficult for the microliter gas volumes involved. This limitation is even more critical when the effects of temperature and pressure on gas volumes are considered. Careful evaluation of the methods for direct measurement of carboxyhemoglobin has been reviewed in detail. Of these methods, three are considered to be feasible for con sideration as the recommended method.\n# (a)\nThe colorimetric method of Amenta uses small blood samples and measures the absorbance of an ammonia-hemolyzed sample at three wave-length\n# Analytical Methodology\nIX-1 settings on the spectrophotometer: 560, 575, and 498 nm. In calculating the results, the absorbance of the mixture at 498 nm (an isosbestic point) is the denominator in the equation for oxyhemoglobin, carboxyhemoglobin, and the unknown. This mathematical manipulation gives a value corrected for the total hemoglobin concentration (i.e., the R factor). The values (IL = 1.097, R = 0.057) are then used for calculating percentage COHb by 2 the ratio R^ -R^/R^^-R^q XIOO = percentage COHb. The relatively small absorbance difference observed with this method reduces its precision and accuracy, especially in the low COHb range (ca. 10 percent).\n# (b) The method of Harper\ninvolves hemolyssis of blood by distilled water, addition of a buffer (pH 7.2) and reduction of oxyhemoglobin by sodium hydrosulfite. The reduced hemoglobin is then converted to methemoglobin by the addition of potassium ferricyanide. The carboxyhemoglobin is converted to methemoglobin at a slower rate than reduced hemoglobin; therefore, the carboxyhemoglobin can be measured before appreciable conversion to methemoglobin takes place. The method requires a careful control of timed manipulations to obtain reproducible results. \n# Range and Sensitivity\nFor 1 ml of oxalated blood the range is 0 to 100 percent saturation COHb. Sensitivity is 0.5 percent saturation.\n# Interferences\nHemolyzed blood contains pigments arising from the breakdown of hemoglobin and will cause interference in the method. Bile pigments may also interfere.\n# Precision and Accuracy\nThe difference in concentrations obtained by this procedure and compared to results obtained on the same samples analyzed by the Van Slyke method are not significant at the 5 percent level [t-Value = 1.81 (14 deg. (A) Chemical stability, incompatibility, hazardous decomposition products, and hazardous polymerization.\nX-2 (A) Detailed procedures to be followed with emphasis on precautions to be taken in cleaning up and safe disposal of materials leaked or spilled.\nThis includes proper labeling and disposal of containers containing residues, contaminated absorbants, etc.\n(ix) Section VIII. Special Protection Information.\n(A) Requirements for personal protective equipment, such as respirators, eye protection and protective clothing, and ventilation, such as local exhaust (at site of product use or application), general, or other special types.\n(x) Section IX. Special Precautions.\n(A) Any other general precautionary information, such as personal protective equipment for exposure to the thermal decomposition products listed in Section VI, and to particulates formed by abrading a dry coating, such as by a power sanding disc.\n(xi) Hie signature of the responsible person filling out the data sheet, his address, and the date on which it is filled out.\n(xii) The NFPA 704M numerical hazard ratings as defined in Section (c) (5) following. The entry shall be made immediately to the right of the heading, \"Material Safety Data Sheet\" at the top of the page and within a diamond symbol preprinted on the forms. \nN i in O ir * -1 • • • • • • • • • • • • • • • • • • • • (M ao r» < NO »o m < r\"\n< u e O o O O O o o o O o ' J o O O O O o O 0 0 • • • * • • • • • • • * • • • • • • • • o o O •O o *»? o o o c o o CJ o o O í j O o o •H\nO o © O o o o o o o o O O O © © O o © O • • • • • • • • • • • • • • • • • • • • © o © © © © © © o o © © © o o © c © o o C M ro 4* tn o O' <\\l i f s co •«4 4-f-o rr. 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Higher proportions of the lesions were located on the upper (39%) or lower (32%) extremities than on the trunk/back (16%) or face/neck (13%). Typically, the lesions were painless, had enlarged slowly, and ultimately had central ulceration, often covered with eschar and surrounded by an erythematous, indurated border (Figure 2). Regional lymph nodes (e.g., epitrochlear, axillary, and inguinal), if palpable, usually were <1 cm in diameter. None of the patients had systemic symptoms.\nIn 17 (77%) of the 22 cases, parasites were noted on lightmicroscopic examination of tissue. Of the 19 patients who had tissue cultured for parasites, 14 (74%) had positive cultures, of which 13 (93%) had sufficient organisms for species identification by isoenzyme electrophoresis. All nine of the 13 patients whose cultures had been tested as of October 20, 2003, were infected with Leishmania major. Additional evidence that 21 (95%) of the 22 patients had CL was obtained by testing tissue with an investigational, fluorogenic, genusspecific polymerase chain reaction (PCR) assay developed and conducted by staff of WRAMC and Walter Reed Army Institute of Research (Silver Spring, Maryland) (6).\nSince 1978, military personnel with potential cases of leishmaniasis have been referred to WRAMC for evaluation and therapy with the pentavalent antimonial compound sodium stibogluconate (Pentostam ® , The Wellcome Foundation, United Kingdom). Although treatment of cases of CL with pentavalent antimonial compounds has been considered the standard of care for over half a century (1), these compounds Editorial Note: Leishmaniasis is a vector-borne parasitic disease endemic in parts of the tropics, subtropics, and Southern Europe. The World Health Organization estimates that 1.5 million cases of CL and 500,000 cases of visceral leishmaniasis (VL) occur each year (1).\nBoth cutaneous and visceral infection can remain asymptomatic or be associated with mild, nonspecific, and nonprogressive symptoms (1). Clinical manifestations, if they develop, typically are first noted weeks to months after exposure. The skin lesions of CL, which can be chronic and disfiguring, typically evolve from papules to nodules to ulcerative lesions but can persist as nodules or plaques (1). Host (e.g., immune status) and parasite (e.g., species and strain) characteristics affect the natural history and the ease and importance of diagnosing and treating cases of CL. Although both L. major and L. tropica are common etiologic agents of CL in Afghanistan, Iraq, and Kuwait (1,7,8), which species has caused a particular case of CL depends on such factors as the geographic area and ecologic setting of exposure and the species of the sand-fly vector. VL is more prevalent in Iraq (8) than in Afghanistan or Kuwait. Manifestations of cases of advanced VL include fever, cachexia, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia; such cases can be fatal if not treated appropriately and quickly (1).\nNo FDA-approved vaccines or prophylactic medications to prevent leishmaniasis are available (1). Control measures against vectors or reservoir hosts of infection might be effective in particular settings (1,8,9). Personal protective measures to decrease risk for infection include avoiding, if possible, areas where leishmaniasis is endemic, particularly from dusk through dawn; using permethrin-treated bed nets and clothing; minimizing the amount of exposed skin; and applying insect repellents containing 30%-35% DEET (lower percentages for children) to exposed skin.\nTransmission of leishmanial parasites through blood transfusion has not been reported in the United States. However, as a precautionary measure, the Armed Services Blood Program Office of the Department of Defense (DoD) (Falls Church, Virginia) and the American Association of Blood Banks (AABB) (Bethesda, Maryland) are implementing policies to defer prospective blood donors who have been in Iraq from donating blood for 12 months after the last date they left Iraq. Additional information about these deferral policies is available from DoD at / downloads/prevmed/leishmanAug03.pdf and from AABB at .\nIn Operations Desert Storm and Shield during 1990-1991, among approximately 697,000 deployed military personnel, WRAMC identified 12 cases of so-called viscerotropic leishmaniasis caused by L. tropica (a syndrome associated with visceral infection but not necessarily the classic clinical manifestations of VL) and 20 cases of CL (3,10;WRAMC, unpublished data, 2003). During August 2002-September 2003, WRAMC identified 22 cases of CL among personnel participating in Operations Iraqi and Enduring Freedom. The apparent decline in numbers of cases of CL with self-reported onset of lesions during July-August 2003 (Figure 1) could reflect delays in persons seeking medical evaluation for skin lesions that might not cause concern initially. U.S. personnel in Iraq have reported being bitten by sand flies (some persons have received >100 bites in a single night), and up to 2% of female phlebotomine sand flies collected in Iraq were infected with leishmanial parasites. As of October 21, WRAMC had identified nine more cases of CL in addition to the 22 cases described in this report. WRAMC is evaluating additional potential cases of CL in deployed personnel, and the number of confirmed cases probably will continue to increase.\nU.S. health-care providers should consider the possibility of CL in persons with chronic skin lesions who were deployed to Southwest/Central Asia or who were in other areas where leishmaniasis is endemic and that of VL in such persons with persistent, febrile illnesses, especially if associated with other manifestations suggestive of VL (e.g., splenomegaly and pancytopenia) (1,4,8,10). Information about diagnosing and treating CL and VL has been published (1,5). Both WRAMC and CDC provide diagnostic services and the antileishmanial compound sodium stibogluconate. For treatment of health-care beneficiaries of the military, health-care providers should contact WRAMC, telephone 202-782-6740. For treatment of civilians, providers should contact CDC's Drug Service, telephone 404-639-3670.\n\n# Infant Health Among Puerto Ricans -Puerto Rico and U.S. Mainland, 1989-2000\nAlthough the overall U.S. infant mortality rate (IMR) declined dramatically during the 1900s, striking racial/ethnic disparities in infant mortality remain (1,2). Infant health disparities associated with maternal place of birth also exist within some racial/ethnic populations (3,4). Eliminating disparities in infant health is crucial to achieving the 2010 national health objective of reducing the infant death rate to 4.5 per 1,000 live births (objective 16-1c) (5). Hispanics comprise the largest racial/ethnic minority population in the United States. Among U.S. Hispanics, considerable heterogeneity exists in infant health, with the poorest outcomes reported among Puerto Rican infants (6). This report compares trends during the previous decade in IMRs and major determinants of these rates such as low birthweight (LBW), preterm delivery (PTD), and selected maternal characteristics among infants born to Puerto Rican women on the U.S. mainland (50 states and the District of Columbia) with corresponding trends among infants born in Puerto Rico. The findings indicate that despite having lower prevalence of selected maternal risk factors, Puerto Rico-born infants are at greater risk for LBW, PTD, and infant death than mainland-born Puerto Rican infants. This report also highlights a persistent disparity in IMRs and an emerging disparity in LBW and PTD rates between Puerto Rico-born infants and mainland-born Puerto Rican infants. Future research should focus on identifying factors responsible for these disparities to improve infant health in Puerto Rico.\nLinked birth/infant death files for the 50 states, the District of Columbia, and Puerto Rico for 1989-1991 and 1998-2000 were used to assess IMR trends. Natality files for 1990-2000 were used to examine trends in rates of LBW (<2,500 g), know what matters.\n\n# Dispatch\nup-to-the-minute: adj 1 : extending up to the immediate present, including the very latest information; see also MMWR. PTD (<37 weeks' gestation), and selected maternal characteristics among live-born infants. Analyses were limited to infants born to Puerto Rican women (i.e., those born in Puerto Rico, those born on the mainland to Puerto Rico-born mothers, or those born on the mainland to mothers who reported being of Puerto Rican ethnicity). Infants born in Puerto Rico to women not born either in Puerto Rico or on the mainland were excluded. Four subpopulations of Puerto Rican infants were examined initially: infants born in Puerto Rico to Puerto Rico-born mothers, infants born in Puerto Rico to mainlandborn mothers, infants born on the mainland to Puerto Ricoborn mothers, and infants born on the mainland to mainland-born mothers of Puerto Rican ethnicity. However, because maternal place of birth was not associated substantially with infant health outcomes, data are shown for Puerto Rico-born and mainland-born infants without regard to maternal place of birth. Chi square tests were used to compare differences in the prevalence of infant and maternal characteristics and differences in IMRs among the groups.\n\n# Low Birthweight and Preterm Delivery\nIn 1990, Puerto Rico-born infants were 1.03 times more likely to be of LBW than mainland-born infants, and in 2000, this disparity increased to 1.2 (Figure). From 1990 to 2000, the LBW rate for Puerto Rico-born infants increased 18.0%, from 9.2% to 10.9%; for mainland-born infants, the LBW rate increased 3.7%, from 8.9% to 9.3%. Similar differences in LBW rate increases were observed when analyses were restricted to full-term and singleton births. The increase in the LBW rate among Puerto Rico-born infants was associated predominantly with an increase in the percentage of infants with an intermediate LBW (ILBW; 1,500-2,499 g); however, a small increase also was observed in the percentage with a very low birthweight (VLBW; <1,500 g) (Table 1). In 2000, Puerto Rico-born infants were less likely than mainlandborn infants to be of VLBW (ratio = 0.7) but more likely to be of ILBW (ratio = 1.3) (Table 1).\nIn 1990, Puerto Rico-born infants were less likely than mainland-born infants to be born preterm (ratio = 0.9) (Figure ). From 1990 to 2000, the PTD rate among Puerto Rico-born infants increased 29.3% (from 11.6% to 15.0%), and that among mainland-born infants increased 0.9% (from 13.3% to 13.4%). As a result, in 2000, Puerto Rico-born infants were 1.1 times more likely than mainland-born infants to be born preterm. Similar differences in PTD rates were observed when analyses were limited to singleton births. The increase in the PTD rate among Puerto Rico-born infants was attributable primarily to an increase in the rate of moderately preterm births (32-36 weeks' gestation), although the rate of very preterm births (<32 weeks' gestation) also increased slightly (Table 1).\nIn 2000, despite higher rates of LBW and PTD among Puerto Rico-born infants, their mothers were less likely than mothers of mainland-born infants to report selected maternal risk factors, including receiving late/no prenatal care, having <12 years of education, not being married, having plural births, and using tobacco (Table 1). The prevalence of first trimester prenatal care and the percentage of mothers aged <19 years at their infant's birth were similar for the two groups (Table 1). The prevalence of these maternal characteristics did not differ by maternal place of birth.\n\n# Infant Mortality\nFrom 1989-1991 to 1998-2000, the combined IMR for Puerto Rico-born and mainland-born infants declined approximately 24%. The 1989-1991 IMR for Puerto (6), risk factors such as maternal tobacco use might be reported less completely in Puerto Rico than on the mainland. Second, because Hispanic origin is not recorded on birth certificates in Puerto Rico, this study was based on records for infants born either in Puerto Rico or on the mainland; mainland-born infants were defined as having Puerto Rican ethnicity if their mothers were born in Puerto Rico or reported being Puerto Rican.\nThis report highlights a continuing disparity in infant mortality rates and an emerging disparity in LBW and PTD rates between Puerto Rico-born infants and infants born on the mainland to Puerto Rican mothers. These differences should be considered in the planning and implementation of efforts to reduce IMRs among Puerto Ricans. The higher birthweightand gestational age-specific IMRs in Puerto Rico contribute more to the overall higher IMR in Puerto Rico than do the differences in birthweight and gestational age distributions between Puerto Rico-and mainland-born infants (8). Efforts to reduce IMR in Puerto Rico should focus on reducing mortality rates among LBW and preterm infants, perhaps by examining existing perinatal services. Additional opportunities might exist for lowering the overall IMR if the underlying causes of the increases in the prevalence of LBW and PTD can be identified and prevented. Improving infant health in Puerto Ricans will most likely require interventions at the individual, provider, and health-care system levels.\n\n# West Nile Virus Infection Among Turkey Breeder Farm Workers -Wisconsin, 2002\nIn 2002, Wisconsin public health officials were notified of two cases of febrile illness in workers at a commercial turkey breeder farm (farm A) in county A. The Wisconsin Division of Public Health (WDPH) initiated an investigation that found a high prevalence of West Nile virus (WNV) antibody among farm A workers and turkeys. An associated high incidence of febrile illness among farm A workers also was observed. This report summarizes the results of this investigation, which indicate possible nonmosquito transmission among birds and subsequent infection of humans at farm A. Because the mode of transmission in this outbreak is unknown, turkey handlers should take appropriate precautions, including use of DEETcontaining mosquito repellents, protective clothing and gloves, respiratory protection, and proper hand hygiene. Suspected occupationally acquired WNV infections should be reported immediately to local and state health departments.\nDuring November 2002, WDPH and the Wisconsin State Laboratory of Hygiene (WSLH) confirmed that two ill residents of county A had been infected with WNV. Before these reports, only one human WNV infection had been reported in this county. Both persons worked at farm A and had febrile illness with rash during late September-early October. These human illnesses occurred after a suspected fowl pox outbreak among farm A turkeys in September. Workers were concerned the pox outbreak might be associated with their illnesses.\nFarm A is one of six turkey breeder farms in county A owned by a company that also operates nonbreeder farms and a turkey meat processing plant in county A. The five other turkey breeder farms are located within 10 miles of farm A, and multiple private residences are within a quarter mile. In February 2003, county and state public health staff, in collaboration with the company, identified workers at the six turkey breeder farms, the nonbreeder farms, and the plant, and requested their consent to participate in a serosurvey. Serum samples were collected from participating workers (N = 93) to identify persons infected recently. A questionnaire was administered to identify persons who had a febrile illness during August-October 2002. Serum samples also were collected from residents (N = 14) who lived within a quarter mile of farm A. All serum samples were tested for WNV-specific IgM antibody at WSLH (1). IgM-positive specimens were confirmed by plaque-reduction neutralization tests at CDC (2). Of 107 total participants, 10 (9%) were seropositive. Of approximately 90 workers at the six breeder farms, 57 (63%) participated; of these, 10 (18%) were infected recently with WNV (Table ). None of the meat processing workers or other area residents was infected. Of 11 persons who worked exclusively at farm A, six (55%) were WNV IgM-positive, compared with two (25%) of eight who worked at both farm A and other breeder farms and two (5%) of 38 who worked only at other breeder farms. Of the 10 IgM-positive workers, six (60%) reported febrile headaches during August-October (all occurring during the last week of September), compared with seven (7%) of 97 IgM-negative persons sampled (p = 0.0002 by Fisher exact test). All six IgMpositive persons who reported febrile headache had worked at farm A. All six noted a skin rash, and one had meningoencephalitis and was hospitalized; no deaths occurred. Reported mosquito exposures and bites were similar for IgM-positive (nine and eight of 10, respectively) and IgMnegative workers (67 and 54 of 79, respectively). Only one (2%) of 57 breeder farm workers reported using insect repellent while working.\nFarm A includes two breeder bird barns and a juvenile flock barn. The breeder barns separate uncaged females from male turkeys with a solid plywood wall. The sides of the barns housing the female turkeys are covered with 1 in. x 1 in. mesh wire fencing and plastic curtains that can be adjusted to lower the temperature during warm months.\nSerum from farm A turkeys and turkeys from the nearest breeder farm were collected in late January 2003. The farm A flock sampled was the group of birds housed in the juvenile flock barn from mid-June to early December 2002, at which time this flock was moved to a breeder barn on farm A to replace a flock slaughtered in November. The flock sampled on the nearby farm was a breeder flock also in place in Editorial Note: The investigation described in this report found that workers at farm A had a higher incidence of febrile illness and prevalence of WNV antibodies than workers at other breeder and nonbreeder farms, workers at a turkey meat processing facility, or persons who lived on or near the affected farm and who did not work in the turkey barns. The mode of transmission to these workers is unknown. Although the majority of human WNV infections are mosquito-borne, transmission by less typical routes might have occurred, including percutaneous (e.g., exposure of broken skin or mucosa to infected turkey feces or serous exudates from duallyinfected pox lesions), fecal-oral, or respiratory (e.g., exposure to aerosolized infected turkey feces). The WNV seroprevalence (96%) among female turkeys on farm A was high. However, experimental evidence suggests that turkeys develop insufficient levels of WNV viremia to contribute to a bird-mosquito-bird amplification cycle (3). Although WNV was detected in the feces of these turkeys, no oropharyngeal shedding or transmission to cage mates was observed (3). Nonvector-borne WNV transmission has been demonstrated experimentally among rodents and among certain bird species other than turkeys (4,5). Once WNV was introduced to female turkeys at farm A (presumably by mosquitoes), widespread transmission within that flock might have taken place by fecal-oral, respiratory, or another atypical (e.g., percutaneous exposure associated with pecking behavior or vaccination) route. In addition, other unique conditions at farm A, including possible co-infection with an avian pox virus, might have resulted in higher WNV viremias or infectious materials with higher WNV titers than laboratory studies have suggested.\nDespite uncertainty over the mode(s) of transmission, epidemiologic evidence suggests that this outbreak was related to occupational exposure. Occupationally acquired WNV infections have been reported previously among laboratory or field workers who experienced a known percutaneous injury or aerosol exposure while working with high concentrations of WNV in cell culture or infected animal tissues (6)(7)(8)(9). In this investigation, no such exposure was documented. Because the mode of transmission in this outbreak is unknown, turkey handlers should 1) take personal protective measures, including wearing protective clothing and using mosquito repellents (e.g., those containing DEET on skin and clothing and those containing permethrin on clothing), as recommended for outdoor workers; 2) wear gloves; and 3) wash hands frequently. In addition, respiratory protection has been recommended for reducing other exposures to workers in turkey barns (10). Respiratory protection should be selected and used in accordance with the Occupational Safety and Health Administration (OSHA) respiratory protection standard (Title 29 CFR 1910.134).\nWorkers should receive training that reinforces awareness of potential occupational hazards and risks and stresses the importance of timely reporting of all injuries and illnesses of suspected occupational origin. Health-care workers should inquire about a patient's outdoor exposure and occupation when a human WNV infection is suspected or identified and consider WNV as a possible etiology among turkey farm workers with febrile headache or rash, meningitis, encephalitis, or other severe neurologic illness, especially when WNV illnesses exist among co-workers or birds. Suspected occupationally acquired WNV infections should be reported immediately to local and state health departments.\nThe investigation of turkey breeder farm workers in county A is ongoing. In addition, further studies are needed to determine the factors involved in this outbreak, to better define the occupational risk for WNV infections, and to assess appropriate personal protective measures. On the basis of recommendations from public health staff, the company has made mosquito repellent containing 30% DEET available at farm A and other turkey breeder farms. Recommendations that were outlined previously in place at the company farms include protective clothing, frequent hand washing, and an OSHArequired respiratory protection program. Gloves and safety glasses also are available to workers.\n\n# Public Health and Aging\n\n# Nonfatal Injuries Among Older Adults Treated in Hospital Emergency Departments -United States, 2001\nBecause injuries generally are considered a problem of the young, injuries among older adults (i.e., persons aged >65 years) have received little attention. However, injuries are the eighth leading cause of death among older adults in the United States (1). In 2001, approximately 2.7 million older adults were treated for nonfatal injuries in hospital emergency departments (EDs); the majority of these injuries were the result of falls (1). To characterize nonfatal injuries among older adults, CDC analyzed data from the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP). This report summarizes the results of that analysis, which indicate differences in type and mechanism of injury by sex, suggesting that prevention programs should be designed and tailored differently for men and women.\nNEISS-AIP is operated by the U.S. Consumer Product Safety Commission and collects data about initial visits for all (MMWR on line) cdc.gov/mmwr Online types and causes of injuries treated in U.S. EDs, drawing from a nationally representative sample of 66 hospitals selected as a stratified probability sample of hospitals in the United States. Data from these cases are weighted by the inverse of the probability of selection to produce national estimates (2). For this report, annualized estimates were calculated on the basis of weighted data for 36,752 nonfatal injuries among older adults treated in EDs during January-December 2001. U.S. Census Bureau population estimates for 2001 were used to calculate injury rates (3). A direct variance estimation procedure was used to calculate 95% confidence intervals and to account for the complex sample design (2). All nonfatal injuries were classified according to the mechanism of injury (e.g., fall, struck by/against, or motor vehicle crash), diagnosis, primary body part injured, disposition, location of injury, and intent. The diagnosis and intent of the injury were classified according to the most severe injury (4). Injuries of unknown intent were grouped with those classified as unintentional.\nDuring 2001, an estimated 935,556 men and 1,731,640 women aged >65 years were treated in EDs for nonfatal injuries. The overall injury rate per 100,000 persons was higher among women (8,466 per 100,000 persons) than among men (6,404). Injury rates increased with age, to 15,272 for women aged >85 years and 11,547 for men aged >85 years. Nearly all injuries (99%) were classified as unintentional/unknown intent (Table ).\nOverall, falls resulted in the highest rates of injury (4,684 per 100,000 persons) and were the most common mechanism of injury, accounting for 62% of all nonfatal injury ED visits in this population. The injury rate from falls was higher among women (5,659) than men (3,319). However, the injury rates for women were lower with certain other types of injuries, such as being struck by/against (588 versus 617), occupying a motor vehicle (525 versus 540), and being cut or pierced (243 versus 488) (Table ).\nThe greatest number of nonfatal injuries among older adults were diagnosed as fractures (26%), followed by contusions/ abrasions (23%), lacerations (17%), strains/sprains (13%), and internal injuries (5%). Diagnoses varied by sex. Fractures of all parts of the body were more common among women than men (30% versus 19%), and lacerations were more common among men than women (22% versus 14%). The parts of the body affected most were the head/neck (25%) and arms/hands (22%). The majority (82%) of older adults were treated and released; 16% were hospitalized. The ratio of patients treated/ released to those hospitalized was lower among women (4.7:1) than men (5.9:1), suggesting women were more often hospitalized after a nonfatal injury. The most common (47%) location for nonfatal injuries was the home (Table ). Editorial Note: Falls remain the leading cause of both nonfatal and fatal injury among older adults aged >65 years in the United States (1). The findings in this report, which indicate that falls were the most common reason for injury-related ED visits among persons aged >65 years, are consistent with previous studies indicating that approximately 40% of older adults living in community settings (e.g., in private residences or minimally assisted environments) fall each year (5).\nIn this study, 82% of persons aged >65 years were treated and released following injury, compared with 95% of persons aged <65 years. Older adults were more than three times more likely (1,217 per 100,000 persons) to be hospitalized than persons aged <65 years (353) (1).\nThe findings in this report are subject to at least five limitations. First, NEISS-AIP provides national estimates and does not allow for estimates by region, state, or local jurisdiction. Second, injury outcomes are specific to ED visits and do not include subsequent outcomes. Third, NEISS-AIP data reflect only those injuries that were severe enough to require treatment in an ED. Fourth, in cases with multiple injuries, only data regarding the most severe injury are recorded. Finally, data for intent are classified on the basis of information contained in the medical record. Injuries for which intent cannot be determined conclusively from the ED record are grouped with unintentional injuries.\nThe findings in this report can form the basis for targeting prevention efforts to different populations of older adults. For example, exercise can reduce the risk for fall among older adults by 15% (6). Because women are more likely to sustain fallrelated injuries, exercise can be an especially important preventive measure for this population. Data from NEISS-AIP can continue to be a source for monitoring trends, evaluating interventions, and characterizing nonfatal injuries among persons aged >65 years. (n = four), New Mexico (n = four), North Dakota (n = four), Alabama (n = three), Ohio (n = three), Indiana (n = two), Missouri (n = two), Montana (n = two), New Jersey (n = two), Delaware (n = one), Illinois (n = one), Kansas (n = one), Kentucky (n = one), Louisiana (n = one), Michigan (n = one), Mississippi (n = one), Tennessee (n = one), and Virginia (n = one). A total of 682 presumptive West Nile viremic blood donors have been reported to ArboNET. Of these, 596 (87%) were reported from the following nine western and midwestern states: Colorado, Kansas, Nebraska, New Mexico, North Dakota, Oklahoma, South Dakota, Texas, and Wyoming. Of the 529 donors for whom data were reported completely, six subsequently had meningoencephalitis, and 76 subsequently had West Nile fever.\nIn addition, 10,453 dead birds with WNV infection have been reported from 42 states, the District of Columbia, and New York City; 3,270 WNV infections in horses, 16 WNV infections in dogs, 14 infections in squirrels, and 24 infections in unidentified\n\n# Human WNV disease and animal WNV activity\nAnimal WNV activity only one. In addition, seropositivity was reported from one other unidentified animal species. A total of 6,667 WNV-positive mosquito pools have been reported from 38 states, the District of Columbia, and New York City.\nAdditional information about WNV activity is available from CDC at / index.htm and .\n\n# Notice to Readers\n\n# Guidelines for Maintaining and Managing the Vaccine Cold Chain\nIn February 2002, the Advisory Committee on Immunization Practices (ACIP) and American Academy of Family Physicians (AAFP) released their revised General Recommendations on Immunization (1), which included recommendations on the storage and handling of immunobiologics. Because of increased concern over the potential for errors with the vaccine cold chain (i.e., maintaining proper vaccine temperatures during storage and handling to preserve potency), this notice advises vaccine providers of the importance of proper cold chain management practices. This report describes proper storage units and storage temperatures, outlines appropriate temperature-monitoring practices, and recommends steps for evaluating a temperature-monitoring program. The success of efforts against vaccine-preventable diseases is attributable in part to proper storage and handling of vaccines. Exposure of vaccines to temperatures outside the recommended ranges can affect potency adversely, thereby reducing protection from vaccine-preventable diseases (1). Good practices to maintain proper vaccine storage and handling can ensure that the full benefit of immunization is realized.\n\n# Recommended Storage Temperatures\nThe majority of commonly recommended vaccines require storage temperatures of 35°F-46°F (2°C-8°C) and must not be exposed to freezing temperatures. Introduction of varicella vaccine in 1995 and of live attenuated influenza vaccine (LAIV) more recently increased the complexity of vaccine storage. Both varicella vaccine and LAIV must be stored in a continuously frozen state <5°F (-15°C) with no freeze-thaw cycles (Table 1). In recent years, instances of improper vaccine storage have been reported. An estimated 17%-37% of providers expose vaccines to improper storage temperatures, and refrigerator temperatures are more commonly kept too cold than too warm (2,3).\nFreezing temperatures can irreversibly reduce the potency of vaccines required to be stored at 35°F-46°F (2°C-8°C). Certain freeze-sensitive vaccines contain an aluminum adjuvant that precipitates when exposed to freezing temperatures. This results in loss of the adjuvant effect and vaccine potency (4). Physical changes are not always apparent after exposure to freezing temperatures and visible signs of freezing are not necessary to result in a decrease in vaccine potency.\nAlthough the potency of the majority of vaccines can be affected adversely by storage temperatures that are too warm, these effects are usually more gradual, predictable, and smaller in magnitude than losses from temperatures that are too cold. In contrast, varicella vaccine and LAIV are required to be stored in continuously frozen states and lose potency when stored above the recommended temperature range.\n\n# Vaccine Storage Requirements\nVaccine storage units must be selected carefully and used properly. A combination refrigerator/freezer unit sold for home use is acceptable for vaccine storage if the refrigerator and freezer compartments each have a separate door. However, vaccines should not be stored near the cold air outlet from the freezer to the refrigerator. Many combination units cool the refrigerator compartment by using air from the freezer compartment. In these units, the freezer thermostat controls freezer temperature while the refrigerator thermostat controls the volume of freezer temperature air entering the refrigerator. This can result in different temperature zones within the refrigerator.\nRefrigerators without freezers and stand-alone freezers usually perform better at maintaining the precise temperatures required for vaccine storage, and such single-purpose units sold for home use are less expensive alternatives to medical specialty equipment. Any refrigerator or freezer used for vaccine storage must maintain the required temperature range year-round, be large enough to hold the year's largest inventory, and be dedicated to storage of biologics (i.e., food or beverages should not be stored in vaccine storage units). In addition, vaccines should be stored centrally in the refrigerator or freezer, not in the door or on the bottom of the storage unit, and sufficiently away from walls to allow air to circulate.\n\n# Temperature Monitoring\nProper temperature monitoring is key to proper cold chain management. Thermometers should be placed in a central location in the storage unit, adjacent to the vaccine. Temperatures should be read and documented twice each day, once when the office or clinic opens and once at the end of the day. Temperature logs should be kept on file for >3 years, unless state statutes or rules require a longer period. Immediate action must be taken to correct storage temperatures that are outside the recommended ranges. Mishandled vaccines should not be administered.\nOne person should be assigned primary responsibility for maintaining temperature logs, along with one backup person. Temperature logs should be reviewed by the backup person at least weekly. All staff members working with vaccines should be familiar with proper temperature monitoring.\nDifferent types of thermometers can be used, including standard fluid-filled, min-max, and continuous chart recorder thermometers (Table 2). Standard fluid-filled thermometers are the simplest and least expensive products, but some models might perform poorly. Product temperature thermometers (i.e., those encased in biosafe liquids) might reflect vaccine temperature more accurately. Min-max thermometers monitor the temperature range. Continuous chart recorder thermometers monitor temperature range and duration and can be recalibrated at specified intervals. All thermometers used for monitoring vaccine storage temperatures should be calibrated and certified by an appropriate agency (e.g., National Institute of Standards and Technology). In addition, temperature indicators (e.g., Freeze Watch ™ or ColdMark ™ ) can be considered as a backup monitoring system (5); however, such indicators should not be used as a substitute for twice daily temperature readings and documentation.\nAll medical care providers who administer vaccines should evaluate their cold chain maintenance and management to ensure that 1) designated personnel and backup personnel have written duties and are trained in vaccine storage and handling; 2) accurate thermometers are placed properly in all vaccine storage units and any limitations of the storage system are fully known; 3) vaccines are placed properly within the refrigerator or freezer in which proper temperatures are maintained; 4) temperature logs are reviewed for completeness and any deviations from recommended temperature ranges; 5) any outof-range temperatures prompt immediate action to fix the problem, with results of these actions documented; 6) any vaccines exposed to out-of-range temperatures are marked \"do not use\" and isolated physically; 7) when a problem is discovered, the exposed vaccine is maintained at proper temperatures while state or local health departments, or the vaccine manufacturers, are contacted for guidance; and 8) written emergency retrieval and storage procedures are in place in case of equipment failures or power outages. Around-the-clock monitoring systems might be considered to alert staff to afterhours emergencies, particularly if large vaccine inventories are maintained.\nAdditional information on vaccine storage and handling is available from the Immunization Action Coalition at http:// www.immunize.org/izpractices/index.htm. Links to state and local health departments are available at / other.htm. Especially detailed guidelines from the Commonwealth of Australia on vaccine storage and handling, vaccine storage units, temperature monitoring, and stability of vaccines at different temperatures (6)\n\n# Notice to Readers\n\n# International Conference on Emerging Infectious Diseases\nCDC's National Center for Infectious Diseases, the Council of State and Territorial Epidemiologists, the American Society for Microbiology, and the World Health Organization will cosponsor the International Conference on Emerging Infectious Diseases February 29-March 3, 2004, at the Marriott Marquis Hotel in Atlanta, Georgia. The conference will explore the most current research, surveillance, and prevention and control programs addressing all aspects of emerging infectious diseases. Attendance is limited to 2,500 participants.\nThe conference will include general and plenary sessions, symposia, panels of speakers, presentations on emerging infections activities, oral and poster presentations, and exhibits. The deadline for abstract submission for presentations is November 14, 2003. Information about submitting abstracts is available at . Abstracts should address new, reemerging, or drug-resistant infectious diseases that affect human health. The deadline for late-breaker abstracts is January 16, 2004.\nRegistration information is available at and at and by e-mail at meetinginfo@asmusa.org or at dsy1@cdc.gov.\n\n# Errata: Vol. 52, No. 40\nIn the article, \"Cigarette Smoking Among Adults -United States, 2001,\" an error occurred in the table on page 955. Total prevalence for persons with 0-12 yrs (no diploma) of education was reported to be 28.4% (95% CI +1.4). The correct prevalence for this population should have been 27.5% (95% CI +1.4).\nIn the article, \"Recommended Adult Immunization Schedule -United States, 2003-2004,\" on page 968, an incorrect volume number was given for the fourth reference. The reference should read, \"4. CDC. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(No. RR-8).\"\n\n# Errata: Vol. 52, No. RR-10\nIn the MMWR Recommendations and Reports, \"Guidelines for Environmental Infection Control in Health-Care Facilities: Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC),\" On page 10, in Figure 1, the third bullet under the footnote should read as follows:\n\"- air volume differential >125 cfm supply versus exhaust.\" On page 11, in Figure 2, the label \"Neutral anteroom\" should read \"anteroom.\" Also, the first, second, and seventh bullets under the footnote should read as follows: \"- pressure differential of 2.5 Pa (0.01-in. water gauge) measured at the door between patient room and anteroom;\n- air volume differential >125 cfm, depending on anteroom airflow direction (i.e., pressurized versus depressurized);\n- anteroom airflow patterns (i.e., anteroom is pressurized in top and middle panels, and depressurized in bottom panel).\"\nOn page 12, in Figure 3, the third bullet under the footnote should read as follows:\n\" e ncore.\nWeek after week, MMWR Online plays an important role in helping you stay informed. From the latest CDC guidance to breaking health news, count on MMWR Online to deliver the news you need, when you need it.\nLog on to cdc.gov/mmwr and enjoy MMWR performance.\n- No measles or rubella cases were reported for the current 4-week period yielding a ratio for week 42 of zero (0). † Ratio of current 4-week total to mean of 15 4-week totals (from previous, comparable, and subsequent 4-week periods for the past 5 years). The point where the hatched area begins is based on the mean and two standard deviations of these 4-week totals.\nU: Unavailable.\n-:No reported cases. - Mortality data in this table are voluntarily reported from 122 cities in the United States, most of which have populations of >100,000. A death is reported by the place of its occurrence and by the week that the death certificate was filed. Fetal deaths are not included. † Pneumonia and influenza. § Because of changes in reporting methods in this Pennsylvania city, these numbers are partial counts for the current week. Complete counts will be available in 4 to 6 weeks. ¶ Total includes unknown ages."},"raw_text":{"kind":"string","value":"depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# \nWhen first evaluated at WRAMC, the 22 patients had a median of three (range: one to nine) skin lesions, which ranged from 3 mm to 40 mm in diameter. Higher proportions of the lesions were located on the upper (39%) or lower (32%) extremities than on the trunk/back (16%) or face/neck (13%). Typically, the lesions were painless, had enlarged slowly, and ultimately had central ulceration, often covered with eschar and surrounded by an erythematous, indurated border (Figure 2). Regional lymph nodes (e.g., epitrochlear, axillary, and inguinal), if palpable, usually were <1 cm in diameter. None of the patients had systemic symptoms.\nIn 17 (77%) of the 22 cases, parasites were noted on lightmicroscopic examination of tissue. Of the 19 patients who had tissue cultured for parasites, 14 (74%) had positive cultures, of which 13 (93%) had sufficient organisms for species identification by isoenzyme electrophoresis. All nine of the 13 patients whose cultures had been tested as of October 20, 2003, were infected with Leishmania major. Additional evidence that 21 (95%) of the 22 patients had CL was obtained by testing tissue with an investigational, fluorogenic, genusspecific polymerase chain reaction (PCR) assay developed and conducted by staff of WRAMC and Walter Reed Army Institute of Research (Silver Spring, Maryland) (6).\nSince 1978, military personnel with potential cases of leishmaniasis have been referred to WRAMC for evaluation and therapy with the pentavalent antimonial compound sodium stibogluconate (Pentostam ® , The Wellcome Foundation, United Kingdom). Although treatment of cases of CL with pentavalent antimonial compounds has been considered the standard of care for over half a century (1), these compounds Editorial Note: Leishmaniasis is a vector-borne parasitic disease endemic in parts of the tropics, subtropics, and Southern Europe. The World Health Organization estimates that 1.5 million cases of CL and 500,000 cases of visceral leishmaniasis (VL) occur each year (1).\nBoth cutaneous and visceral infection can remain asymptomatic or be associated with mild, nonspecific, and nonprogressive symptoms (1). Clinical manifestations, if they develop, typically are first noted weeks to months after exposure. The skin lesions of CL, which can be chronic and disfiguring, typically evolve from papules to nodules to ulcerative lesions but can persist as nodules or plaques (1). Host (e.g., immune status) and parasite (e.g., species and strain) characteristics affect the natural history and the ease and importance of diagnosing and treating cases of CL. Although both L. major and L. tropica are common etiologic agents of CL in Afghanistan, Iraq, and Kuwait (1,7,8), which species has caused a particular case of CL depends on such factors as the geographic area and ecologic setting of exposure and the species of the sand-fly vector. VL is more prevalent in Iraq (8) than in Afghanistan or Kuwait. Manifestations of cases of advanced VL include fever, cachexia, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia; such cases can be fatal if not treated appropriately and quickly (1).\nNo FDA-approved vaccines or prophylactic medications to prevent leishmaniasis are available (1). Control measures against vectors or reservoir hosts of infection might be effective in particular settings (1,8,9). Personal protective measures to decrease risk for infection include avoiding, if possible, areas where leishmaniasis is endemic, particularly from dusk through dawn; using permethrin-treated bed nets and clothing; minimizing the amount of exposed skin; and applying insect repellents containing 30%-35% DEET (lower percentages for children) to exposed skin.\nTransmission of leishmanial parasites through blood transfusion has not been reported in the United States. However, as a precautionary measure, the Armed Services Blood Program Office of the Department of Defense (DoD) (Falls Church, Virginia) and the American Association of Blood Banks (AABB) (Bethesda, Maryland) are implementing policies to defer prospective blood donors who have been in Iraq from donating blood for 12 months after the last date they left Iraq. Additional information about these deferral policies is available from DoD at http://www-nehc.med.navy.mil/ downloads/prevmed/leishmanAug03.pdf and from AABB at http://www.aabb.org.\nIn Operations Desert Storm and Shield during 1990-1991, among approximately 697,000 deployed military personnel, WRAMC identified 12 cases of so-called viscerotropic leishmaniasis caused by L. tropica (a syndrome associated with visceral infection but not necessarily the classic clinical manifestations of VL) and 20 cases of CL (3,10;WRAMC, unpublished data, 2003). During August 2002-September 2003, WRAMC identified 22 cases of CL among personnel participating in Operations Iraqi and Enduring Freedom. The apparent decline in numbers of cases of CL with self-reported onset of lesions during July-August 2003 (Figure 1) could reflect delays in persons seeking medical evaluation for skin lesions that might not cause concern initially. U.S. personnel in Iraq have reported being bitten by sand flies (some persons have received >100 bites in a single night), and up to 2% of female phlebotomine sand flies collected in Iraq were infected with leishmanial parasites. As of October 21, WRAMC had identified nine more cases of CL in addition to the 22 cases described in this report. WRAMC is evaluating additional potential cases of CL in deployed personnel, and the number of confirmed cases probably will continue to increase.\nU.S. health-care providers should consider the possibility of CL in persons with chronic skin lesions who were deployed to Southwest/Central Asia or who were in other areas where leishmaniasis is endemic and that of VL in such persons with persistent, febrile illnesses, especially if associated with other manifestations suggestive of VL (e.g., splenomegaly and pancytopenia) (1,4,8,10). Information about diagnosing and treating CL and VL has been published (1,5). Both WRAMC and CDC provide diagnostic services and the antileishmanial compound sodium stibogluconate. For treatment of health-care beneficiaries of the military, health-care providers should contact WRAMC, telephone 202-782-6740. For treatment of civilians, providers should contact CDC's Drug Service, telephone 404-639-3670.\n# Infant Health Among Puerto Ricans -Puerto Rico and U.S. Mainland, 1989-2000\nAlthough the overall U.S. infant mortality rate (IMR) declined dramatically during the 1900s, striking racial/ethnic disparities in infant mortality remain (1,2). Infant health disparities associated with maternal place of birth also exist within some racial/ethnic populations (3,4). Eliminating disparities in infant health is crucial to achieving the 2010 national health objective of reducing the infant death rate to 4.5 per 1,000 live births (objective 16-1c) (5). Hispanics comprise the largest racial/ethnic minority population in the United States. Among U.S. Hispanics, considerable heterogeneity exists in infant health, with the poorest outcomes reported among Puerto Rican infants (6). This report compares trends during the previous decade in IMRs and major determinants of these rates such as low birthweight (LBW), preterm delivery (PTD), and selected maternal characteristics among infants born to Puerto Rican women on the U.S. mainland (50 states and the District of Columbia) with corresponding trends among infants born in Puerto Rico. The findings indicate that despite having lower prevalence of selected maternal risk factors, Puerto Rico-born infants are at greater risk for LBW, PTD, and infant death than mainland-born Puerto Rican infants. This report also highlights a persistent disparity in IMRs and an emerging disparity in LBW and PTD rates between Puerto Rico-born infants and mainland-born Puerto Rican infants. Future research should focus on identifying factors responsible for these disparities to improve infant health in Puerto Rico.\nLinked birth/infant death files for the 50 states, the District of Columbia, and Puerto Rico for 1989-1991 and 1998-2000 were used to assess IMR trends. Natality files for 1990-2000 were used to examine trends in rates of LBW (<2,500 g), know what matters.\n# Dispatch\nup-to-the-minute: adj 1 : extending up to the immediate present, including the very latest information; see also MMWR. PTD (<37 weeks' gestation), and selected maternal characteristics among live-born infants. Analyses were limited to infants born to Puerto Rican women (i.e., those born in Puerto Rico, those born on the mainland to Puerto Rico-born mothers, or those born on the mainland to mothers who reported being of Puerto Rican ethnicity). Infants born in Puerto Rico to women not born either in Puerto Rico or on the mainland were excluded. Four subpopulations of Puerto Rican infants were examined initially: infants born in Puerto Rico to Puerto Rico-born mothers, infants born in Puerto Rico to mainlandborn mothers, infants born on the mainland to Puerto Ricoborn mothers, and infants born on the mainland to mainland-born mothers of Puerto Rican ethnicity. However, because maternal place of birth was not associated substantially with infant health outcomes, data are shown for Puerto Rico-born and mainland-born infants without regard to maternal place of birth. Chi square tests were used to compare differences in the prevalence of infant and maternal characteristics and differences in IMRs among the groups.\n# Low Birthweight and Preterm Delivery\nIn 1990, Puerto Rico-born infants were 1.03 times more likely to be of LBW than mainland-born infants, and in 2000, this disparity increased to 1.2 (Figure). From 1990 to 2000, the LBW rate for Puerto Rico-born infants increased 18.0%, from 9.2% to 10.9%; for mainland-born infants, the LBW rate increased 3.7%, from 8.9% to 9.3%. Similar differences in LBW rate increases were observed when analyses were restricted to full-term and singleton births. The increase in the LBW rate among Puerto Rico-born infants was associated predominantly with an increase in the percentage of infants with an intermediate LBW (ILBW; 1,500-2,499 g); however, a small increase also was observed in the percentage with a very low birthweight (VLBW; <1,500 g) (Table 1). In 2000, Puerto Rico-born infants were less likely than mainlandborn infants to be of VLBW (ratio = 0.7) but more likely to be of ILBW (ratio = 1.3) (Table 1).\nIn 1990, Puerto Rico-born infants were less likely than mainland-born infants to be born preterm (ratio = 0.9) (Figure ). From 1990 to 2000, the PTD rate among Puerto Rico-born infants increased 29.3% (from 11.6% to 15.0%), and that among mainland-born infants increased 0.9% (from 13.3% to 13.4%). As a result, in 2000, Puerto Rico-born infants were 1.1 times more likely than mainland-born infants to be born preterm. Similar differences in PTD rates were observed when analyses were limited to singleton births. The increase in the PTD rate among Puerto Rico-born infants was attributable primarily to an increase in the rate of moderately preterm births (32-36 weeks' gestation), although the rate of very preterm births (<32 weeks' gestation) also increased slightly (Table 1).\nIn 2000, despite higher rates of LBW and PTD among Puerto Rico-born infants, their mothers were less likely than mothers of mainland-born infants to report selected maternal risk factors, including receiving late/no prenatal care, having <12 years of education, not being married, having plural births, and using tobacco (Table 1). The prevalence of first trimester prenatal care and the percentage of mothers aged <19 years at their infant's birth were similar for the two groups (Table 1). The prevalence of these maternal characteristics did not differ by maternal place of birth.\n# Infant Mortality\nFrom 1989-1991 to 1998-2000, the combined IMR for Puerto Rico-born and mainland-born infants declined approximately 24%. The 1989-1991 IMR for Puerto (6), risk factors such as maternal tobacco use might be reported less completely in Puerto Rico than on the mainland. Second, because Hispanic origin is not recorded on birth certificates in Puerto Rico, this study was based on records for infants born either in Puerto Rico or on the mainland; mainland-born infants were defined as having Puerto Rican ethnicity if their mothers were born in Puerto Rico or reported being Puerto Rican.\nThis report highlights a continuing disparity in infant mortality rates and an emerging disparity in LBW and PTD rates between Puerto Rico-born infants and infants born on the mainland to Puerto Rican mothers. These differences should be considered in the planning and implementation of efforts to reduce IMRs among Puerto Ricans. The higher birthweightand gestational age-specific IMRs in Puerto Rico contribute more to the overall higher IMR in Puerto Rico than do the differences in birthweight and gestational age distributions between Puerto Rico-and mainland-born infants (8). Efforts to reduce IMR in Puerto Rico should focus on reducing mortality rates among LBW and preterm infants, perhaps by examining existing perinatal services. Additional opportunities might exist for lowering the overall IMR if the underlying causes of the increases in the prevalence of LBW and PTD can be identified and prevented. Improving infant health in Puerto Ricans will most likely require interventions at the individual, provider, and health-care system levels. \n# West Nile Virus Infection Among Turkey Breeder Farm Workers -Wisconsin, 2002\nIn 2002, Wisconsin public health officials were notified of two cases of febrile illness in workers at a commercial turkey breeder farm (farm A) in county A. The Wisconsin Division of Public Health (WDPH) initiated an investigation that found a high prevalence of West Nile virus (WNV) antibody among farm A workers and turkeys. An associated high incidence of febrile illness among farm A workers also was observed. This report summarizes the results of this investigation, which indicate possible nonmosquito transmission among birds and subsequent infection of humans at farm A. Because the mode of transmission in this outbreak is unknown, turkey handlers should take appropriate precautions, including use of DEETcontaining mosquito repellents, protective clothing and gloves, respiratory protection, and proper hand hygiene. Suspected occupationally acquired WNV infections should be reported immediately to local and state health departments.\nDuring November 2002, WDPH and the Wisconsin State Laboratory of Hygiene (WSLH) confirmed that two ill residents of county A had been infected with WNV. Before these reports, only one human WNV infection had been reported in this county. Both persons worked at farm A and had febrile illness with rash during late September-early October. These human illnesses occurred after a suspected fowl pox outbreak among farm A turkeys in September. Workers were concerned the pox outbreak might be associated with their illnesses.\nFarm A is one of six turkey breeder farms in county A owned by a company that also operates nonbreeder farms and a turkey meat processing plant in county A. The five other turkey breeder farms are located within 10 miles of farm A, and multiple private residences are within a quarter mile. In February 2003, county and state public health staff, in collaboration with the company, identified workers at the six turkey breeder farms, the nonbreeder farms, and the plant, and requested their consent to participate in a serosurvey. Serum samples were collected from participating workers (N = 93) to identify persons infected recently. A questionnaire was administered to identify persons who had a febrile illness during August-October 2002. Serum samples also were collected from residents (N = 14) who lived within a quarter mile of farm A. All serum samples were tested for WNV-specific IgM antibody at WSLH (1). IgM-positive specimens were confirmed by plaque-reduction neutralization tests at CDC (2). Of 107 total participants, 10 (9%) were seropositive. Of approximately 90 workers at the six breeder farms, 57 (63%) participated; of these, 10 (18%) were infected recently with WNV (Table ). None of the meat processing workers or other area residents was infected. Of 11 persons who worked exclusively at farm A, six (55%) were WNV IgM-positive, compared with two (25%) of eight who worked at both farm A and other breeder farms and two (5%) of 38 who worked only at other breeder farms. Of the 10 IgM-positive workers, six (60%) reported febrile headaches during August-October (all occurring during the last week of September), compared with seven (7%) of 97 IgM-negative persons sampled (p = 0.0002 by Fisher exact test). All six IgMpositive persons who reported febrile headache had worked at farm A. All six noted a skin rash, and one had meningoencephalitis and was hospitalized; no deaths occurred. Reported mosquito exposures and bites were similar for IgM-positive (nine [90%] and eight [80%] of 10, respectively) and IgMnegative workers (67 [85%] and 54 [68%] of 79, respectively). Only one (2%) of 57 breeder farm workers reported using insect repellent while working.\nFarm A includes two breeder bird barns and a juvenile flock barn. The breeder barns separate uncaged females from male turkeys with a solid plywood wall. The sides of the barns housing the female turkeys are covered with 1 in. x 1 in. mesh wire fencing and plastic curtains that can be adjusted to lower the temperature during warm months.\nSerum from farm A turkeys and turkeys from the nearest breeder farm were collected in late January 2003. The farm A flock sampled was the group of birds housed in the juvenile flock barn from mid-June to early December 2002, at which time this flock was moved to a breeder barn on farm A to replace a flock slaughtered in November. The flock sampled on the nearby farm was a breeder flock also in place in Editorial Note: The investigation described in this report found that workers at farm A had a higher incidence of febrile illness and prevalence of WNV antibodies than workers at other breeder and nonbreeder farms, workers at a turkey meat processing facility, or persons who lived on or near the affected farm and who did not work in the turkey barns. The mode of transmission to these workers is unknown. Although the majority of human WNV infections are mosquito-borne, transmission by less typical routes might have occurred, including percutaneous (e.g., exposure of broken skin or mucosa to infected turkey feces or serous exudates from duallyinfected pox lesions), fecal-oral, or respiratory (e.g., exposure to aerosolized infected turkey feces). The WNV seroprevalence (96%) among female turkeys on farm A was high. However, experimental evidence suggests that turkeys develop insufficient levels of WNV viremia to contribute to a bird-mosquito-bird amplification cycle (3). Although WNV was detected in the feces of these turkeys, no oropharyngeal shedding or transmission to cage mates was observed (3). Nonvector-borne WNV transmission has been demonstrated experimentally among rodents and among certain bird species other than turkeys (4,5). Once WNV was introduced to female turkeys at farm A (presumably by mosquitoes), widespread transmission within that flock might have taken place by fecal-oral, respiratory, or another atypical (e.g., percutaneous exposure associated with pecking behavior or vaccination) route. In addition, other unique conditions at farm A, including possible co-infection with an avian pox virus, might have resulted in higher WNV viremias or infectious materials with higher WNV titers than laboratory studies have suggested.\nDespite uncertainty over the mode(s) of transmission, epidemiologic evidence suggests that this outbreak was related to occupational exposure. Occupationally acquired WNV infections have been reported previously among laboratory or field workers who experienced a known percutaneous injury or aerosol exposure while working with high concentrations of WNV in cell culture or infected animal tissues (6)(7)(8)(9). In this investigation, no such exposure was documented. Because the mode of transmission in this outbreak is unknown, turkey handlers should 1) take personal protective measures, including wearing protective clothing and using mosquito repellents (e.g., those containing DEET on skin and clothing and those containing permethrin on clothing), as recommended for outdoor workers; 2) wear gloves; and 3) wash hands frequently. In addition, respiratory protection has been recommended for reducing other exposures to workers in turkey barns (10). Respiratory protection should be selected and used in accordance with the Occupational Safety and Health Administration (OSHA) respiratory protection standard (Title 29 CFR 1910.134).\nWorkers should receive training that reinforces awareness of potential occupational hazards and risks and stresses the importance of timely reporting of all injuries and illnesses of suspected occupational origin. Health-care workers should inquire about a patient's outdoor exposure and occupation when a human WNV infection is suspected or identified and consider WNV as a possible etiology among turkey farm workers with febrile headache or rash, meningitis, encephalitis, or other severe neurologic illness, especially when WNV illnesses exist among co-workers or birds. Suspected occupationally acquired WNV infections should be reported immediately to local and state health departments.\nThe investigation of turkey breeder farm workers in county A is ongoing. In addition, further studies are needed to determine the factors involved in this outbreak, to better define the occupational risk for WNV infections, and to assess appropriate personal protective measures. On the basis of recommendations from public health staff, the company has made mosquito repellent containing 30% DEET available at farm A and other turkey breeder farms. Recommendations that were outlined previously in place at the company farms include protective clothing, frequent hand washing, and an OSHArequired respiratory protection program. Gloves and safety glasses also are available to workers. \n# Public Health and Aging\n\n# Nonfatal Injuries Among Older Adults Treated in Hospital Emergency Departments -United States, 2001\nBecause injuries generally are considered a problem of the young, injuries among older adults (i.e., persons aged >65 years) have received little attention. However, injuries are the eighth leading cause of death among older adults in the United States (1). In 2001, approximately 2.7 million older adults were treated for nonfatal injuries in hospital emergency departments (EDs); the majority of these injuries were the result of falls (1). To characterize nonfatal injuries among older adults, CDC analyzed data from the National Electronic Injury Surveillance System-All Injury Program (NEISS-AIP). This report summarizes the results of that analysis, which indicate differences in type and mechanism of injury by sex, suggesting that prevention programs should be designed and tailored differently for men and women.\nNEISS-AIP is operated by the U.S. Consumer Product Safety Commission and collects data about initial visits for all (MMWR on line) cdc.gov/mmwr Online types and causes of injuries treated in U.S. EDs, drawing from a nationally representative sample of 66 hospitals selected as a stratified probability sample of hospitals in the United States. Data from these cases are weighted by the inverse of the probability of selection to produce national estimates (2). For this report, annualized estimates were calculated on the basis of weighted data for 36,752 nonfatal injuries among older adults treated in EDs during January-December 2001. U.S. Census Bureau population estimates for 2001 were used to calculate injury rates (3). A direct variance estimation procedure was used to calculate 95% confidence intervals and to account for the complex sample design (2). All nonfatal injuries were classified according to the mechanism of injury (e.g., fall, struck by/against, or motor vehicle crash), diagnosis, primary body part injured, disposition, location of injury, and intent. The diagnosis and intent of the injury were classified according to the most severe injury (4). Injuries of unknown intent were grouped with those classified as unintentional.\nDuring 2001, an estimated 935,556 men and 1,731,640 women aged >65 years were treated in EDs for nonfatal injuries. The overall injury rate per 100,000 persons was higher among women (8,466 per 100,000 persons) than among men (6,404). Injury rates increased with age, to 15,272 for women aged >85 years and 11,547 for men aged >85 years. Nearly all injuries (99%) were classified as unintentional/unknown intent (Table ).\nOverall, falls resulted in the highest rates of injury (4,684 per 100,000 persons) and were the most common mechanism of injury, accounting for 62% of all nonfatal injury ED visits in this population. The injury rate from falls was higher among women (5,659) than men (3,319). However, the injury rates for women were lower with certain other types of injuries, such as being struck by/against (588 versus 617), occupying a motor vehicle (525 versus 540), and being cut or pierced (243 versus 488) (Table ).\nThe greatest number of nonfatal injuries among older adults were diagnosed as fractures (26%), followed by contusions/ abrasions (23%), lacerations (17%), strains/sprains (13%), and internal injuries (5%). Diagnoses varied by sex. Fractures of all parts of the body were more common among women than men (30% versus 19%), and lacerations were more common among men than women (22% versus 14%). The parts of the body affected most were the head/neck (25%) and arms/hands (22%). The majority (82%) of older adults were treated and released; 16% were hospitalized. The ratio of patients treated/ released to those hospitalized was lower among women (4.7:1) than men (5.9:1), suggesting women were more often hospitalized after a nonfatal injury. The most common (47%) location for nonfatal injuries was the home (Table ). Editorial Note: Falls remain the leading cause of both nonfatal and fatal injury among older adults aged >65 years in the United States (1). The findings in this report, which indicate that falls were the most common reason for injury-related ED visits among persons aged >65 years, are consistent with previous studies indicating that approximately 40% of older adults living in community settings (e.g., in private residences or minimally assisted environments) fall each year (5).\nIn this study, 82% of persons aged >65 years were treated and released following injury, compared with 95% of persons aged <65 years. Older adults were more than three times more likely (1,217 per 100,000 persons) to be hospitalized than persons aged <65 years (353) (1).\nThe findings in this report are subject to at least five limitations. First, NEISS-AIP provides national estimates and does not allow for estimates by region, state, or local jurisdiction. Second, injury outcomes are specific to ED visits and do not include subsequent outcomes. Third, NEISS-AIP data reflect only those injuries that were severe enough to require treatment in an ED. Fourth, in cases with multiple injuries, only data regarding the most severe injury are recorded. Finally, data for intent are classified on the basis of information contained in the medical record. Injuries for which intent cannot be determined conclusively from the ED record are grouped with unintentional injuries.\nThe findings in this report can form the basis for targeting prevention efforts to different populations of older adults. For example, exercise can reduce the risk for fall among older adults by 15% (6). Because women are more likely to sustain fallrelated injuries, exercise can be an especially important preventive measure for this population. Data from NEISS-AIP can continue to be a source for monitoring trends, evaluating interventions, and characterizing nonfatal injuries among persons aged >65 years. (n = four), New Mexico (n = four), North Dakota (n = four), Alabama (n = three), Ohio (n = three), Indiana (n = two), Missouri (n = two), Montana (n = two), New Jersey (n = two), Delaware (n = one), Illinois (n = one), Kansas (n = one), Kentucky (n = one), Louisiana (n = one), Michigan (n = one), Mississippi (n = one), Tennessee (n = one), and Virginia (n = one). A total of 682 presumptive West Nile viremic blood donors have been reported to ArboNET. Of these, 596 (87%) were reported from the following nine western and midwestern states: Colorado, Kansas, Nebraska, New Mexico, North Dakota, Oklahoma, South Dakota, Texas, and Wyoming. Of the 529 donors for whom data were reported completely, six subsequently had meningoencephalitis, and 76 subsequently had West Nile fever.\nIn addition, 10,453 dead birds with WNV infection have been reported from 42 states, the District of Columbia, and New York City; 3,270 WNV infections in horses, 16 WNV infections in dogs, 14 infections in squirrels, and 24 infections in unidentified \n# Human WNV disease and animal WNV activity\nAnimal WNV activity only one. In addition, seropositivity was reported from one other unidentified animal species. A total of 6,667 WNV-positive mosquito pools have been reported from 38 states, the District of Columbia, and New York City.\nAdditional information about WNV activity is available from CDC at http://www.cdc.gov/ncidod/dvbid/westnile/ index.htm and http://westnilemaps.usgs.gov.\n# Notice to Readers\n\n# Guidelines for Maintaining and Managing the Vaccine Cold Chain\nIn February 2002, the Advisory Committee on Immunization Practices (ACIP) and American Academy of Family Physicians (AAFP) released their revised General Recommendations on Immunization (1), which included recommendations on the storage and handling of immunobiologics. Because of increased concern over the potential for errors with the vaccine cold chain (i.e., maintaining proper vaccine temperatures during storage and handling to preserve potency), this notice advises vaccine providers of the importance of proper cold chain management practices. This report describes proper storage units and storage temperatures, outlines appropriate temperature-monitoring practices, and recommends steps for evaluating a temperature-monitoring program. The success of efforts against vaccine-preventable diseases is attributable in part to proper storage and handling of vaccines. Exposure of vaccines to temperatures outside the recommended ranges can affect potency adversely, thereby reducing protection from vaccine-preventable diseases (1). Good practices to maintain proper vaccine storage and handling can ensure that the full benefit of immunization is realized.\n# Recommended Storage Temperatures\nThe majority of commonly recommended vaccines require storage temperatures of 35°F-46°F (2°C-8°C) and must not be exposed to freezing temperatures. Introduction of varicella vaccine in 1995 and of live attenuated influenza vaccine (LAIV) more recently increased the complexity of vaccine storage. Both varicella vaccine and LAIV must be stored in a continuously frozen state <5°F (-15°C) with no freeze-thaw cycles (Table 1). In recent years, instances of improper vaccine storage have been reported. An estimated 17%-37% of providers expose vaccines to improper storage temperatures, and refrigerator temperatures are more commonly kept too cold than too warm (2,3).\nFreezing temperatures can irreversibly reduce the potency of vaccines required to be stored at 35°F-46°F (2°C-8°C). Certain freeze-sensitive vaccines contain an aluminum adjuvant that precipitates when exposed to freezing temperatures. This results in loss of the adjuvant effect and vaccine potency (4). Physical changes are not always apparent after exposure to freezing temperatures and visible signs of freezing are not necessary to result in a decrease in vaccine potency.\nAlthough the potency of the majority of vaccines can be affected adversely by storage temperatures that are too warm, these effects are usually more gradual, predictable, and smaller in magnitude than losses from temperatures that are too cold. In contrast, varicella vaccine and LAIV are required to be stored in continuously frozen states and lose potency when stored above the recommended temperature range.\n# Vaccine Storage Requirements\nVaccine storage units must be selected carefully and used properly. A combination refrigerator/freezer unit sold for home use is acceptable for vaccine storage if the refrigerator and freezer compartments each have a separate door. However, vaccines should not be stored near the cold air outlet from the freezer to the refrigerator. Many combination units cool the refrigerator compartment by using air from the freezer compartment. In these units, the freezer thermostat controls freezer temperature while the refrigerator thermostat controls the volume of freezer temperature air entering the refrigerator. This can result in different temperature zones within the refrigerator.\nRefrigerators without freezers and stand-alone freezers usually perform better at maintaining the precise temperatures required for vaccine storage, and such single-purpose units sold for home use are less expensive alternatives to medical specialty equipment. Any refrigerator or freezer used for vaccine storage must maintain the required temperature range year-round, be large enough to hold the year's largest inventory, and be dedicated to storage of biologics (i.e., food or beverages should not be stored in vaccine storage units). In addition, vaccines should be stored centrally in the refrigerator or freezer, not in the door or on the bottom of the storage unit, and sufficiently away from walls to allow air to circulate.\n# Temperature Monitoring\nProper temperature monitoring is key to proper cold chain management. Thermometers should be placed in a central location in the storage unit, adjacent to the vaccine. Temperatures should be read and documented twice each day, once when the office or clinic opens and once at the end of the day. Temperature logs should be kept on file for >3 years, unless state statutes or rules require a longer period. Immediate action must be taken to correct storage temperatures that are outside the recommended ranges. Mishandled vaccines should not be administered.\nOne person should be assigned primary responsibility for maintaining temperature logs, along with one backup person. Temperature logs should be reviewed by the backup person at least weekly. All staff members working with vaccines should be familiar with proper temperature monitoring.\nDifferent types of thermometers can be used, including standard fluid-filled, min-max, and continuous chart recorder thermometers (Table 2). Standard fluid-filled thermometers are the simplest and least expensive products, but some models might perform poorly. Product temperature thermometers (i.e., those encased in biosafe liquids) might reflect vaccine temperature more accurately. Min-max thermometers monitor the temperature range. Continuous chart recorder thermometers monitor temperature range and duration and can be recalibrated at specified intervals. All thermometers used for monitoring vaccine storage temperatures should be calibrated and certified by an appropriate agency (e.g., National Institute of Standards and Technology). In addition, temperature indicators (e.g., Freeze Watch ™ [3M, St. Paul, Minnesota] or ColdMark ™ [Cold Ice, Inc., Oakland, California]) can be considered as a backup monitoring system (5); however, such indicators should not be used as a substitute for twice daily temperature readings and documentation.\nAll medical care providers who administer vaccines should evaluate their cold chain maintenance and management to ensure that 1) designated personnel and backup personnel have written duties and are trained in vaccine storage and handling; 2) accurate thermometers are placed properly in all vaccine storage units and any limitations of the storage system are fully known; 3) vaccines are placed properly within the refrigerator or freezer in which proper temperatures are maintained; 4) temperature logs are reviewed for completeness and any deviations from recommended temperature ranges; 5) any outof-range temperatures prompt immediate action to fix the problem, with results of these actions documented; 6) any vaccines exposed to out-of-range temperatures are marked \"do not use\" and isolated physically; 7) when a problem is discovered, the exposed vaccine is maintained at proper temperatures while state or local health departments, or the vaccine manufacturers, are contacted for guidance; and 8) written emergency retrieval and storage procedures are in place in case of equipment failures or power outages. Around-the-clock monitoring systems might be considered to alert staff to afterhours emergencies, particularly if large vaccine inventories are maintained.\nAdditional information on vaccine storage and handling is available from the Immunization Action Coalition at http:// www.immunize.org/izpractices/index.htm. Links to state and local health departments are available at http://www.cdc.gov/ other.htm. Especially detailed guidelines from the Commonwealth of Australia on vaccine storage and handling, vaccine storage units, temperature monitoring, and stability of vaccines at different temperatures (6) \n# Notice to Readers\n\n# International Conference on Emerging Infectious Diseases\nCDC's National Center for Infectious Diseases, the Council of State and Territorial Epidemiologists, the American Society for Microbiology, and the World Health Organization will cosponsor the International Conference on Emerging Infectious Diseases February 29-March 3, 2004, at the Marriott Marquis Hotel in Atlanta, Georgia. The conference will explore the most current research, surveillance, and prevention and control programs addressing all aspects of emerging infectious diseases. Attendance is limited to 2,500 participants.\nThe conference will include general and plenary sessions, symposia, panels of speakers, presentations on emerging infections activities, oral and poster presentations, and exhibits. The deadline for abstract submission for presentations is November 14, 2003. Information about submitting abstracts is available at http://www.iceid.org/abssub.asp. Abstracts should address new, reemerging, or drug-resistant infectious diseases that affect human health. The deadline for late-breaker abstracts is January 16, 2004.\nRegistration information is available at http://www.iceid.org and at http://www.cdc.gov/ncidod and by e-mail at meetinginfo@asmusa.org or at dsy1@cdc.gov.\n# Errata: Vol. 52, No. 40\nIn the article, \"Cigarette Smoking Among Adults -United States, 2001,\" an error occurred in the table on page 955. Total prevalence for persons with 0-12 yrs (no diploma) of education was reported to be 28.4% (95% CI +1.4). The correct prevalence for this population should have been 27.5% (95% CI +1.4).\nIn the article, \"Recommended Adult Immunization Schedule -United States, 2003-2004,\" on page 968, an incorrect volume number was given for the fourth reference. The reference should read, \"4. CDC. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(No. RR-8).\"\n# Errata: Vol. 52, No. RR-10\nIn the MMWR Recommendations and Reports, \"Guidelines for Environmental Infection Control in Health-Care Facilities: Recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC),\" On page 10, in Figure 1, the third bullet under the footnote should read as follows:\n\"• air volume differential >125 cfm supply versus exhaust.\" On page 11, in Figure 2, the label \"Neutral anteroom\" should read \"anteroom.\" Also, the first, second, and seventh bullets under the footnote should read as follows: \"• pressure differential of 2.5 Pa (0.01-in. water gauge) measured at the door between patient room and anteroom;\n• air volume differential >125 cfm, depending on anteroom airflow direction (i.e., pressurized versus depressurized);\n• anteroom airflow patterns (i.e., anteroom is pressurized in top and middle panels, and depressurized in bottom panel).\"\nOn page 12, in Figure 3, the third bullet under the footnote should read as follows:\n\" e ncore.\nWeek after week, MMWR Online plays an important role in helping you stay informed. From the latest CDC guidance to breaking health news, count on MMWR Online to deliver the news you need, when you need it.\nLog on to cdc.gov/mmwr and enjoy MMWR performance.\n* No measles or rubella cases were reported for the current 4-week period yielding a ratio for week 42 of zero (0). † Ratio of current 4-week total to mean of 15 4-week totals (from previous, comparable, and subsequent 4-week periods for the past 5 years). The point where the hatched area begins is based on the mean and two standard deviations of these 4-week totals. \n# \nU: Unavailable.\n-:No reported cases. * Mortality data in this table are voluntarily reported from 122 cities in the United States, most of which have populations of >100,000. A death is reported by the place of its occurrence and by the week that the death certificate was filed. Fetal deaths are not included. † Pneumonia and influenza. § Because of changes in reporting methods in this Pennsylvania city, these numbers are partial counts for the current week. Complete counts will be available in 4 to 6 weeks. ¶ Total includes unknown ages. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":273,"cells":{"id":{"kind":"string","value":"25629bb57077b675ba61b02f3677d2ee20e15fcf"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices . MMWR 2008;57). Information on vaccination issues related to the recently identified novel influenza A H1N1 virus will be published later in 2009. The 2009 seasonal influenza recommendations include new and updated information. Highlights of the 2009 recommendations include 1) a recommendation that annual vaccination be administered to all children aged 6 months-18 years for the 2009-10 influenza season; 2) a recommendation that vaccines containing the 2009-10 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)like, A/Brisbane/10/2007 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; and 3) a notice that recommendations for influenza diagnosis and antiviral use will be published before the start of the 2009-10 influenza season. Vaccination efforts should begin as soon as vaccine is available and continue through the influenza season. Approximately 83% of the United States population is specifically recommended for annual vaccination against seasonal influenza; however, <40% of the U.S. population received the 2008-09 influenza vaccine. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (/ flu); any updates or supplements that might be required during the 2009-10 influenza season also can be found at this website. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.# Introduction\nIn the United States, annual epidemics of seasonal influenza occur typically during the late fall through early spring. Influenza viruses can cause disease among persons in any age group, but rates of infection are highest among children (1)(2)(3). Rates of serious illness and death are highest among persons aged >65 years, children aged <2 years, and persons of any age who have medical conditions that place them at increased risk for complications from influenza (1,4,5). An annual average of approximately 36,000 deaths during 1990-1999 and 226,000 hospitalizations during 1979-2001 have been associated with influenza epidemics (6,7).\nAnnual influenza vaccination is the most effective method for preventing influenza virus infection and its complications. Influenza vaccine can be administered to any person aged >6 months who does not have contraindications to vaccination to reduce the likelihood of becoming ill with influenza or of transmitting influenza to others. Trivalent inactivated influenza vaccine (TIV) can be used for any person aged >6 months, including those with high-risk conditions (Boxes 1 and 2). Live, attenuated influenza vaccine (LAIV) may be used for healthy, nonpregnant persons aged 2-49 years. No preference All children aged 6 months-18 years should be vaccinated annually.\nChildren and adolescents at higher risk for influenza complications should continue to be a focus of vaccination efforts as providers and programs transition to routinely vaccinating all children and adolescents, including those who:\nare aged 6 months-4 years ( - 59 months); have chronic pulmonary (including asthma), cardiovas-- cular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematological or metabolic disorders (including diabetes mellitus); are immunosuppressed (including immunosuppression - caused by medications or by human immunodeficiency virus); are receiving long-term aspirin therapy and therefore - might be at risk for experiencing Reye syndrome after influenza virus infection; are residents of long-term care facilities; and - will be pregnant during the influenza season. - Note: Children aged <6 months cannot receive influenza vaccination. Household and other close contacts (e.g., daycare providers) of children aged <6 months, including older children and adolescents, should be vaccinated. is indicated for LAIV or TIV when considering vaccination of healthy, nonpregnant persons aged 2-49 years. Because the safety or effectiveness of LAIV has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications, these persons should be vaccinated only with TIV. Influenza viruses undergo frequent antigenic change (i.e., antigenic drift); to gain immunity against viruses in circulation, patients must receive an annual vaccination against the influenza viruses that are predicted on the basis of viral surveillance data. . Although vaccination coverage has increased in recent years for many groups targeted for routine vaccination, coverage remains low among most of these groups, and strategies to improve vaccination coverage, including use of reminder/recall systems and standing orders programs, should be implemented or expanded.\nAntiviral medications are an adjunct to vaccination and are effective when administered as treatment and when used for chemoprophylaxis after an exposure to influenza virus. However, the emergence since 2005 of resistance to one or more of the four licensed antiviral agents (oseltamivir, zanamivir, amantadine and rimantadine) among circulating strains Annual vaccination against influenza is recommended for any adult who wants to reduce the risk of becoming ill with influenza or of transmitting it to others. Vaccination is recommended for all adults without contraindications in the following groups, because these persons either are at higher risk for influenza complications, or are close contacts of persons at higher risk has complicated antiviral treatment and chemoprophylaxis recommendations. Updated antiviral treatment and chemoprophylaxis recommendations will be provided in a separate set of guidelines later in 2009. CDC has issued interim recommendations for antiviral treatment and chemoprophylaxis of influenza (8), and these guidelines should be consulted pending issuance of new recommendations.\nIn April 2009, a novel influenza A (H1N1) virus that is similar to influenza viruses previously identified in swine was determined to be the cause of an influenza respiratory illness that spread across North America and was identified in many areas of the world by May 2009. The symptoms of novel influenza A (H1N1) virus infection are similar to those of seasonal influenza, and specific diagnostic testing is required to distinguish novel influenza A (H1N1) virus infection from seasonal influenza (9). The epidemiology of this illness is still being studied and prevention issues related to this newly emerging influenza virus will be published separately.\n\n# Methods\nCDC's Advisory Committee on Immunization Practices (ACIP) provides annual recommendations for the prevention and control of influenza. The ACIP Influenza Vaccine Working Group- meets monthly throughout the year to discuss newly published studies, review current guidelines, and consider revisions to the recommendations. As they review the annual recommendations for ACIP consideration of the full committee, members of the working group consider a variety of issues, including burden of influenza illness, vaccine effectiveness, safety, and coverage in groups recommended for vaccination, feasibility, cost-effectiveness, and anticipated vaccine supply. Working group members also request periodic updates on vaccine and antiviral production, supply, safety and efficacy from vaccinologists, epidemiologists, and manufacturers. State and local vaccination program representatives are consulted. CDC's Influenza Division (available at / flu) provides influenza surveillance and antiviral resistance data. The Vaccines and Related Biological Products Advisory Committee provides advice on vaccine strain selection to the Food and Drug Administration (FDA), which selects the viral strains to be used in the annual trivalent influenza vaccines.\nPublished, peer-reviewed studies are the primary source of data used by ACIP in making recommendations for the prevention and control of influenza, but unpublished data that are relevant to issues under discussion also might be considered. Among studies discussed or cited, those of greatest scientific quality and those that measured influenza-specific outcomes are the most influential. For example, population-based estimates that use outcomes associated with laboratory-confirmed influenza virus infection outcomes contribute the most specific data for estimates of influenza burden. The best evidence for vaccine or antiviral efficacy and effectiveness comes from randomized controlled trials that assess laboratory-confirmed influenza infections as an outcome measure and consider factors such as timing and intensity of influenza circulation and degree of match between vaccine strains and wild circulating strains (10,11). Randomized, placebo-controlled trials cannot be performed ethically in populations for which vaccination already is recommended, but observational studies that assess outcomes associated with laboratory-confirmed influenza infection can provide important vaccine or antiviral effectiveness data. Randomized, placebo-controlled clinical trials are the best source of vaccine and antiviral safety data for common adverse events; however, such studies do not have the statistical power to identify rare but potentially serious adverse events. The frequency of rare adverse events that might be associated with vaccination is best assessed by reviewing computerized medical records from large linked clinical databases and medical charts of persons who are identified as having a potential adverse event after vaccination (12,13). Vaccine coverage data from a nationally representative, randomly selected population that includes verification of vaccination through health-care record review are superior to coverage data derived from limited populations or without verification of vaccination; however, these data rarely are available for older children or adults (14). Finally, studies that assess vaccination program practices that improve vaccination coverage are most influential in formulating recommendations if the study design includes a nonintervention comparison group. In cited studies that included statistical comparisons, a difference was considered to be statistically significant if the p-value was <0.05 or the 95% confidence interval (CI) around an estimate of effect allowed rejection of the null hypothesis (i.e., no effect).\nThese recommendations were presented to the full ACIP and approved in February 2009. Modifications were made to the ACIP statement during the subsequent review process at CDC to update and clarify wording in the document. Vaccine recommendations apply only to persons who do not have contraindications to vaccine use (see Contraindications and Precautions for use of TIV and Contraindications and Precautions for use of LAIV). Data presented in this report were current as of July 17, 2009. Further updates, if needed, will be posted at CDC's influenza website (. gov/flu).\n\n# Primary Changes and Updates in the Recommendations\nThe 2009 recommendations include three principal changes or updates:\nAnnual vaccination of all children aged 6 months-18 - years should begin as soon as the 2009-10 influenza vaccine is available. Annual vaccination of all children aged 6 months-4 years (59 months) and older children with conditions that place them at increased risk for complications from influenza should continue to be a primary focus of vaccination efforts as providers and programs transition to routinely vaccinating all children. from the United States and other countries are now resistant to oseltamivir. Recommendations for influenza diagnosis and antiviral use will be published later in 2009. CDC issued interim recommendations for antiviral treatment and chemoprophylaxis of influenza in December 2008, and these should be consulted for guidance pending recommendations from the ACIP (8).\n\n# Background and Epidemiology\n\n# Biology of Influenza\nInfluenza A and B are the two types of influenza viruses that cause epidemic human disease. Influenza A viruses are categorized into subtypes on the basis of two surface antigens: hemagglutinin and neuraminidase. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have circulated globally. Influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses also have been identified in some influenza seasons. In April 2009, human infections with a novel influenza A (H1N1) virus were identified; as of June 2009, infections with the novel influenza A (H1N1) virus have been reported worldwide. This novel virus is derived partly from influenza A viruses that circulate in swine and is antigenically distinct from human influenza A (H1N1) viruses in circulation since 1977. Influenza A subtypes and B viruses are further separated into groups on the basis of antigenic similarities. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations and recombination events that occur during viral replication (15). Recent studies have begun to shed some light on the complex molecular evolution and epidemiologic dynamics of influenza A viruses (16)(17)(18).\nCurrently circulating influenza B viruses are separated into two distinct genetic lineages (Yamagata and Victoria) but are not categorized into subtypes. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. Influenza B viruses from both lineages have circulated in most recent influenza seasons (19).\nImmunity to the surface antigens, particularly the hemagglutinin, reduces the likelihood of infection (20). Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza virus. Furthermore, antibody to one antigenic type or subtype of influenza virus might not protect against infection with a new antigenic variant of the same type or subtype (21). Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and is the reason for annually reassessing the need to change one or more of the recommended strains for influenza vaccines.\nMore dramatic changes, or antigenic shifts, occur less frequently. Antigenic shift occurs when a new subtype of influenza A virus appears and can result in the emergence of a novel influenza A virus with the potential to cause a pandemic. New influenza A subtypes have the potential to cause a pandemic when they are able to cause human illness and demonstrate efficient human-to-human transmission and little or no previously existing immunity has been identified among humans (15). Novel influenza A (H1N1) virus is not a new subtype, but because the large majority of humans appear to have no pre-existing antibody to key novel influenza A (H1N1) virus hemagglutinin epitopes, substantial potential exists for widespread infection (16).\n\n# Health-Care Use, Hospitalizations, and Deaths Attributed to Influenza\nIn the United States, annual epidemics of influenza typically occur during the fall or winter months, but the peak of influenza activity can occur as late as April or May (Figure 1). Influenza-related complications requiring urgent medical care, including hospitalizations or deaths, can result from the direct effects of influenza virus infection, from complications associated with age or pregnancy, or from complications of underlying cardiopulmonary conditions or other chronic diseases. Studies that have measured rates of a clinical outcome without a laboratory confirmation of influenza virus infection (e.g., respiratory illness requiring hospitalization during influenza season) to assess the effect of influenza can be difficult to interpret because of circulation of other respiratory pathogens (e.g., respiratory syncytial virus) during the same time as influenza viruses (22)(23)(24). However, increases in healthcare provider visits for acute febrile respiratory illness occur each year during the time when influenza viruses circulate. Data from the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet) demonstrate the annual increase in physician visits for influenza-like illness (ILI) † and for each influenza season; for 2009, the data also indicate the recent resurgence of respiratory illness associated with circulation of novel influenza A (H1N1) virus (Figure 2) (25,26).\nDuring seasonal influenza epidemics from 1979-1980 through 2000-2001, the estimated annual overall number of influenza-associated hospitalizations in the United States ranged from approximately 55,000 to 431,000 per annual epidemic (mean: 226,000) (7). The estimated annual number of deaths attributed to influenza from the 1990-91 influenza season through the 1998-99 season ranged from 17,000 to 51,000 per epidemic (mean: 36,000) (6). In the United States, the estimated number of influenza-associated deaths 53; therefore the week 53 data point for those seasons is an average of weeks 52 and 1. ¶ The national baseline is the mean percentage of visits for ILI during noninfluenza weeks for the previous three seasons plus two standard deviations. A noninfluenza week is a week during which 65 years who were at increased risk for death from influenza complications (6). In one study, an average of approximately 19,000 influenza-associated pulmonary and circulatory deaths per influenza season occurred during 1976-1990 compared with an average of approximately 36,000 deaths per season during 1990-1999 (6). In addition, influenza A (H3N2) viruses, which have been associated with higher mortality (27), predominated in 90% of influenza seasons during 1990-1999 compared with compared with 57% of seasons during 1976-1990 (6).\nInfluenza viruses cause disease among persons in all age groups (1)(2)(3)(4)(5). Rates of infection are highest among children, but the risks for complications, hospitalizations, and deaths from influenza are higher among persons aged >65 years, young children, and persons of any age who have medical conditions that place them at increased risk for complications from influenza (1,4,5,(28)(29)(30)(31). Estimated rates of influenzaassociated hospitalizations and deaths varied substantially by age group in studies conducted during different influenza epidemics. During 1990-1999, estimated average rates of influenza-associated pulmonary and circulatory deaths per 100,000 persons were 0.4-0.6 among persons aged 0-49 years, 7.5 among persons aged 50-64 years, and 98.3 among persons aged >65 years (6).\n\n# Children\nAmong children aged <5 years, influenza-related illness is a common cause of visits to medical practices and emergency departments (EDs). During two influenza seasons (2002-03 and 2003-04), the percentage of visits among children aged <5 years with acute respiratory illness or fever caused by laboratory-confirmed influenza ranged from 10%-19% of medical office visits to 6%-29% of EDs visits during the influenza season. On the basis of these data, the rate of visits to medical clinics for influenza was estimated to be 50-95 per 1,000 children, and the rate of visits to EDs was estimated to be 6-27 per 1,000 children (32). A multiyear study in New York City used viral surveillance data to estimate influenza strain-specific illness rates among ED visits. In addition to the expected variation by season and age group, influenza B epidemics were found to be an important cause of illness among school-aged children in several seasons, and annual epidemics of both influenza A and B peaked among school-aged children before other age groups (33). Retrospective studies using medical records data have demonstrated similar rates of illness among children aged <5 years during other influenza seasons (29,34,35). During the influenza season, an estimated 7-12 additional outpatient visits and 5-7 additional antibiotic prescriptions per 100 children aged <15 years have been documented when compared with periods when influenza viruses are not circulating, with rates decreasing with increasing age of the child (35). During 1993During -2004 in the Boston area, the rate of ED visits for respiratory illness that was attributed to influenza virus based on viral surveillance data among children aged <7 years during the winter respiratory illness season ranged from 22.0 per 1,000 children aged 6-23 months to 5.4 per 1,000 children aged 5-7 years (36).\nRates of influenza-associated hospitalization are substantially higher among infants and young children than among older children when influenza viruses are in circulation and are similar to rates for other groups considered at high risk for influenza-related complications (37)(38)(39)(40)(41)(42), including persons aged >65 years (35,39). During 1979-2001, on the basis of data from a national sample of hospital discharges of influenzaassociated hospitalizations among children aged <5 years, the estimated rate of influenza-associated hospitalizations in the United States was 108 hospitalizations per 100,000 personyears (7). Recent population-based studies that measured hospitalization rates for laboratory-confirmed influenza in young children have documented hospitalization rates that are similar to or higher than rates derived from studies that analyzed hospital discharge data (32,34,41,43,44). Annual hospitalization rates for laboratory-confirmed influenza decrease with increasing age, ranging from 240-720 per 100,000 children aged <6 months to approximately 20 per 100,000 children aged 2-5 years (32). Hospitalization rates for children aged <5 years with high-risk medical conditions are approximately 250-500 per 100,000 children (29,31,45).\nInfluenza-associated deaths are uncommon among children. An estimated annual average of 92 influenza-related deaths (0.4 deaths per 100,000 persons) occurred among children aged 65 years (6). Of 153 laboratory-confirmed influenza-related pediatric deaths reported during the 2003-04 influenza season, 96 (63%) deaths occurred among children aged <5 years and 61 (40%) among children aged <2 years. Among the 149 children who died and for whom information on underlying health status was available, 100 (67%) did not have an underlying medical condition that was an indication for vaccination at that time (46). In California during the 2003-04 and 2004-05 influenza seasons, 51% of children with laboratory-confirmed influenza who died and 40% of those who required admission to an intensive care unit had no underlying medical conditions (47). These data indicate that although children with risk factors for influenza complications are at higher risk for death, the majority of pediatric deaths occur among children with no known high-risk conditions. The annual number of influenza-associated deaths among children reported to CDC for the past four influenza seasons has ranged from 44 during 2004-05 to 84 during 2007-08 (48). As of July 8, 2009, a total of 17 deaths caused by novel influenza A (H1N1) virus infection have occurred in 2009 among children in the United States (CDC, unpublished data, 2009). Death associated with laboratory-confirmed influenza virus infection among children (defined as persons aged <18 years) is a nationally reportable condition. Deaths among children that have been attributed to co-infection with influenza and Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), have increased during the preceding four influenza seasons (26,49). The reason for this increase is not established but might reflect an increasing prevalence within the general population of colonization with MRSA strains, some of which carry certain virulence factors (50,51).\n\n# Adults\nHospitalization rates during the influenza season are substantially increased for persons aged >65 years. One retrospective analysis based on data from managed-care organizations collected during 1996-2000 estimated that the risk during influenza season among persons aged >65 years with underlying conditions that put them at risk for influenza-related complications (i.e., one or more of the conditions listed as indications for vaccination) was approximately 560 influenzaassociated hospitalizations per 100,000 persons compared with approximately 190 per 100,000 healthy persons. Persons aged 50-64 years with underlying medical conditions also were at substantially increased risk for hospitalizations during influenza season compared with healthy adults aged 50-64 years. No increased risk for influenza-related hospitalizations was demonstrated among healthy adults aged 50-64 years or among those aged 19-49 years, regardless of underlying medical conditions (28).\nInfluenza is an important contributor to the annual increase in deaths attributed to pneumonia and influenza that is observed during the winter months (Figure 3). During 1976-2001, an estimated yearly average of 32,651 (90%) influenza-related deaths occurred among adults aged >65 years (6). Risk for influenza-related death was highest among the oldest elderly, with persons aged >85 years 16 times more likely to die from an influenza-related illness than persons aged 65-69 years (6).\nThe duration of influenza symptoms is prolonged and the severity of influenza illness increased among persons with human immunodeficiency virus (HIV) infection (52)(53)(54)(55)(56). A retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program determined that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than it was either before or after influenza was circulating. The risk for hospitalization was higher for HIV-infected women than it was for women with other underlying medical conditions (57). Another study estimated that the risk for influenza- - Each week, the vital statistics offices of 122 cities report the total number of death certificates received and the number of those for which pneumonia or influenza (P&I) was listed as the underlying or contributing cause of death by age group. The percentage of all deaths attributable to P&I are compared with a seasonal baseline and epidemic threshold value calculated for each week. † An increase of 1.645 standard deviations above the seasonal baseline deaths is considered the \"epidemic threshold,\" i.e., the point at which the observed proportion of deaths attributed to pneumonia or influenza was significantly higher than would be expected at that time of the year in the absence of substantial influenza-related mortality. § The seasonal baseline of P&I deaths is calculated using a periodic regression model that incorporates a robust regression procedure applied to data from the previous 5 years. related death was 94-146 deaths per 100,000 persons with acquired immunodeficiency syndrome (AIDS) compared with 0.9-1.0 deaths per 100,000 persons aged 25-54 years and 64-70 deaths per 100,000 persons aged >65 years in the general population (58).\nInfluenza-related excess deaths among pregnant women were reported during the pandemics of 1918-1919 and 1957-1958 (59-63). Case reports and several epidemiologic studies also indicate that pregnancy increases the risk for influenza complications (64-69) for the mother. The majority of studies that have attempted to assess the effect of influenza on pregnant women have measured changes in excess hospitalizations for respiratory illness during influenza season but not laboratoryconfirmed influenza hospitalizations. Pregnant women have an increased number of medical visits for respiratory illnesses during influenza season compared with nonpregnant women (70). Hospitalized pregnant women with respiratory illness during influenza season have increased lengths of stay compared with hospitalized pregnant women without respiratory illness. Rates of hospitalization for respiratory illness were twice as common during influenza season (71). A retrospective cohort study of approximately 134,000 pregnant women conducted in Nova Scotia during 1990-2002 compared medical record data for pregnant women to data from the same women during the year before pregnancy. Among pregnant women, 0.4% were hospitalized and 25% visited a clinician during pregnancy for a respiratory illness. The rate of third-trimester hospital admissions during the influenza season was five times higher than the rate during the influenza season in the year before pregnancy and more than twice as high as the rate during the noninfluenza season. An excess of 1,210 hospital admissions in the third trimester per 100,000 pregnant women with comorbidities and 68 admissions per 100,000 women without comorbidities was reported (72). In one study, pregnant women with respiratory hospitalizations did not have an increase in adverse perinatal outcomes or delivery complications (73); another study indicated an increase in delivery complications, including fetal distress, preterm labor, and cesarean delivery. However, infants born to women with laboratory-confirmed influenza during pregnancy do not have higher rates of low birth weight, congenital abnormalities, or lower Apgar scores compared with infants born to uninfected women (64,74).\n\n# options for Controlling Influenza\nThe most effective strategy for preventing influenza is annual vaccination (10,15). Strategies that focus on providing routine vaccination to persons at higher risk for influenza complications have long been recommended, although coverage among the majority of these groups remains low. Routine vaccination of certain persons (e.g., children, contacts of persons at risk for influenza complications, and health-care personnel ) who serve as a source of influenza virus transmission might provide additional protection to persons at risk for influenza complications and reduce the overall influenza burden. However, coverage levels among these persons need to be increased before effects on transmission can be measured reliably. Antiviral drugs used for chemoprophylaxis or treatment of influenza are adjuncts to vaccine but are not substitutes for annual vaccination. However, antiviral drugs might be underused among those hospitalized with influenza (75). Nonpharmacologic interventions (e.g., advising frequent handwashing and improved respiratory hygiene) are reasonable and inexpensive; these strategies have been demonstrated to reduce respiratory diseases; reductions in detectable influenza A viruses on hands after handwashing also have been demonstrated (76)(77)(78). Few data are available to assess the effects of community-level respiratory disease mitigation strategies (e.g., closing schools, avoiding mass gatherings, or using respiratory protection) on reducing influenza virus transmission during typical seasonal influenza epidemics (79,80).\n\n# Influenza Vaccine Efficacy, Effectiveness, and Safety Evaluating Influenza Vaccine Efficacy and Effectiveness Studies\nThe efficacy (i.e., prevention of illness among vaccinated persons in controlled trials) and effectiveness (i.e., prevention of illness in vaccinated populations) of influenza vaccines depend in part on the age and immunocompetence of the vaccine recipient, the degree of similarity between the viruses in the vaccine and those in circulation (see Effectiveness of Influenza Vaccination when Circulating Influenza Virus Strains Differ from Vaccine Strains), and the outcome being measured. Influenza vaccine efficacy and effectiveness studies have used multiple possible outcome measures, including the prevention of medically attended acute respiratory illness (MAARI), prevention of laboratory-confirmed influenza virus illness, prevention of influenza or pneumonia-associated hospitalizations or deaths, or prevention of seroconversion to circulating influenza virus strains. Efficacy or effectiveness for more specific outcomes such as laboratory-confirmed influenza typically will be higher than for less specific outcomes such as MAARI because the causes of MAARI include infections with other pathogens that influenza vaccination would not be expected to prevent (81). Observational studies that compare less-specific outcomes among vaccinated populations to those among unvaccinated populations are subject to biases that are difficult to control for during analyses. For example, an observational study that determines that influenza vaccination reduces overall mortality might be biased if healthier persons in the study are more likely to be vaccinated (82,83). Randomized controlled trials that measure laboratory-confirmed influenza virus infections as the outcome are the most persuasive evidence of vaccine efficacy, but such trials cannot be conducted ethically among groups recommended to receive vaccine annually.\n\n# Influenza Vaccine Composition\nBoth LAIV and TIV contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one influenza A (H1N1) virus, and one influenza B virus. Each year, one or more virus strains in the vaccine might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains. For the 2009-10 influenza season, the influenza B vaccine virus strain was changed to B/Brisbane/60/2008, a representative of the B/Victoria lineage) compared with the 2008-09 season. The influenza A (H1N1 and H3N2 vaccine virus strains were not changed (84). Viruses for both types of currently licensed vaccines are grown in eggs. Both vaccines are administered annually to provide optimal protection against influenza virus infection (Table 1). Both TIV and LAIV are widely available in the United States. Although both types of vaccines are expected to be effective, the vaccines differ in several respects (Table 1).\n\n# Major Differences Between tIV and LAIV\nDuring the preparation of TIV, the vaccine viruses are made noninfectious (i.e., inactivated or killed) (15). Only subvirion and purified surface antigen preparations of TIV (often referred to as \"split\" and subunit vaccines, respectively) are available in the United States. TIV contains killed viruses and thus cannot cause influenza. LAIV contains live, attenuated influenza viruses that have the potential to cause mild signs or symptoms (e.g., runny nose, nasal congestion, fever, or sore throat). LAIV is administered intranasally by sprayer, whereas TIV is administered intramuscularly by injection. LAIV is licensed for use among nonpregnant persons aged 2-49 years; safety has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications. TIV is licensed for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions (Table 1).\n\n# Correlates of Protection after Vaccination\nImmune correlates of protection against influenza infection after vaccination include serum hemagglutination inhibition antibody and neutralizing antibody (20,85). Increased levels of antibody induced by vaccination decrease the risk for illness caused by strains that are antigenically similar to those strains of the same type or subtype included in the vaccine (86)(87)(88)(89). The majority of healthy children and adults have high titers of antibody after vaccination (87,90). Although immune correlates such as achievement of certain antibody titers after vaccination correlate well with immunity on a population level, the significance of reaching or failing to reach a certain antibody threshold is not well understood on the individual level. Other immunologic correlates of protection that might best indicate clinical protection after receipt of an intranasal vaccine such as LAIV (e.g., mucosal antibody) are more difficult to measure (91,92). Laboratory measurements that correlate with protective immunity induced by LAIV have been described, including measurement of cell-mediated immunity with ELISPOT assays that measure gamma-interferon (89). If not simultaneously administered, can be administered within 4 wks of an inactivated vaccine Yes Yes - Children aged 6 months-8 years who have never received influenza vaccine before should receive 2 doses. Those who only receive 1 dose in their first year of vaccination should receive 2 doses in the following year, spaced 4 weeks apart. † Persons at higher risk for complications of influenza infection because of underlying medical conditions should not receive LAIV. Persons at higher risk for complications of influenza infection because of underlying medical conditions include adults and children with chronic disorders of the pulmonary or cardiovascular systems; adults and children with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunnosuppression; children and adolescents receiving long-term aspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); persons who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration; pregnant women; and residents of nursing homes and other chronic-care facilities that house persons with chronic medical conditions. § Clinicians and immunization programs should screen for possible reactive airways diseases when considering use of LAIV for children aged 2-4 years and should avoid use of this vaccine in children with asthma or a recent wheezing episode. Health-care providers should consult the medical record, when available, to identify children aged 2-4 years with asthma or recurrent wheezing that might indicate asthma. In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving LAIV, parents or caregivers of children aged 2-4 years should be asked: \"In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?\" Children whose parents or caregivers answer \"yes\" to this question and children who have asthma or who had a wheezing episode noted in the medical record during the preceding 12 months should not receive LAIV. ¶ LAIV coadministration has been evaluated systematically only among children aged 12-15 months who received measles, mumps, and rubella vaccine or varicella vaccine. TIV coadministration has been evaluated systematically only among adults who received pneumococcal polysaccharide or zoster vaccine.\n\n# Immunogenicity, Efficacy, and Effectiveness of tIV Children\nChildren aged >6 months typically have protective levels of anti-influenza antibody against specific influenza virus strains after receiving the recommended number of doses of influenza vaccine (85 90 93-97). In most seasons, one or more vaccine antigens are changed compared with the previous season. In consecutive years when vaccine antigens change, children aged <9 years who received only 1 dose of vaccine in their first year of vaccination are less likely to have protective antibody responses when administered only a single dose during their second year of vaccination compared with children who received 2 doses in their first year of vaccination (98)(99)(100).\nWhen the vaccine antigens do not change from one season to the next, priming children aged 6-23 months with a single dose of vaccine in the spring followed by a dose in the fall engenders similar antibody responses compared with a regimen of 2 doses in the fall (101). However, one study conducted during a season when the vaccine antigens did not change compared with the previous season estimated 62% effectiveness against ILI for healthy children who had received only 1 dose in the previous influenza season and only 1 dose in the study season compared with 82% for those who received 2 doses separated by >4 weeks during the study season (102).\nThe antibody response among children at higher risk for influenza-related complications (e.g., children with chronic medical conditions) might be lower than those reported typically among healthy children (103,104). However, antibody responses among children with asthma are similar to those of healthy children and are not substantially altered during asthma exacerbations requiring short-term prednisone treatment (105).\nVaccine effectiveness studies also have indicated that 2 doses are needed to provide adequate protection during the first season that young children are vaccinated. Among children aged <5 years who have never received influenza vaccine previously or who received only 1 dose of influenza vaccine in their first year of vaccination, vaccine effectiveness is lower compared with children who received 2 doses in their first year of being vaccinated. Two large retrospective studies of young children who had received only 1 dose of TIV in their first year of being vaccinated determined that no decrease was observed in ILI-related office visits compared with unvaccinated children (102,106). Similar results were reported in a case-control study of children aged 6-59 months (107). These results, along with the immunogenicity data indicating that antibody responses are significantly higher when young children are given 2 doses, are the basis for the recommendation that all children aged <9 years who are being vaccinated for the first time should receive 2 vaccine doses separated by at least 4 weeks.\nEstimates of vaccine efficacy or effectiveness among children aged >6 months have varied by season and study design. In a randomized trial conducted during five influenza seasons (1985)(1986)(1987)(1988)(1989)(1990) in the United States among children aged 1-15 years, annual vaccination reduced laboratory-confirmed influenza A substantially (77%-91%) (87). A limited 1-year placebo-controlled study reported vaccine efficacy against laboratory-confirmed influenza illness of 56% among healthy children aged 3-9 years and 100% among healthy children and adolescents aged 10-18 years (108). A randomized, double-blind, placebo-controlled trial conducted during two influenza seasons among children aged 6-24 months indicated that efficacy was 66% against culture-confirmed influenza illness during the 1999-00 influenza season but did not reduce culture-confirmed influenza illness significantly during the 2000-20 influenza season (109).\nA case-control study conducted during the 2003-04 season found vaccine effectiveness of 49% against laboratory-confirmed influenza (107). An observational study among children aged 6-59 months with laboratory-confirmed influenza compared with children who tested negative for influenza reported vaccine effectiveness of 44% in the 2003-04 influenza season and 57% during the 2004-05 season (110). Partial vaccination (only 1 dose for children being vaccinated for the first time) was not effective in either study. During an influenza season (2003-04) with a suboptimal vaccine match, a retrospective cohort study conducted among approximately 30,000 children aged 6 months-8 years indicated vaccine effectiveness of 51% against medically attended, clinically diagnosed pneumonia or influenza (i.e., no laboratory confirmation of influenza) among fully vaccinated children and 49% among approximately 5,000 children aged 6-23 months (106). Another retrospective cohort study of similar size conducted during the same influenza season in Denver but limited to healthy children aged 6-21 months estimated clinical effectiveness of 2 TIV doses to be 87% against pneumonia or influenza-related office visits (102). Among children, TIV effectiveness might increase with age (87,111). A systematic review of published studies estimated vaccine effectiveness at 59% for children aged >2 years but concluded that additional evidence was needed to demonstrate effectiveness among children aged 6 months-2 years (112).\nBecause of the recognized influenza-related disease burden among children with other chronic diseases or immunosuppression and the long-standing recommendation for vaccination of these children, randomized placebo-controlled studies to study efficacy in these children have not been conducted. In a nonrandomized controlled trial among children aged 2-6 years and 7-14 years who had asthma, vaccine efficacy was 54% and 78% against laboratory-confirmed influenza type A infection and 22% and 60% against laboratory-confirmed influenza type B infection, respectively. Vaccinated children aged 2-6 years with asthma did not have substantially fewer type B influenza virus infections compared with the control group in this study (113). The association between vaccination and prevention of asthma exacerbations is unclear. One study suggested that vaccination might provide protection against asthma exacerbations (114); however, other studies of children with asthma have not demonstrated decreased exacerbations (115).\nTIV has been demonstrated to reduce acute otitis media in some studies. Two studies have reported that TIV decreases the risk for influenza-related otitis media by approximately 30% among children with mean ages of 20 and 27 months, respectively (116,117). However, a large study conducted among children with a mean age of 14 months indicated that TIV was not effective against acute otitis media (109). Influenza vaccine effectiveness against a nonspecific clinical outcome such as acute otitis media, which is caused by a variety of pathogens and is not typically diagnosed using influenza virus culture, would be expected to be relatively low.\n\n# Adults Aged <65 Years\nOne dose of TIV is highly immunogenic in healthy adults aged <65 years. Limited or no increase in antibody response is reported among adults when a second dose is administered during the same season (118)(119)(120). When the vaccine and circulating viruses are antigenically similar, TIV prevents laboratory-confirmed influenza illness among approximately 70%-90% of healthy adults aged <65 years in randomized controlled trials (121)(122)(123)(124). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources, including use of antibiotics, when the vaccine and circulating viruses are well-matched (121)(122)(123). Efficacy or effectiveness against laboratory-confirmed influenza illness was 47%-77% in studies conducted during different influenza seasons when the vaccine strains were antigenically dissimilar to the majority of circulating strains (117,119,(121)(122)(123)(124). However, effectiveness among healthy adults against influenza-related hospitalization, measured in the most recent of these studies, was 90% (125).\nIn certain studies, persons with certain chronic diseases have lower serum antibody responses after vaccination compared with healthy young adults and can remain susceptible to influenza virus infection and influenza-related upper respiratory tract illness (126,127). Vaccine effectiveness among adults aged <65 years who are at higher risk for influenza complications typically is lower than that reported for healthy adults. In a case-control study conducted during the 2003-04 influenza season, when the vaccine was a suboptimal antigenic match to many circulating virus strains, effectiveness for prevention of laboratory-confirmed influenza illness among adults aged 50-64 years with high-risk conditions was 48% compared with 60% for healthy adults (125). Effectiveness against hospitalization among adults aged 50-64 years with high-risk conditions was 36% compared with 90% effectiveness among healthy adults in that age range (125). A randomized controlled trial among adults in Thailand with chronic obstructive pulmonary disease (median age: 68 years) indicated a vaccine effectiveness of 76% in preventing laboratory-confirmed influenza during a season when viruses were well-matched to vaccine viruses. Effectiveness did not decrease with increasing severity of underlying lung disease (128).\nFew randomized controlled trials have studied the effect of influenza vaccination on noninfluenza outcomes. A randomized controlled trial conducted in Argentina among 301 adults hospitalized with myocardial infarction or undergoing angioplasty for cardiovascular disease (56% of whom were aged >65 years) found that a significantly lower percentage (6%) of cardiovascular deaths occurred among vaccinated persons at 1 year after vaccination compared with unvaccinated persons (17%) (129). A randomized, double-blind, placebo-controlled study conducted in Poland among 658 persons with coronary artery disease indicated that significantly fewer vaccinated persons vaccinated persons had a cardiac ischemic event during the 9 months of follow up compared with unvaccinated persons (p <0.05) (130).\nObservational studies that have measured clinical endpoints without laboratory confirmation of influenza virus infection, typically have demonstrated substantial reductions in hospitalizations or deaths among adults with risk factors for influenza complications. In a case-control study conducted during 1999-2000 in Denmark among adults aged <65 years with underlying medical conditions, vaccination reduced deaths attributable to any cause 78% and reduced hospitalizations attributable to respiratory infections or cardiopulmonary diseases 87% (131). A benefit was reported after the first vaccination and increased with subsequent vaccinations in subsequent years (132). Among patients with diabetes mellitus, vaccination was associated with a 56% reduction in any complication, a 54% reduction in hospitalizations, and a 58% reduction in deaths (133). Certain experts have noted that the substantial effects on morbidity and mortality among those who received influenza vaccination in these observational studies should be interpreted with caution because of the difficulties in ensuring that those who received vaccination had similar baseline health status as those who did not (82,83). One meta-analysis of published studies concluded that evidence was insufficient to demonstrate that persons with asthma benefit from vaccination (134). However, a meta-analysis that examined effectiveness among persons with chronic obstructive pulmonary disease identified evidence of benefit from vaccination (135).\n\n# Immunocompromised Persons\nTIV produces adequate antibody concentrations against influenza among vaccinated HIV-infected persons who have minimal AIDS-related symptoms and normal or near-normal CD4+ T-lymphocyte cell counts (136)(137)(138). Among persons who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, TIV might not induce protective antibody titers (138,139); a second dose of vaccine does not improve the immune response in these persons (139,140). A randomized, placebo-controlled trial determined that TIV was highly effective in preventing symptomatic, laboratory-confirmed influenza virus infection among HIV-infected persons with a mean of 400 CD4+ T-lymphocyte cells/mm3; however, a limited number of persons with CD4+ T-lymphocyte cell counts of 100 CD4+ cells and among those with <30,000 viral copies of HIV type-1/mL (53).\nOn the basis of certain limited studies, immunogenicity for persons with solid organ transplants varies according to transplant type. Among persons with kidney or heart transplants, the proportion who developed seroprotective antibody concentrations was similar or slightly reduced compared with healthy persons (141)(142)(143). However, a study among persons with liver transplants indicated reduced immunologic responses to influenza vaccination (144)(145)(146), especially if vaccination occurred within the 4 months after the transplant procedure (144).\n\n# Pregnant Women and neonates\nPregnant women have protective levels of anti-influenza antibodies after vaccination (147,148). Passive transfer of anti-influenza antibodies that might provide protection from vaccinated women to neonates has been reported (147,(149)(150)(151). A retrospective, clinic-based study conducted during 1998-2003 documented a nonsignificant trend toward fewer episodes of MAARI during one influenza season among vaccinated pregnant women compared with unvaccinated pregnant women and substantially fewer episodes of MAARI during the peak influenza season (148). However, a retrospective study conducted during 1997-2002 that used clinical records data did not indicate a reduction in ILI among vaccinated pregnant women or their infants (152). In another study conducted during 1995-2001, medical visits for respiratory illness among the infants were not substantially reduced (153). One randomized controlled trial conducted in Bangladesh that provided vaccination to pregnant women during the third trimester demonstrated a 29% reduction in respiratory illness with fever and a 36% reduction in respiratory illness with fever among their infants during the first 6 months after birth. In addition, infants born to vaccinated women had a 63% reduction in laboratory-confirmed influenza illness during the first 6 months of life (154). All women in this trial breastfed their infants (mean duration: 14 weeks).\n\n# older Adults\nAdults aged >65 years typically have a diminished immune response to influenza vaccination compared with young healthy adults, suggesting that immunity might be of shorter duration (although still extending through one influenza season) (155,156). However, a review of the published literature concluded that no clear evidence existed that immunity declined more rapidly in the elderly (157), and additional vaccine doses during the same season do not increase the antibody response (118,120). Infections among the vaccinated elderly might be associated with an age-related reduction in ability to respond to vaccination rather than reduced duration of immunity (127,128). One prospective cohort study found that immunogenicity among hospitalized persons who were either aged >65 years or who were aged 18-64 years and had one or more chronic medical conditions was similar compared with outpatients (158).\nThe only randomized controlled trial among communitydwelling persons aged >60 years reported a vaccine efficacy of 58% (CI = 26%-77%) against laboratory-confirmed influenza illness during a season when the vaccine strains were considered to be well-matched to circulating strains (159). Additional information from this trial published separately indicated that efficacy among those aged >70 years was 57% (CI = -36%-87%), similar to younger persons. However, few persons aged >75 years participated in this study, and the wide confidence interval for the estimate of efficacy among participants aged >70 years included 0 (160). Influenza vaccine effectiveness in preventing MAARI among the elderly in nursing homes has been estimated at 20%-40% (161,162), and reported outbreaks among well-vaccinated nursing home populations have suggested that vaccination might not have any significant effectiveness when circulating strains are drifted from vaccine strains (163,164). In contrast, some studies have indicated that vaccination can be up to 80% effective in preventing influenzarelated death (161,(165)(166)(167). Among elderly persons not living in nursing homes or similar long-term-care facilities, influenza vaccine is 27%-70% effective in preventing hospitalization for pneumonia and influenza (168)(169)(170). Influenza vaccination reduces the frequency of secondary complications and reduces the risk for influenza-related hospitalization and death among community-dwelling adults aged >65 years with and without high-risk medical conditions (e.g., heart disease and diabetes) (169)(170)(171)(172)(173)(174). However, studies demonstrating large reductions in hospitalizations and deaths among the vaccinated elderly have been conducted using medical record databases and have not measured reductions in laboratory-confirmed influenza illness. These studies have been challenged because of concerns that they have not adequately controlled for differences in the propensity for healthier persons to be more likely than less healthy persons to receive vaccination (82,83,166,(175)(176)(177).\n\n# tIV Dosage, Administration, and Storage\nThe composition of TIV varies according to manufacturer, and package inserts should be consulted. TIV formulations in multidose vials contain the vaccine preservative thimerosal; preservative-free, single-dose preparations also are available. TIV should be stored at 35°F-46°F (2°C-8°C) and should not be frozen. TIV that has been frozen should be discarded. Dosage recommendations and schedules vary according to age group (Table 2). Vaccine prepared for a previous influenza season should not be administered to provide protection for any subsequent season.\nThe intramuscular route is recommended for TIV. Adults and older children should be vaccinated in the deltoid muscle. A needle length of >1 inch (>25 mm) should be considered for persons in these age groups because needles of <1 inch might be of insufficient length to penetrate muscle tissue in certain adults and older children (178). When injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8-1.25 inches is recommended (179).\nInfants and young children should be vaccinated in the anterolateral aspect of the thigh. A needle length of 7/8-1 inch should be used for children aged <12 months. In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving FluMist, parents or caregivers of children aged 2-4 years should be asked: \"In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?\" Children whose parents or caregivers answer \"yes\" to this question and children who have asthma or who had a wheezing episode noted in the medical record during the preceding 12 months should not receive FluMist. † † Two doses administered at least 4 weeks apart are recommended for children aged 2-8 years who are receiving LAIV for the first time, and those who only received 1 dose in their first year of vaccination should receive 2 doses in the following year.\n\n# Adverse Events After Receipt of tIV Children\nStudies support the safety of annual TIV in children and adolescents. The largest published postlicensure populationbased study assessed TIV safety in 251,600 children aged <18 years, (including 8,476 vaccinations in children aged 6-23 months) through the Vaccine Safety Datalink (VSD), who were enrolled in one of five health maintenance organizations (HMOs) during 1993-1999. This study indicated no increase in clinically important medically attended events during the 2 weeks after inactivated influenza vaccination compared with control periods 3-4 weeks before and after vaccination (180). A retrospective cohort study using VSD medical records data from 45,356 children aged 6-23 months provided additional evidence supporting overall safety of TIV in this age group. During the 2 weeks after vaccination, TIV was not associated with statistically significant increases in any clinically important medically attended events other than gastritis/duodenitis, and 13 diagnoses, including acute upper respiratory illness, otitis media and asthma, were significantly less common (181). On chart review, most children with a diagnosis of gastritis/duodenitis had self-limited vomiting or diarrhea. The positive or negative associations between TIV and any of these diagnoses do not necessarily indicate a causal relationship (181).\nIn a study of 791 healthy children aged 1-15 years, postvaccination fever was noted among 12% of those aged 1-5 years, 5% among those aged 6-10 years, and 5% among those aged 11-15 years (87). Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with inactivated vaccine most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children) (182,183). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Data about potential adverse events among children after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). Because of the limitations of passive reporting systems, determining causality for specific types of adverse events usually is not possible using VAERS data alone.\nPublished reviews of VAERS reports submitted after administration of TIV to children aged 6-23 months indicated that the most frequently reported adverse events were fever, rash, injection-site reactions, and seizures; the majority of the limited number of reported seizures appeared to be febrile (184,185). Seizure and fever were the leading serious adverse events (SAEs), defined using standard criteria, reported to VAERS in these studies (184,185); further investigation in VSD did not confirm an association with febrile seizures as identified in VAERS (181).\n\n# Adults\nIn placebo-controlled studies among adults, the most frequent side effect of vaccination was soreness at the vaccination site (affecting 10%-64% of patients) that lasted 65 years or were aged 18-64 years and had one or more chronic medical conditions compared with outpatients (158). Adverse events in adults aged >18 years reported to VAERS during 1990-2005 were analyzed. The most common adverse events reported to VAERS in adults included injection-site reactions, pain, fever, myalgia, and headache. The VAERS review identified no new safety concerns. In clinical trials, SAEs were reported to occur after vaccination with TIV at a rate of <1%. A small proportion (14%) of the TIV VAERS reports in adults were classified as SAEs, without assessment of causality. The most common SAE reported after TIV in VAERS in adults was Guillain-Barré Syndrome (GBS) (189). The potential association between TIV and GBS has been an area of ongoing research (see Guillain-Barré Syndrome and TIV).\n\n# Pregnant Women and neonates\nFDA has classified TIV as a \"Pregnancy Category C\" medication, indicating that adequate animal reproduction studies have not been conducted.. Available data indicate that influenza vaccine does not cause fetal harm when administered to a pregnant woman or affect reproductive capacity. One study of approximately 2,000 pregnant women who received TIV during pregnancy demonstrated no adverse fetal effects and no adverse effects during infancy or early childhood (190). A matched case-control study of 252 pregnant women who received TIV within the 6 months before delivery determined no adverse events after vaccination among pregnant women and no difference in pregnancy outcomes compared with 826 pregnant women who were not vaccinated (148). During 2000-2003, an estimated 2 million pregnant women were vaccinated, and only 20 adverse events among women who received TIV were reported to VAERS during this time, including nine injection-site reactions and eight systemic reactions (e.g., fever, headache, and myalgias). In addition, three miscarriages were reported, but these were not known to be causally related to vaccination (191). Similar results have been reported in certain smaller studies (147,149,192), and a recent international review of data on the safety of TIV concluded that no evidence exists to suggest harm to the fetus (193). The rate of adverse events associated with TIV was similar to the rate of adverse events among pregnant women who received pneumococcal polysaccharide vaccine in one small randomized controlled trial in Bangladesh, and no severe adverse events were reported in any study group (154).\n\n# Persons with Chronic Medical Conditions\nIn a randomized cross-over study of children and adults with asthma, no increase in asthma exacerbations was reported for either age group (194), and two additional studies also have indicated no increase in wheezing among vaccinated asthmatic children (114) or adults (195). One study reported that 20%-28% of children with asthma aged 9 months-18 years had local pain and swelling at the site of influenza vaccination ( 104), and another study reported that 23% of children aged 6 months-4 years with chronic heart or lung disease had local reactions (93). A blinded, randomized, cross-over study of 1,952 adults and children with asthma demonstrated that only self-reported \"body aches\" were reported more frequently after TIV (25%) than placebo-injection (21%) (194). However, a placebo-controlled trial of TIV indicated no difference in local reactions among 53 children aged 6 months-6 years with high-risk medical conditions or among 305 healthy children aged 3-12 years (97).\nAmong children with high-risk medical conditions, one study of 52 children aged 6 months-3 years reported fever among 27% and irritability and insomnia among 25% (93); and a study among 33 children aged 6-18 months reported that one child had irritability and one had a fever and seizure after vaccination (196). No placebo comparison group was used in these studies.\n\n# Immunocompromised Persons\nData demonstrating safety of TIV for HIV-infected persons are limited, but no evidence exists that vaccination has a clinically important impact on HIV infection or immunocompetence. One study demonstrated a transient (i.e., 2-4 week) increase in HIV RNA (ribonucleic acid) levels in one HIV-infected person after influenza virus infection (197). Studies have demonstrated a transient increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (138,198). However, more recent and better-designed studies have not documented a substantial increase in the replication of HIV (199)(200)(201)(202). CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated to change substantially after influenza vaccination among HIV-infected persons compared with unvaccinated HIV-infected persons (138,203). Limited information is available about the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza virus infection or influenza vaccination (52,204).\nData are similarly limited for persons with other immunocompromising conditions. In small studies, vaccination did not affect allograft function or cause rejection episodes in recipients of kidney transplants (141,142), heart transplants (143), or liver transplants (144).\n\n# Immediate Hypersensitivity Reactions after Influenza Vaccines\nVaccine components can rarely cause allergic reactions, also called immediate hypersensitivity reactions, among certain recipients. Immediate hypersensitivity reactions are mediated by preformed immunoglobulin E (IgE) antibodies against a vaccine component and usually occur within minutes to hours of exposure (205). Symptoms of immediate hypersensitivity range from mild urticaria (hives) and angioedema to anaphylaxis. Anaphylaxis is a severe life-threatening reaction that involves multiple organ systems and can progress rapidly. Symptoms and signs of anaphylaxis can include but are not limited to generalized urticaria, wheezing, swelling of the mouth and throat, difficulty breathing, vomiting, hypotension, decreased level of consciousness, and shock. Minor symptoms such as red eyes or hoarse voice also might be present (179,(205)(206)(207)(208).\nAllergic reactions might be caused by the vaccine antigen, residual animal protein, antimicrobial agents, preservatives, stabilizers, or other vaccine components (209). Manufacturers use a variety of compounds to inactivate influenza viruses and add antibiotics to prevent bacterial growth. Package inserts for specific vaccines of interest should be consulted for additional information. ACIP has recommended that all vaccine providers should be familiar with the office emergency plan and be certified in cardiopulmonary resuscitation (179). The Clinical Immunization Safety Assessment (CISA) network, a collaboration between CDC and six medical research centers with expertise in vaccination safety, has developed an algorithm to guide evaluation and revaccination decisions for persons with suspected immediate hypersensitivity after vaccination (205).\nImmediate hypersensitivity reaction after TIV and LAIV are rare. A VSD study of children aged <18 years in four HMOs during 1991-1997 estimated the overall risk of postvaccination anaphylaxis to be less than 1 case per 500,000 doses administered and in this study no cases were identified in TIV recipients (210). Reports of anaphylaxis occurring after receipt of TIV and LAIV in adults have rarely been reported to VAERS (189). Some immediate hypersensitivity reactions after TIV or LAIV are caused by the presence of residual egg protein in the vaccines (211). Although influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Asking persons if they can eat eggs without adverse effects is a reasonable way to determine who might be at risk for allergic reactions from receiving influenza vaccines (179). Persons who have had symptoms such as hives or swelling of the lips or tongue, or who have experienced acute respiratory distress after eating eggs, should consult a physician for appropriate evaluation to help determine if future influenza vaccine should be administered. Persons who have documented (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma related to egg exposure or other allergic responses to egg protein, also might be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician before vaccination should be considered (212)(213)(214). A regimen has been developed for administering influenza vaccine to asthmatic children with severe disease and egg hypersensitivity (213).\nHypersensitivity reactions to other vaccine components also can rarely occur. Although exposure to vaccines containing thimerosal can lead to hypersensitivity (215), the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (216,217). When reported, hypersensitivity to thimerosal typically has consisted of local delayed hypersensitivity reactions (216).\n\n# ocular and Respiratory Symptoms after tIV\nOcular or respiratory symptoms have occasionally been reported within 24 hours after TIV administration, but these symptoms typically are mild and resolve quickly without specific treatment. In some trials conducted in the United States, ocular or respiratory symptoms included red eyes (<1%-6%), cough (1%-7%), wheezing (1%), and chest tightness (1%-3%) (207,208,(218)(219)(220). However, most of these trials were not placebo-controlled, and causality cannot be determined. In addition, ocular and respiratory symptoms are features of a variety of respiratory illnesses and seasonal allergies that would be expected to occur coincidentally among vaccine recipients unrelated to vaccination. A placebo-controlled vaccine effectiveness study among young adults found that 2% of persons who received the 2006-07 formulation of Fluzone (Sanofi Pasteur) reported red eyes compared with none of the controls (p = 0.03) (221). A similar trial conducted during the 2005-06 influenza season found that 3% of Fluzone recipients reported red eyes compared with 1% of placebo recipients; however the difference was not statistically significant (222) .\nOculorespiratory syndrome (ORS), an acute, self-limited reaction to TIV with prominent ocular and respiratory symptoms, was first described during the 2000-01 influenza season in Canada. The initial case-definition for ORS was the onset of one or more of the following within 2-24 hours after receiving TIV: bilateral red eyes and/or facial edema and/or respiratory symptoms (coughing, wheezing, chest tightness, difficulty breathing, sore throat, hoarseness or difficulty swallowing, cough, wheeze, chest tightness, difficulty breathing, sore throat, or facial swelling) (223). ORS was first described in Canada and strongly associated with one vaccine preparation (Fluviral S/F, Shire Biologics, Quebec, Canada) not available in the United States during the 2000-01 influenza season (224). Subsequent investigations identified persons with ocular or respiratory symptoms meeting an ORS case-definition in safety monitoring systems and trials that had been conducted before 2000 in Canada, the United States, and several European countries (225)(226)(227).\nThe cause of ORS has not been established; however studies suggest the reaction is not IgE-mediated (228). After changes in the manufacturing process of the vaccine preparation associated with ORS during 2000-01, the incidence of ORS in Canada was greatly reduced (226). In one placebo-controlled study, only hoarseness, cough, and itchy or sore eyes (but not red eyes) were significantly associated with a reformulated Fluviral preparation. These findings indicated that ORS symptoms following use of the reformulated vaccine were mild, resolved within 24 hours, and might not typically be of sufficient concern to cause vaccine recipients to seek medical care (229).\nOcular and respiratory symptoms reported after TIV administration, including ORS, have some similarities with immediate hypersensitivity reactions. One study indicated that the risk for ORS recurrence with subsequent vaccination is low, and persons with ocular or respiratory symptoms (e.g., bilateral red eyes, cough, sore throat, or hoarseness) after TIV that did not involve the lower respiratory tract have been revaccinated without reports of SAEs after subsequent exposure to TIV (230). VAERS routinely monitors for adverse events such as ocular or respiratory symptoms after receipt of TIV.\n\n# Contraindications and Precautions for Use of tIV\nTIV is contraindicated and should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine unless the recipient has been desensitized. Prophylactic use of antiviral agents is an option for preventing influenza among such persons. Information about vaccine components is located in package inserts from each manufacturer. Persons with moderate to severe acute febrile illness usually should not be vaccinated until their symptoms have abated. Moderate or severe acute illness with or without fever is a precaution § for TIV. GBS within 6 weeks following a previous dose of influenza vaccine is considered to be a precaution for use of influenza vaccines.\n\n# Revaccination in Persons Who Experienced ocular or Respiratory Symptoms After tIV\nWhen assessing whether a patient who experienced ocular and respiratory symptoms should be revaccinated, providers should determine if concerning signs and symptoms of Ig-E mediated immediate hypersensitivity are present (see Immediate Hypersensitivity after Influenza Vaccines). Healthcare providers who are unsure whether symptoms reported or observed after TIV represent an IgE-mediated hypersensitivity immune response should seek advice from an allergist/immunologist. Persons with symptoms of possible IgE-mediated hypersensitivity after TIV should not receive influenza vaccination unless hypersensitivity is ruled out or revaccination is administered under close medical supervision (205).\nOcular or respiratory symptoms observed after TIV often are coincidental and unrelated to TIV administration, as observed among placebo recipients in some randomized controlled studies. Determining whether ocular or respiratory symptoms are coincidental or related to possible ORS might not be possible. Persons who have had red eyes, mild upper facial swelling, or mild respiratory symptoms (e.g., sore throat, cough, or hoarseness) after TIV without other concerning signs or symptoms of hypersensitivity can receive TIV in subsequent seasons without further evaluation. Two studies showed that persons who had symptoms of ORS after TIV were at a higher risk for ORS after subsequent TIV administration; however, these events usually were milder than the first episode (230,231).\n\n# Guillain-Barré Syndrome and tIV\nThe annual incidence of GBS is 10-20 cases per 1 million adults (232). Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni gastrointestinal infections and upper respiratory tract infections, are associated with GBS (233)(234)(235). A recent study identified serologically confirmed influenza virus infection as a trigger of GBS, with time from onset of influenza illness to GBS of 3-30 days. The estimated frequency of influenza-related GBS was four to seven times higher than the frequency that has been estimated for influenza-vaccine-associated GBS (236).\nThe 1976 swine influenza vaccine was associated with an increased frequency of GBS, estimated at one additional case of GBS per 100,000 persons vaccinated (237,238). The risk for influenza-vaccine-associated GBS was higher among persons aged >25 years than among persons aged <25 years (239). However, obtaining epidemiologic evidence for a small increase in risk for a rare condition with multiple causes is difficult, and no evidence consistently exists for a causal relation between subsequent vaccines prepared from other influenza viruses and GBS.\nNone of the studies conducted using influenza vaccines other than the 1976 swine influenza vaccine has demonstrated a substantial increase in GBS associated with influenza vaccines. During three of four influenza seasons studied during 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were not statistically significant in any of these studies (240)(241)(242). However, in a study of the 1992-93 and 1993-94 seasons, the overall relative risk for GBS was 1.7 (CI = 1.0-2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately one additional case of GBS per 1 million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination (238). Results of a study that examined health-care data from Ontario, Canada, during 1992-2004 demonstrated a small but statistically significant temporal association between receiving influenza vaccination and subsequent hospital admission for GBS. However, no increase in cases of GBS at the population level was reported after introduction of a mass public influenza vaccination program in Ontario beginning in 2000 (243). Data from VAERS have documented decreased reporting of GBS occurring after vaccination across age groups over time, despite overall increased reporting of other non-GBS conditions occurring after administration of influenza vaccine (237). Published data from the United Kingdom's General Practice Research Database (GPRD) found influenza vaccine to be associated with a decreased risk for GBS, although whether this was associated with protection against influenza or confounding because of a \"healthy vaccinee\" (e.g., healthier persons might be more likely to be vaccinated and also be at lower risk for GBS) (244) is unclear. A separate GPRD analysis found no association between vaccination and GBS for a 9-year period; only three cases of GBS occurred within 6 weeks after administration of influenza vaccine (245). A third GPRD analysis found that GBS was associated with recent ILI, but not influenza vaccination (246). § A precaution is a condition in a recipient that might increase the risk for a serious adverse reaction or that might compromise the ability of the vaccine to produce immunity (179).\nThe estimated risk for GBS (on the basis of the few studies that have demonstrated an association between vaccination and GBS) is low (i.e., approximately one additional case per 1 million persons vaccinated). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh these estimates of risk for vaccine-associated GBS. No evidence indicates that the casefatality ratio for GBS differs among vaccinated persons and those not vaccinated.\n\n# Use of tIV Among Patients with a History of GBS\nThe incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (232). Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown. Among 311 patients with GBS who responded to a survey, 11 (4%) reported some worsening of symptoms after influenza vaccination; however, some of these patients had received other vaccines at the same time, and recurring symptoms were generally mild (247). However, as a precaution, persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks generally should not be vaccinated. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. Although data are limited, the established benefits of influenza vaccination might outweigh the risks for many persons who have a history of GBS and who also are at high risk for severe complications from influenza.\n\n# Vaccine Preservative (thimerosal) in Multidose Vials of tIV\nThimerosal, a mercury-containing antibacterial compound, has been used as a preservative in vaccines and other medications since the 1930s (248) and is used in multidose vial preparations of TIV to reduce the likelihood of bacterial growth. No scientific evidence indicates that thimerosal in vaccines, including influenza vaccines, is a cause of adverse events other than occasional local hypersensitivity reactions in vaccine recipients. In addition, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received vaccine during pregnancy. The weight of accumulating evidence does not suggest an increased risk for neurodevelopment disorders from exposure to thimerosal-containing vaccines (249)(250)(251)(252)(253)(254)(255)(256)(257)(258). The U.S. Public Health Service and other organizations have recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines as part of a strategy to reduce mercury exposures from all sources (249,250,259) Also, continuing public concerns about exposure to mercury in vaccines has been viewed as a potential barrier to achieving higher vaccine coverage levels and reducing the burden of vaccine-preventable diseases. Since mid-2001, vaccines routinely recommended for infants aged <6 months in the United States have been manufactured either without or with greatly reduced (trace) amounts of thimerosal. As a result, a substantial reduction in the total mercury exposure from vaccines for infants and children already has been achieved ( 179)). ACIP and other federal agencies and professional medical organizations continue to support efforts to provide thimerosal-preservative-free vaccine options.\nThe benefits of influenza vaccination for all recommended groups, including pregnant women and young children, outweigh concerns on the basis of a theoretical risk from thimerosal exposure through vaccination. The risks for severe illness from influenza virus infection are elevated among both young children and pregnant women, and vaccination has been demonstrated to reduce the risk for severe influenza illness and subsequent medical complications. In contrast, no scientifically conclusive evidence has demonstrated harm from exposure to vaccine containing thimerosal preservative. For these reasons, persons recommended to receive TIV may receive any age-and risk factor-appropriate vaccine preparation, depending on availability. An analysis of VAERS reports found no difference in the safety profile of preservative-containing compared with preservative-free TIV vaccines in infants aged 6-23 months (184).\nNonetheless, as of May 2009, some states have enacted legislation banning the administration of vaccines containing mercury; the provisions defining mercury content vary (260). LAIV and many of the single-dose vial or syringe preparations of TIV are thimerosal-free, and the number of influenza vaccine doses that do not contain thimerosal as a preservative is expected to increase (Table 2). However, these laws might present a barrier to vaccination unless influenza vaccines that do not contain thimerosal as a preservative are easily available in those states.\nThe U.S. vaccine supply for infants and pregnant women is in a period of transition as manufacturers expand the availability of thimerosal-reduced or thimerosal-free vaccine to reduce the cumulative exposure of infants to mercury. Other environmental sources of mercury exposure are more difficult or impossible to avoid or eliminate (249).\n\n# LAIV Dosage, Administration, and Storage\nEach dose of LAIV contains the same three vaccine antigens used in TIV. However, the antigens are constituted as live, attenuated, cold-adapted, temperature-sensitive vaccine viruses. Providers should refer to the package insert, which contains additional information about the formulation of this vaccine and other vaccine components. LAIV does not contain thimerosal. LAIV is made from attenuated viruses that are able to replicate efficiently only at temperatures present in the nasal mucosa. LAIV does not cause systemic symptoms of influenza in vaccine recipients, although a minority of recipients experience nasal congestion or fever, which is probably a result of effects of intranasal vaccine administration or local viral replication or fever (261).\nLAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route. LAIV is not licensed for vaccination of children aged 49 years. LAIV is supplied in a prefilled, single-use sprayer containing 0.2 mL of vaccine. Approximately 0.1 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril. LAIV is shipped at 35°F-46°F (2°C-8°C). LAIV should be stored at 35°F-46°F (2°C-8°C) on receipt and can remain at that temperature until the expiration date is reached (261). Vaccine prepared for a previous influenza season should not be administered to provide protection for any subsequent season.\n\n# Shedding, transmission, and Stability of Vaccine Viruses\nAvailable data indicate that both children and adults vaccinated with LAIV can shed vaccine viruses after vaccination, although in lower amounts than occur typically with shedding of wild-type influenza viruses. In rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated persons. However, serious illnesses have not been reported among unvaccinated persons who have been infected inadvertently with vaccine viruses.\nOne study of 197 children aged 8-36 months in a child care center assessed transmissibility of vaccine viruses from 98 vaccinated children to the other 99 unvaccinated children; 80% of vaccine recipients shed one or more virus strains (mean duration: 7.6 days). One influenza type B vaccine strain isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the coldadapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient who was in the same play group. The placebo recipient from whom the influenza type B vaccine strain was isolated had symptoms of a mild upper respiratory illness but did not experience any serious clinical events. The estimated probability of acquiring vaccine virus after close contact with a single LAIV recipient in this child care population was 1%-2% (262).\nStudies assessing whether vaccine viruses are shed have been based on viral cultures or PCR detection of vaccine viruses in nasal aspirates from persons who have received LAIV. Among 345 subjects aged 5-49 years, 30% had detectable virus in nasal secretions obtained by nasal swabbing after receiving LAIV. The duration of virus shedding and the amount of virus shed was inversely correlated with age, and maximal shedding occurred within 2 days of vaccination. Symptoms reported after vaccination, including runny nose, headache, and sore throat, did not correlate with virus shedding (263). Other smaller studies have reported similar findings (264,265). Vaccine strain virus was detected from nasal secretions in one (2%) of 57 HIV-infected adults who received LAIV, none of 54 HIV-negative participants (266), and three (13%) of 23 HIV-infected children compared with seven (28%) of 25 children who were not HIV-infected (267). No participants in these studies had detectable virus beyond 10 days after receipt of LAIV. The possibility of person-to-person transmission of vaccine viruses was not assessed in these studies (264)(265)(266)(267).\nIn clinical trials, viruses isolated from vaccine recipients have retained attenuated phenotypes. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt (268). Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes. A study conducted in a child care setting demonstrated that limited genetic change occurred in the LAIV strains following replication in the vaccine recipients (269).\n\n# Immunogenicity, Efficacy, and Effectiveness of LAIV\nLAIV virus strains replicate primarily in nasopharyngeal epithelial cells. The protective mechanisms induced by vaccination with LAIV are not understood completely but appear to involve both serum and nasal secretory antibodies. The immunogenic-ity of the approved LAIV has been assessed in multiple studies conducted among children and adults (270)(271)(272)(273)(274)(275)(276).\n\n# Healthy Children\nA randomized, double-blind, placebo-controlled trial among 1,602 healthy children aged 15-71 months assessed the efficacy of LAIV against culture-confirmed influenza during two seasons (277,278). This trial included a subset of children aged 60-71 months who received 2 doses in the first season. During season one (1996-97), when vaccine and circulating virus strains were well-matched, efficacy against culture-confirmed influenza was 94% for participants who received 2 doses of LAIV separated by >6 weeks, and 89% for those who received 1 dose. During season two (1997-98), when the A (H3N2) component in the vaccine was not well-matched with circulating virus strains, efficacy (1 dose) was 86%, for an overall efficacy for two influenza seasons of 92%. Receipt of LAIV also resulted in 21% fewer febrile illnesses and a significant decrease in acute otitis media requiring antibiotics (277,279). Other randomized, placebo-controlled trials demonstrating the efficacy of LAIV in young children against culture-confirmed influenza include a study conducted among children aged 6-35 months attending child care centers during consecutive influenza seasons (280) in which 85%-89% efficacy was observed, and a study conducted among children aged 12-36 months living in Asia during consecutive influenza seasons in which 64%-70% efficacy was documented (281). In one community-based, nonrandomized open-label study, reductions in MAARI were observed among children who received 1 dose of LAIV during the 1990-00 and 2000-01 influenza seasons even though antigenically drifted influenza A/H1N1 and B viruses were circulating during that season (282). LAIV efficacy in preventing laboratory-confirmed influenza also has been demonstrated in studies comparing the efficacy of LAIV with TIV rather than with a placebo (see Comparisons of LAIV and TIV Efficacy or Effectiveness).\n\n# Healthy Adults\nA randomized, double-blind, placebo-controlled trial of LAIV effectiveness among 4,561 healthy working adults aged 18-64 years assessed multiple endpoints, including reductions in self-reported respiratory tract illness without laboratory confirmation, work loss, health-care visits, and medication use during influenza outbreak periods . The study was conducted during the 1997-98 influenza season, when the vaccine and circulating A (H3N2) strains were not well-matched. The frequency of febrile illnesses was not significantly decreased among LAIV recipients compared with those who received placebo. However, vaccine recipients had significantly fewer severe febrile illnesses (19% reduction) and febrile upper respiratory tract illnesses (24% reduction), and significant reductions in days of illness, days of work lost, days with health-care-provider visits, and use of prescription antibiotics and over-the-counter medications (283). Efficacy against culture-confirmed influenza in a randomized, placebo-controlled study was 57% in the 2004-05 influenza season and 43% in the 2005-06 influenza season, although efficacy in these studies was not demonstrated to be significantly greater than placebo (221,222).\n\n# Adverse Events after Receipt of LAIV Healthy Children Aged 2-18 Years\nIn a subset of healthy children aged 60-71 months from one clinical trial, certain signs and symptoms were reported more often after the first dose among LAIV recipients (n = 214) than among placebo recipients (n = 95), including runny nose (48% and 44%, respectively); headache (18% and 12%, respectively); vomiting (5% and 3%, respectively); and myalgias (6% and 4%, respectively) (277). However, these differences were not statistically significant. In other trials, signs and symptoms reported after LAIV administration have included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0-26%), vomiting (3%-13%), abdominal pain (2%), and myalgias (0-21%) (270,272,273,280,(284)(285)(286)(287). These symptoms were associated more often with the first dose and were self-limited. A placebo-controlled trial in 9,689 children aged 1-17 years assessed prespecified medically attended outcomes during the 42 days after vaccination (286). Following >1,500 statistical analyses in the 42 days after LAIV, elevated risks that were biologically plausible were observed for the following conditions: asthma, upper respiratory infection, musculoskeletal pain, otitis media with effusion, and adenitis/ adenopathy. The increased risk for wheezing events after LAIV was observed among children aged 18-35 months (RR: 4.06; 90% CI = 1.3-17.9). In this study, the rate of SAEs was 0.2% in LAIV and placebo recipients; none of the SAEs was judged to be related to the vaccine by the study investigators (286).\nIn a randomized trial published in 2007, LAIV and TIV were compared among children aged 6-59 months (288). Children with medically diagnosed or treated wheezing within 42 days before enrollment or with a history of severe asthma were excluded from this study. Among children aged 24-59 months who received LAIV, the rate of medically significant wheezing, using a prespecified definition, was not greater compared with those who received TIV (288). Wheezing was observed more frequently among younger LAIV recipients aged 6-23 months in this study; LAIV is not licensed for this age group. In a previous randomized placebo-controlled safety trial among children aged 12 months-17 years without a history of asthma by parental report, an elevated risk for asthma events (RR: 4.1; CI = 1.3-17.9) was documented among 728 children aged 18-35 months who received LAIV. Of the 16 children with asthma-related events in this study, seven had a history of asthma on the basis of subsequent medical record review. None required hospitalization, and elevated risks for asthma were not observed in other age groups (286).\nAnother study was conducted among >11,000 children aged 18 months-18 years in which 18,780 doses of vaccine were administered for 4 years. For children aged 18 months-4 years, no increase was reported in asthma visits 0-15 days after vaccination compared with the prevaccination period. A significant increase in asthma events was reported 15-42 days after vaccination, but only in vaccine year 1 (289). A 4-year, open-label field trial study assessed LAIV safety of more than 2000 doses administered to children aged 18 months-18 years with a history of intermittent wheeze who were otherwise healthy. Among these children, no increased risk was reported for medically attended acute respiratory illnesses, including acute asthma exacerbation, during the 0-14 or 0-42 days after LAIV compared with the pre-and postvaccination reference periods (290).\nInitial data from VAERS during 2007-2008, following ACIP's recommendation for LAIV use in healthy children aged 2-4 years, did not suggest a concern for wheezing after LAIV in young children. However data also suggest uptake of LAIV was limited, and safety monitoring for wheezing events after LAIV is ongoing (CDC, unpublished data, 2008).\n\n# Adults Aged 19-49 Years\nAmong adults, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients (277,291). In one clinical trial among a subset of healthy adults aged 18-49 years, signs and symptoms reported significantly more often (p<0.05) among LAIV recipients (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (14% and 11%, respectively), runny nose (45% and 27%, respectively), sore throat (28% and 17%, respectively), chills (9% and 6%, respectively), and tiredness/weakness (26% and 22%, respectively) (92). A review of 460 reports to VAERS after distribution of approximately 2.5 million doses during the 2003-04 and 2004-05 influenza seasons did not indicate any new safety concerns (292). Few of the LAIV VAERS reports (9%) were SAEs; respiratory events were the most common conditions reported.\n\n# Persons at Higher Risk for Influenza-Related Complications\nLimited data assessing the safety of LAIV use for certain groups at higher risk for influenza-related complications are available. In one study of 54 HIV-infected persons aged 18-58 years and with CD4+ counts >200 cells/mm 3 who received LAIV, no SAEs were reported during a 1-month follow-up period (266). Similarly, one study demonstrated no significant difference in the frequency of adverse events or viral shedding among HIV-infected children aged 1-8 years on effective antiretroviral therapy who were administered LAIV compared with HIV-uninfected children receiving LAIV (267). LAIV was well-tolerated among adults aged >65 years with chronic medical conditions (293). These findings suggest that persons at risk for influenza complications who have inadvertent exposure to LAIV would not have significant adverse events or prolonged viral shedding and that persons who have contact with persons at higher risk for influenza-related complications may receive LAIV.\n\n# Comparisons of LAIV and tIV Efficacy or Effectiveness\nBoth TIV and LAIV have been demonstrated to be effective in children and adults. However, data directly comparing the efficacy or effectiveness of these two types of influenza vaccines are limited and insufficient to identify whether one vaccine might offer a clear advantage over the other in certain settings or populations. Studies comparing the efficacy of TIV to that of LAIV have been conducted in a variety of settings and populations using several different outcomes. One randomized, double-blind, placebo-controlled challenge study that was conducted among 92 healthy adults aged 18-41 years assessed the efficacy of both LAIV and TIV in preventing influenza infection when challenged with wild-type strains that were antigenically similar to vaccine strains (294). The overall efficacy in preventing laboratory-documented influenza from all three influenza strains combined was 85% and 71%, respectively, when challenged 28 days after vaccination by viruses to which study participants were susceptible before vaccination. The difference in efficacy between the two vaccines was not statistically significant in this limited study. No additional challenges were conducted to assess efficacy at time points later than 28 days (294). In a randomized, double-blind, placebo-controlled trial that was conducted among young adults during the 2004-05 influenza season, when the majority of circulating H3N2 viruses were antigenically drifted from that season's vaccine viruses, the efficacy of LAIV and TIV against culture-confirmed influenza was 57% and 77%, respectively. The difference in efficacy was not statistically significant and was attributable primarily to a difference in efficacy against influenza B (222). A similar study conducted during the 2005-06 influenza season found no significant difference in vaccine efficacy (221).\nA randomized controlled clinical trial conducted among children aged 6-59 months during the 2004-05 influenza season demonstrated a 55% reduction in cases of culture-confirmed influenza among children who received LAIV compared with those who received TIV (288). In this study, LAIV efficacy was higher compared with TIV against antigenically drifted viruses and well-matched viruses (288). An open-label, nonrandomized, community-based influenza vaccine trial conducted during an influenza season when circulating H3N2 strains were poorly matched with strains contained in the vaccine also indicated that LAIV, but not TIV, was effective against antigenically drifted H3N2 strains during that influenza season. In this study, children aged 5-18 years who received LAIV had significant protection against laboratory-confirmed influenza (37%) and pneumonia and influenza events (50%) (295). A recent observational study conducted among military personnel aged 17-49 years over three influenza seasons indicated that persons who received TIV had a significantly lower incidence of health-care encounters resulting in diagnostic coding for pneumonia and influenza compared with those who received LAIV. However, among new recruits being vaccinated for the first time, the incidence of pneumonia-and influenza-coded health-care encounters among those received LAIV was similar to those receiving TIV (296).\nAlthough LAIV is not licensed for use in persons with risk factors for influenza complications, certain studies have compared the efficacy of LAIV to TIV in these groups. LAIV provided 32% increased protection in preventing culture-confirmed influenza compared with TIV in one study conducted among children aged >6 years and adolescents with asthma (297) and 52% increased protection compared with TIV among children aged 6-71 months with recurrent respiratory tract infections (298).\n\n# Effectiveness of Vaccination for Decreasing transmission to Contacts\nDecreasing transmission of influenza from caregivers and household contacts to persons at high risk might reduce ILI and complications among persons at high risk. Influenza virus infection and ILI are common among HCP (299-301). Influenza outbreaks have been attributed to low vaccination rates among HCP in hospitals and long-term-care facilities (302)(303)(304). One serosurvey demonstrated that 23% of HCP had serologic evidence of influenza virus infection during a single influenza season; the majority had mild illness or subclinical infection (299). Observational studies have demonstrated that vaccination of HCP is associated with decreased deaths among nursing home patients (305,306). In one clusterrandomized controlled trial that included 2,604 residents of 44 nursing homes, significant decreases in mortality, ILI, and medical visits for ILI care were demonstrated among residents in nursing homes in which staff were offered influenza vaccination (coverage rate: 48%) compared with nursing homes in which staff were not provided with vaccination (coverage rate: 6%) (307). A review concluded that vaccination of HCP in settings in which patients also were vaccinated provided significant reductions in deaths among elderly patients from all causes and deaths from pneumonia (308).\nEpidemiologic studies of community outbreaks of influenza demonstrate that school-aged children typically have the highest influenza illness attack rates, suggesting routine universal vaccination of children might reduce transmission to their household contacts and possibly others in the community. Results from certain studies have indicated that the benefits of vaccinating children might extend to protection of their adult contacts and to persons at risk for influenza complications in the community. However, these data are limited, and studies have not used laboratory-confirmed influenza as an outcome measure. A single-blinded, randomized controlled study conducted as part of a 1996-1997 vaccine effectiveness study demonstrated that vaccinating preschool-aged children with TIV reduced influenza-related morbidity among some household contacts (309). A randomized, placebo-controlled trial among children with recurrent respiratory tract infections demonstrated that members of families with children who had received LAIV were significantly less likely to have respiratory tract infections and reported significantly fewer workdays lost compared with families with children who received placebo (310). In nonrandomized community-based studies, administration of LAIV has been demonstrated to reduce MAARI (311,312) and ILI-related economic and medical consequences (e.g., workdays lost and number of health-care provider visits) among contacts of vaccine recipients (312). Households with children attending schools in which school-based LAIV vaccination programs had been established reported less ILI and fewer physician visits during peak influenza season compared with households with children in schools in which no LAIV vaccination had been offered. However a decrease in the overall rate of school absenteeism was not reported in communities in which LAIV vaccination was offered (312). During an influenza outbreak during the 2005-06 influenza season, countywide school-based influenza vaccination was associated with reduced absenteeism among elementary and high school students in one county that implemented a school based vaccination program compared with another county without such a program (313). These community-based studies have not used laboratory-confirmed influenza as an outcome.\nSome studies also have documented reductions in influenza illness among persons living in communities where focused programs for vaccinating children have been conducted. A community-based observational study conducted during the 1968 pandemic using a univalent inactivated vaccine reported that a vaccination program targeting school-aged children (coverage rate: 86%) in one community reduced influenza rates within the community among all age groups compared with another community in which aggressive vaccination was not conducted among school-aged children (314). An observational study conducted in Russia demonstrated reductions in ILI among the community-dwelling elderly after implementation of a vaccination program using TIV for children aged 3-6 years (57% coverage achieved) and children and adolescents aged 7-17 years (72% coverage achieved) (315). In a nonrandomized community-based study conducted over three influenza seasons, 8%-18% reductions in the incidence of MAARI during the influenza season among adults aged >35 years were observed in communities in which LAIV was offered to all children aged >18 months (estimated coverage rate: 20%-25%) compared with communities that did not provide routine influenza vaccination programs for all children (311). In a subsequent influenza season, the same investigators documented a 9% reduction in MAARI rates during the influenza season among persons aged 35-44 years in intervention communities, where coverage was estimated at 31% among school children. However, MAARI rates among persons aged >45 years were lower in the intervention communities regardless of the presence of influenza in the community, suggesting that lower rates could not be attributed to vaccination of school children against influenza (295).\nThe largest study to examine the community effects of increasing overall vaccine coverage was an ecologic study that described the experience in Ontario, Canada, which was the only province to implement a universal influenza vaccination program beginning in 2000. On the basis of models developed from administrative and viral surveillance data, influenzarelated mortality, hospitalizations, ED use, and physicians' office visits decreased significantly more in Ontario after program introduction than in other provinces, with the largest reductions observed in younger age groups (316).\n\n# Effectiveness of Influenza Vaccination When Circulating Influenza Virus Strains Differ from Vaccine Strains\nManufacturing trivalent influenza virus vaccines is a challenging process that takes 6-8 months to complete. Vaccination can provide reduced but substantial cross-protection against drifted strains in some seasons, including reductions in severe outcomes such as hospitalization. Usually one or more circulating viruses with antigenic changes compared with the vaccine strains are identified in each influenza season. In addition, two distinct lineages of influenza B viruses have co-circulated in recent years, and limited cross-protection is observed against the lineage not represented in the vaccine (48). However, assessment of the clinical effectiveness of influenza vaccines cannot be determined solely by laboratory evaluation of the degree of antigenic match between vaccine and circulating strains. In some influenza seasons, circulating influenza viruses with significant antigenic differences predominate, and reductions in vaccine effectiveness sometimes are observed compared with seasons when vaccine and circulating strains are wellmatched, (107,121,125,173,222). However, even during years when vaccine strains were not antigenically well matched to circulating strains (the result of antigenic drift), substantial protection has been observed against severe outcomes, presumably because of vaccine-induced cross-reacting antibodies (121,125,222,283). For example, in one study conducted during the 2003-04 influenza season, when the predominant circulating strain was an influenza A (H3N2) virus that was antigenically different from that season's vaccine strain, effectiveness against laboratory-confirmed influenza illness among persons aged 50-64 years was 60% among healthy persons and 48% among persons with medical conditions that increased the risk for influenza complications (125). An interim, withinseason analysis during the 2007-08 influenza season indicated that vaccine effectiveness was 44% overall, 54% among healthy persons aged 5-49 years, and 58% against influenza A, despite the finding that viruses circulating in the study area were predominately a drifted influenza A (H3N2) and an influenza B strain from a different lineage compared with vaccine strains (317). Among children, both TIV and LAIV provide protection against infection even in seasons when vaccines and circulating strains are not well-matched. Vaccine effectiveness against ILI was 49%-69% in two observational studies, and 49% against medically attended, laboratory-confirmed influenza in a case-control study conducted among young children during the 2003-04 influenza season, when a drifted influenza A (H3N2) strain predominated, based on viral surveillance data (102,106). However, continued improvements in collecting representative circulating viruses and use of surveillance data to forecast antigenic drift are needed. Shortening manufacturing time to increase the time to identify good vaccine candidate strains from among the most recent circulating strains also is important. Data from multiple seasons that are collected in a consistent manner are needed to better understand vaccine effectiveness during seasons when circulating and vaccine virus strains are not well-matched.\nSeasonal influenza vaccines are not expected to provide protection against novel influenza A (H1N1) virus infection because this novel strain hemagglutinin is substantially different from seasonal influenza A (H1N1). Preliminary immunologic data indicate that few persons have antibody that shows evidence of cross-reactivity against novel influenza A (H1N1) virus, and few show increases in antibody titer to novel influenza A (H1N1) virus after vaccination with the 2007-08 or the 2008-09 seasonal influenza vaccines (318). Vaccines currently are being developed that are specific to novel influenza A (H1N1) virus.\n\n# Cost-Effectiveness of Influenza Vaccination\nEconomic studies of influenza vaccination are difficult to compare because they have used different measures of both costs and benefits (e.g., cost-only, cost-effectiveness, costbenefit, or cost-utility). However, most studies find that vaccination reduces or minimizes health care, societal, and individual costs and the productivity losses and absenteeism associated with influenza illness. One national study estimated the annual economic burden of seasonal influenza in the United States (using 2003 population and dollars) to be $87.1 billion, including $10.4 billion in direct medical costs (319).\nStudies of influenza vaccination in the United States among persons aged >65 years have estimated substantial reductions in hospitalizations and deaths and overall societal cost savings (168,169). Studies comparing adults in different age groups also find that vaccination is economically beneficial. One study that compared the economic impact of vaccination among persons aged >65 years with those aged 15-64 years indicated that vaccination resulted in a net savings per quality-adjusted life year (QALY) and that the Medicare program saved costs of treating illness by paying for vaccination (320). A study of a larger population comparing persons aged 50-64 years with those aged >65 years estimated the cost-effectiveness of influenza vaccination to be $28,000 per QALY saved (in 2000 dollars) in persons aged 50-64 years compared with $980 per QALY saved among persons aged >65 years (321).\nEconomic analyses among adults aged <65 years have reported mixed results regarding influenza vaccination. Two studies in the United States found that vaccination can reduce both direct medical costs and indirect costs from work absenteeism and reduced productivity (322,323). However, another U.S. study indicated no productivity and absentee savings in a strategy to vaccinate healthy working adults, although vaccination was still estimated to be cost-effective (324).\nCost analyses have documented the considerable financial burden of illness among children. In a study of 727 children conducted at a medical center during 2000-2004, the mean total cost of hospitalization for influenza-related illness was $13,159 ($39,792 for patients admitted to an intensive care unit and $7,030 for patients cared for exclusively on the wards) (325). A strategy that focuses on vaccinating children with medical conditions that confer a higher risk for influenza complications are more cost-effective than a strategy of vaccinating all children (324). An analysis that compared the costs of vaccinating children of varying ages with TIV and LAIV indicated that costs per QALY saved increased with age for both vaccines. In 2003 dollars per QALY saved, costs for routine vaccination using TIV were $12,000 for healthy children aged 6-23 months and $119,000 for healthy adolescents aged 12-17 years compared with $9,000 and $109,000 using LAIV, respectively (326). Economic evaluations of vaccinating children have demonstrated a wide range of cost estimates, but have generally found this strategy to be either cost-saving or cost-beneficial (327)(328)(329)(330).\nEconomic analyses are sensitive to the vaccination venue, with vaccination in medical care settings incurring higher projected costs. In a published model, the mean cost (year 2004 values) of vaccination was lower in mass vaccination ($17.04) and pharmacy ($11.57) settings than in scheduled doctor's office visits ($28.67) (331). Vaccination in nonmedical settings was projected to be cost saving for healthy adults aged >50 years and for high-risk adults of all ages. For healthy adults aged 18-49 years, preventing an episode of influenza would cost $90 if vaccination were delivered in a pharmacy setting, $210 in a mass vaccination setting, and $870 during a scheduled doctor's office visit (331). Medicare payment rates in recent years have been less than the costs associated with providing vaccination in a medical practice (332).\n\n# Vaccination Coverage Levels\nContinued annual monitoring is needed to determine the effects on vaccination coverage of vaccine supply delays and shortages, changes in influenza vaccination recommendations and target groups for vaccination, reimbursement rates for vaccine and vaccine administration, and other factors related to vaccination coverage among adults and children. One of the Healthy People 2010 objectives (objective no. 14-29a) includes achieving an influenza vaccination coverage level of 90% for persons aged >65 years and among nursing home residents (333,334); new strategies to improve coverage are needed to achieve this objective (335,336). Increasing vaccination coverage among persons who have high-risk conditions and are aged <65 years, including children at high risk, is the highest priority for expanding influenza vaccine use.\nOn 3) and are only slightly lower than coverage levels observed before the 2004-05 vaccine shortage year (337)(338)(339). In the 2006-07 and 2007-08 influenza seasons, estimated vaccination coverage levels among adults with high-risk conditions aged 18-49 years were 25% and 30%, respectively, substantially lower than the Healthy People 2000 and Healthy People 2010 objectives of 60% (Table 3) (333,334).\nStudies conducted among children and adults indicate that opportunities to vaccinate persons at risk for influenza complications (e.g., during hospitalizations for other causes) often are missed. In one study, 23% of children hospitalized with influenza and a comorbidity had a previous hospitalization during the preceding influenza vaccination season (340). In a study of hospitalized Medicare patients, only 31.6% were vaccinated before admission, 1.9% during admission, and 10.6% after admission (341). A study in New York City conducted during 2001-2005 among 7,063 children aged 6-23 months indicated that 2-dose vaccine coverage increased from 1.6% to 23.7% over time; however, although the average number of medical visits during which an opportunity to be vaccinated decreased during the course of the study from 2.9 to 2.0 per child, 55% of all visits during the final year of the study still represented a missed vaccination opportunity (342). Using standing orders in hospitals increases vaccination rates among hospitalized persons (343), and vaccination of hospitalized patients is safe and stimulates an appropriate immune response (158). In one survey, the strongest predictor of receiving vaccination was the survey respondent's belief that he or she was in a high-risk group, based on data from one survey; however, many persons in high-risk groups did not know that they were in a group recommended for vaccination (344).\nReducing racial/ethnic health disparities, including disparities in influenza vaccination coverage, is an overarching national goal that is not being met (334). Estimated vaccination coverage levels in 2007 among persons aged >65 years were 70% for non-Hispanic whites, 58% for non-Hispanic blacks, and 54% for Hispanics (345). Among Medicare beneficiaries, other key factors that contribute to disparities in coverage include variations in the propensity of patients to actively seek vaccination and variations in the likelihood that providers recommend vaccination (346,347). One study estimated that eliminating these disparities in vaccination coverage would have an impact on mortality similar to the impact of eliminating deaths attributable to kidney disease among blacks or liver disease among Hispanics (348).\nReported vaccination levels are low among children at increased risk for influenza complications. Coverage among children aged 2-17 years with asthma for the 2004-05 influenza season was estimated to be 29% (349). One study reported 79% vaccination coverage among children attending a cystic fibrosis treatment center (350). During the first season for which ACIP recommended that all children aged 6 months-23 months receive vaccination, 33% received 1 or more doses of influenza vaccine, and 18% received 2 doses if they were unvaccinated previously (351). Among children enrolled in HMOs who had received a first dose during 2001-2004, second dose coverage varied from 29% to 44% among children aged 6-23 months and from 12% to 24% among children aged 2-8 years (352). A rapid analysis of influenza vaccination coverage levels among members of an HMO in Northern California demonstrated that during the 2004-05 influenza season, the first year of the recommendation for vaccination of children aged 6-23 months, 1-dose coverage was 57% (353). During the 2006-07 influenza season, the second season for which ACIP recommended that all children aged 6 months-23 months receive vaccination, coverage remained low and did not increase substantially from the 2004-05 season. Data collected in 2007 by the National Immunization Survey indicated that for the 2006-07 season, 32% of children aged 6-23 months received at least 1 dose of influenza vaccine and 21% were fully vaccinated (i.e., received 1 or 2 doses depending on previous vaccination history); however, results varied substantially among states (354). As has been reported for older adults, a physician recommendation for vaccination and the perception that having a child be vaccinated \"is a smart idea\" were associated positively with likelihood of vaccination of children aged 6-23 months (355). Similarly, children with asthma were more likely to be vaccinated if their parents recalled a physician recommendation to be vaccinated or believed that the vaccine worked well (356). Implementation of a reminder/recall system in a pediatric clinic increased the percentage of children with asthma receiving vaccination from 5% to 32% (357).\nAlthough annual vaccination is recommended for HCP and is a high priority for reducing morbidity associated with influenza in health-care settings and for expanding influenza vaccine use (358)(359)(360), national survey data demonstrated a vaccination coverage level of only 42% among HCP during the 2005-06 season, and 44% during the 2006-07 season (Table † † Adults categorized as being at high risk for influenza-related complications self-reported one or more of the following: 1) ever being told by a physician they had diabetes, emphysema, coronary heart disease, angina, heart attack, or other heart condition; 2) having a diagnosis of cancer during the previous 12 months (excluding nonmelanoma skin cancer) or ever being told by a physician they have lymphoma, leukemia, or blood cancer during the previous 12 months (post coding for a cancer diagnosis was not yet completed at the time of this publication so this diagnosis was not include in the 2006-07 season data.); 3) being told by a physician they have chronic bronchitis or weak or failing kidneys; or 4) reporting an asthma episode or attack during the preceding 12 months. For children aged <18 years, high-risk conditions included ever having been told by a physician of having diabetes, cystic fibrosis, sickle cell anemia, congenital heart disease, other heart disease, or neuromuscular conditions (seizures, cerebral palsy, and muscular dystrophy), or having an asthma episode or attack during the preceding 12 months. § § Aged 18-44 years, pregnant at the time of the survey and without high-risk conditions. ¶ ¶ Adults were classified as health-care workers if they were employed in a health-care occupation or in a health-care-industry setting, on the basis of standard occupation and industry categories recoded in groups by CDC's National Center for Health Statistics. * Interviewed sample child or adult in each household containing at least one of the following: a child aged <5 years, an adult aged ≥65 years, or any person aged 5-17 years at high risk (see previous footnote † † ). To obtain information on household composition and high-risk status of household members, the sampled adult, child, and person files from NHIS were merged. Interviewed adults who were health-care workers or who had high-risk conditions were excluded. Information could not be assessed regarding high-risk status of other adults aged 18-64 years in the household; therefore, certain adults aged 18-64 years who lived with an adult aged 18-64 years at high risk were not included in the analysis. Also note that although the recommendation for children aged 2-4 years was not in place during the 2005-06 season, children aged 2-4 years in these calculations were considered to have an indication for vaccination to facilitate comparison of coverage data for subsequent years.\n3). Vaccination of HCP has been associated with reduced work absenteeism (300) and with fewer deaths among nursing home patients (305,307) and elderly hospitalized patients (308). Factors associated with a higher rate of influenza vaccination among HCP include older age, being a hospital employee, having employer-provided health-care insurance, having had pneumococcal or hepatitis B vaccination in the past, or having visited a health-care professional during the preceding year. Non-Hispanic black HCP were less likely than non-Hispanic white HCP to be vaccinated (361). HCP who decline vaccination frequently express doubts about the risk for influenza and the need for vaccination, are concerned about vaccine effectiveness and side effects, and dislike injections (362).\nVaccine coverage among pregnant women increased during the 2007-08 influenza season with 24% of pregnant women reporting vaccination, excluding pregnant women who reported diabetes, heart disease, lung disease, and other selected high-risk conditions (Table 3). However, the sample size is small, and the increase in coverage compared with previous seasons was not statistically significant. In a study of influenza vaccine acceptance by pregnant women, 71% of those who were offered the vaccine chose to be vaccinated (363). However, a 1999 survey of obstetricians and gynecologists determined that only 39% administered influenza vaccine to obstetric patients in their practices, although 86% agreed that pregnant women's risk for influenza-related morbidity and mortality increases during the last two trimesters (364).\nInfluenza vaccination coverage in all groups recommended for vaccination remains suboptimal. Despite the timing of the peak of influenza disease, administration of vaccine decreases substantially after November. According to results from the NHIS regarding the two most recent influenza seasons for which these data are available, approximately 84% of all influenza vaccination were administered during September-November. Among persons aged >65 years, the percentage of September-November vaccinations was 92% (365). Because many persons recommended for vaccination remain unvaccinated at the end of November, CDC encourages public health partners and health-care providers to conduct vaccination clinics and other activities that promote seasonal influenza vaccination annually during National Influenza Vaccination Week (December 6-12, 2009) and throughout the remainder of the influenza season.\nSelf-report of influenza vaccination among adults compared with determining vaccination status from the medical record, is a sensitive and specific source of information (366,367). Patient self-reports should be accepted as evidence of influenza vaccination in clinical practice (367). However, information on the validity of parents' reports of pediatric influenza vaccination is not yet available.\n\n# Recommendations for Using tIV and LAIV During the 2009-10 Influenza Season\nBoth TIV and LAIV prepared for the 2009-10 season will include A/Brisbane/59/2007 (H1N1)-like, A/ Brisbane/10/2007 (H3N2)-like, and B/Brisbane/60/2008-like antigens. The influenza B virus component of the 2009-10 vaccine is from the Victoria lineage (368). These viruses will be used because they are representative of seasonal influenza viruses that are predicted to be circulating in the United States during the 2009-10 influenza season and have favorable growth properties in eggs. Seasonal influenza vaccines are not expected to provide substantial protection against infection with the recently identified novel influenza A (H1N1) (318), and guidance for the prevention of infection against this virus will be published separately.\nTIV and LAIV can be used to reduce the risk for influenza virus infection and its complications. Vaccination providers should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.\nHealthy, nonpregnant persons aged 2-49 years can choose to receive either vaccine. Some TIV formulations are FDAlicensed for use in persons as young as age 6 months (see Recommended Vaccines for Different Age Groups). TIV is licensed for use in persons with high-risk conditions (Table 2). LAIV is FDA-licensed for use only for persons aged 2-49 years. In addition, FDA has indicated that the safety of LAIV has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications. All children aged 6 months-8 years who have not been vaccinated previously at any time with at least 1 dose of either LAIV (if appropriate) or TIV should receive 2 doses of ageappropriate vaccine in the same season, with a single dose during subsequent seasons.\n\n# target Groups for Protection through Vaccination\nInfluenza vaccine should be provided to all persons who want to reduce the risk for becoming ill with influenza or of transmitting it to others. However, emphasis on providing routine vaccination annually to certain groups at higher risk for influenza infection or complications is advised, including all children aged 6 months-18 years, all persons aged >50 years, and other adults at risk for medical complications from influenza. In addition, all persons who live with or care for persons at high risk for influenza-related complications, including contacts of children aged <6 months, should receive influenza vaccine annually (Boxes 1 and 2). Approximately 85% of the U.S. population is included in one or more of these target groups; however, <40% of the U.S. population received an influenza vaccination during the 2008-09 influenza season.\n\n# Children Aged 6 Months-18 Years\nBeginning with the 2008-09 influenza season, annual vaccination for all children aged 6 months-18 years was recommended. Children and adolescents at high risk for influenza complications should continue to be a focus of vaccination efforts as providers and programs transition to routinely vaccinating all children.\nHealthy children aged 2-18 years can receive either LAIV or TIV. Children aged 6-23 months, and those aged 2-4 years who have evidence of asthma wheezing or who have medical conditions that put them at higher risk for influenza complications should receive TIV (see Considerations When Using LAIV). All children aged 6 months-8 years who have not received vaccination against influenza previously should receive 2 doses of vaccine the first year they are vaccinated.\n\n# Persons at Risk for Medical Complications\nVaccination to prevent influenza is particularly important for the following persons, who are at increased risk for severe complications from influenza, or at higher risk for influenzarelated outpatient, ED, or hospital visits: all children aged 6 months- facilities. For children, the risk for severe complications from seasonal influenza is highest among those aged <2 years, who have much higher rates of hospitalization for influenza-related complications compared with older children (7,32,39). Medical care and ED visits attributable to influenza are increased among children aged <5 years compared with older children (32).\nChronic neurologic and neuromuscular conditions include any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration (30).\n\n# Persons Who Live With or Care for Persons at High Risk for Influenza-Related Complications\nTo prevent transmission to persons identified above, vaccination with TIV or LAIV (unless contraindicated) also is recommended for the following persons. When vaccine supply is limited, vaccination efforts should focus on delivering vaccination to these persons: HCP; - household contacts (including children) and caregivers - of children aged 50 years; and household contacts (including children) and caregivers - of persons with medical conditions that put them at higher risk for severe complications from influenza.\n\n# Children Aged <6 Months\nChildren aged <6 months are not recommended for vaccination, and antivirals are not licensed for use among infants. Protection of young infants, who have hospitalization rates similar to those observed among the elderly, depends on vaccination of the infants' close contacts. A recent study conducted in Bangladesh demonstrated that infants born to vaccinated women have significant protection from laboratory-confirmed influenza, either through transfer of influenza-specific maternal antibodies or by reducing the risk for exposure to influenza that might occur through vaccination of the mother (154). All household contacts, health-care and day care providers, and other close contacts of young infants should be vaccinated.\n\n# Vaccination of Specific Populations Children Aged 6 Months-18 Years\nAll children aged 6 months-18 years should be vaccinated against influenza annually. In 2004, ACIP recommended routine vaccination for all children aged 6-23 months, and in 2006, ACIP expanded the recommendation to include all children aged 24-59 months. Recommendations to provide routine influenza vaccination to all children and adolescents aged 6 months-18 years are made on the basis of 1) accumulated evidence that influenza vaccine is effective and safe for children (see Influenza Vaccine Efficacy, Effectiveness, and Safety); 2) increased evidence that influenza has substantial adverse impacts among children and their contacts (e.g., school absenteeism, increased antibiotic use, medical care visits, and parental work loss) (see Health-Care Use, Hospitalizations, and Deaths Attributed to Influenza); and 3) an expectation that a simplified age-based influenza vaccine recommendation for all children and adolescents will improve vaccine coverage levels among children who already have a risk-or contact-based indication for annual influenza vaccination.\nChildren typically have the highest attack rates during community outbreaks of influenza and serve as a major source of transmission within communities (1,2). If sufficient vaccination coverage among children can be achieved, potential benefits include the indirect effect of reducing influenza among persons who have close contact with children and reducing overall transmission within communities. Achieving and sustaining community-level reductions in influenza will require mobilization of community resources and development of sustainable annual vaccination campaigns to assist health-care providers and vaccination programs in providing influenza vaccination services to children of all ages. In many areas, innovative community-based efforts, which might include mass vaccination programs in school or other community settings, will be needed to supplement vaccination services provided in health-care providers' offices or public health clinics. In nonrandomized community-based controlled trials, reductions in ILI-related symptoms and medical visits among household contacts have been demonstrated in communities where vaccination programs among school-aged children were established compared with communities without such vaccination programs (295,314,315).Reducing influenza-related illness among children who are at high risk for influenza complications should continue to be a primary focus of influenza-prevention efforts. Children who should be vaccinated because they are at high risk for influenza complications include all children aged 6-59 months, children with certain medical conditions, children who are contacts of children aged 50 years, and children who are contacts of persons at high risk for influenza complications because of medical conditions.\nAll children aged 6 months-8 years who have not received vaccination against influenza previously should receive 2 doses of vaccine the first influenza season that they are vaccinated. The second dose should be administered 4 or more weeks after the initial dose. When only 1 dose is administered to children aged 6 months-8 years during their first year of vaccination, 2 doses should be administered in the following season. However, 2 doses should only be administered in the first season of vaccination, or in the season that immediately follows if only 1 dose is administered in the first season. For example, children aged 6 months-8 years who were vaccinated for the first time with the 2008-09 influenza vaccine but received only 1 dose should receive 2 doses of the 2009-10 influenza vaccine. All other children aged 6 months-8 years who have previously received 1 or more doses of influenza vaccine at any time should receive 1 dose of the 2009-10 influenza vaccine. Children aged 6 months-8 years who received only a single vaccination during a season before 2007-08 should receive 1 dose of the 2009-10 influenza vaccine. If possible, both doses should be administered before onset of influenza season. However, vaccination, including the second dose, is recommended even after influenza virus begins to circulate in a community.\n\n# HCP and other Persons Who Can transmit Influenza to those at High Risk\nHealthy persons who are infected with influenza virus, including those with subclinical infection, can transmit influenza virus to persons at higher risk for complications from influenza. In addition to HCP, groups that can transmit influenza to high-risk persons and that should be vaccinated include employees of assisted living and other residences for All HCP and persons in training for health-care professions should be vaccinated annually against influenza. Persons working in health-care settings who should be vaccinated include physicians, nurses, and other workers in both hospital and outpatient-care settings, medical emergency-response workers (e.g., paramedics and emergency medical technicians), employees of nursing home and long-term-care facilities who have contact with patients or residents, and students in these professions who will have contact with patients (359,360,371).\nFacilities that employ HCP should provide vaccine to workers by using approaches that have been demonstrated to be effective in increasing vaccination coverage. Health-care administrators should consider the level of vaccination coverage among HCP to be one measure of a patient safety quality program and consider obtaining signed declinations from personnel who decline influenza vaccination for reasons other than medical contraindications (360,372,373). Influenza vaccination rates among HCP within facilities should be regularly measured and reported, and ward-, unit-, and specialty-specific coverage rates should be provided to staff and administration (360). Studies have demonstrated that organized campaigns can attain higher rates of vaccination among HCP with moderate effort and by using strategies that increase vaccine acceptance (358,360,374).\nEfforts to increase vaccination coverage among HCP are supported by various national accrediting and professional organizations and in certain states by statute. The Joint Commission on Accreditation of Health-Care Organizations has approved an infection-control standard that requires accredited organizations to offer influenza vaccinations to staff, including volunteers and licensed independent practitioners with close patient contact. The standard became an accreditation requirement beginning January 1, 2007 (375). In addition, the Infectious Diseases Society of America has recommended mandatory vaccination for HCP, with a provision for declination of vaccination based on religious or medical reasons (376). Some states have regulations regarding vaccination of HCP in long-term-care facilities (377), require that health-care facilities offer influenza vaccination to HCP, or require that HCP either receive influenza vaccination or indicate a religious, medical, or philosophic reason for not being vaccinated (378,379).\n\n# Close Contacts of Immunocompromised Persons\nImmunocompromised persons are at risk for influenza complications but might have inadequate protection after vaccination. Close contacts of immunocompromised persons, including HCP, should be vaccinated to reduce the risk for influenza transmission. TIV is recommended for vaccinating household members, HCP, and others who have close contact with severely immunosuppressed persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunosuppressed person requires care in a protective environment (typically defined as a specialized patient-care area with a positive airflow relative to the cor-ridor, high-efficiency particulate air filtration, and frequent air changes) (360,380).\nLAIV transmission from a recently vaccinated person causing clinically important illness in an immunocompromised contact has not been reported. The rationale for avoiding use of LAIV among HCP or other close contacts of severely immunocompromised patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunosuppressed person. As a precautionary measure, HCP who receive LAIV should avoid providing care for severely immunosuppressed patients requiring a protected environment for 7 days after vaccination. Hospital visitors who have received LAIV should avoid contact with severely immunosuppressed persons in protected environments for 7 days after vaccination but should not be restricted from visiting less severely immunosuppressed patients.\nNo preference is indicated for TIV use by persons who have close contact with persons with lesser degrees of immunosuppression (e.g., persons with diabetes, persons with asthma who take corticosteroids, persons who have recently received chemotherapy or radiation but who are not being cared for in a protective environment as defined above, or persons infected with HIV) or for TIV use by HCP or other healthy nonpregnant persons aged 2-49 years in close contact with persons in all other groups at high risk.\n\n# Pregnant Women\nPregnant women and newborns are at risk for influenza complications, and all women who are pregnant or will be pregnant during influenza season should be vaccinated. The American College of Obstetricians and Gynecologists and the American Academy of Family Physicians also have recommended routine vaccination of all pregnant women (381). No preference is indicated for use of TIV that does not contain thimerosal as a preservative (see Vaccine Preservative in Multidose Vials of TIV) for any group recommended for vaccination, including pregnant women. LAIV is not licensed for use in pregnant women. However, pregnant women do not need to avoid contact with persons recently vaccinated with LAIV.\n\n# Breastfeeding Mothers\nVaccination is recommended for all persons, including breastfeeding women, who are contacts of infants or children aged <5 years because infants and young children are at high risk for influenza complications and are more likely to require medical care or hospitalization if infected. Breastfeeding does not affect the immune response adversely and is not a con-traindication for vaccination (179). Unless contraindicated because of other medical conditions, women who are breastfeeding can receive either TIV or LAIV. In one randomized controlled trial conducted in Bangladesh, infants born to women vaccinated during pregnancy had a lower risk for laboratory-confirmed influenza. However, the contribution to protection from influenza of breastfeeding compared with passive transfer of maternal antibodies during pregnancy was not determined (154).\n\n# travelers\nThe risk for exposure to influenza during travel depends on the time of year and destination. In the temperate regions of the Southern Hemisphere, influenza activity occurs typically during April-September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large tourist groups (e.g., on cruise ships) that include persons from areas of the world in which influenza viruses are circulating (382,383). In the tropics, influenza occurs throughout the year. In a study among Swiss travelers to tropical and subtropical countries, influenza was the most frequently acquired vaccine-preventable disease (384).\nAny traveler who wants to reduce the risk for influenza infection should consider influenza vaccination, preferably at least 2 weeks before departure. In particular, persons at high risk for complications of influenza and who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to travel to the tropics, - with organized tourist groups at any time of year, or - to the Southern Hemisphere during April-September. - No information is available about the benefits of revaccinating persons before summer travel who already were vaccinated during the preceding fall, and revaccination is not recommended. Persons at high risk who receive the previous season's vaccine before travel should be revaccinated with the current vaccine the following fall or winter. Persons at higher risk for influenza complications should consult with their health-care practitioner to discuss the risk for influenza or other travel-related diseases before embarking on travel during the summer.\n\n# General Population\nVaccination is recommended for any persons who wish to reduce the likelihood of their becoming ill with influenza or transmitting influenza to others should they become infected. Healthy, nonpregnant persons aged 2-49 years might choose to receive either TIV or LAIV. All other persons aged >6 months should receive TIV. Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories or correctional facilities) should be encouraged to receive vaccine to minimize morbidity and the disruption of routine activities during influenza epidemics (385,386).\n\n# Recommended Vaccines for Different Age Groups\nWhen vaccinating children aged 6-35 months with TIV, health-care providers should use TIV that has been licensed by the FDA for this age group (i.e., TIV manufactured by Sanofi Pasteur ) (219). TIV from Novartis (Fluvirin) is FDA-approved in the United States for use among persons aged >4 years (220). TIV from GlaxoSmithKline (Fluarix and FluLaval) or CSL Biotherapies (Afluria) is labeled for use in persons aged >18 years because data to demonstrate immunogenicity or efficacy among younger persons have not been provided to FDA (207,208,218). LAIV from MedImmune (FluMist) is recommended for use by healthy nonpregnant persons aged 2-49 years (Table 2) (291). If a pediatric vaccine dose (0.25mL) is administered to an adult, an additional pediatric dose (0.25 mL) should be given to provide a full adult dose (0.5mL). If the error is discovered later (after the patient has left the vaccination setting), an adult dose should be administered as soon as the patient can return. No action needs to be taken if an adult dose is administered to a child. Several new vaccine formulations are being evaluated in immunogenicity and efficacy trials; when licensed, these new products will increase the influenza vaccine supply and provide additional vaccine choices for practitioners and their patients.\n\n# Influenza Vaccines and Use of Influenza Antiviral Medications\nUnvaccinated persons who are receiving antiviral medications for treatment or chemoprophylaxis often also are recommended for vaccination. Administration of TIV to persons receiving influenza antivirals is acceptable. The effect on safety and effectiveness of LAIV coadministration with influenza antiviral medications has not been studied. However, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV. Persons receiving antivirals within the period 2 days before to 14 days after vaccination with LAIV should be revaccinated at a later date with any approved vaccine formulation (179,291).\n\n# Considerations When Using LAIV\nLAIV is an option for vaccination of healthy, nonpregnant persons aged 2-49 years, including HCP and other close contacts of high-risk persons (excepting severely immunocompromised persons who require care in a protected environment). No preference is indicated for LAIV or TIV when considering vaccination of healthy, ¶ nonpregnant persons aged 2-49 years. Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response in children, its ease of administration, and the possibly increased acceptability of an intranasal rather than intramuscular route of administration.\nIf the vaccine recipient sneezes after administration, the dose should not be repeated. However, if nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness, or TIV should be administered instead. No data exist about concomitant use of nasal corticosteroids or other intranasal medications (261).\nAlthough FDA licensure of LAIV excludes children aged 2-4 years with a history of asthma or recurrent wheezing, the precise risk, if any, of wheezing caused by LAIV among these children is unknown because experience with LAIV among these young children is limited. Young children might not have a history of recurrent wheezing if their exposure to respiratory viruses has been limited because of their age. Certain children might have a history of wheezing with respiratory illnesses but have not had asthma diagnosed.\nThe following screening recommendations should be used to assist persons who administer influenza vaccines in providing the appropriate vaccine for children aged 2-4 years.\nClinicians and vaccination programs should screen - for asthma or wheezing illness (or history of wheezing illness) when considering use of LAIV for children aged 2-4 years, and should avoid use of this vaccine in children with asthma or a recent wheezing episode within the previous 12 months. Health-care providers should consult the medical record, when available, to identify children aged 2-4 years with asthma or recurrent wheezing that might indicate asthma. In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving LAIV, parents or caregivers of children aged 2-4 years should be asked: \"In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?\" Children whose parents or caregivers answer \"yes\" to this question and children who have asthma or who had a wheezing episode noted in the medical record during the preceding 12 months should not receive LAIV. TIV is available for use in children with asthma or wheezing (387).LAIV can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infection with or without fever). However, if nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness.\n\n# Contraindications and Precautions for Use of LAIV\nThe effectiveness or safety of LAIV is not known for the following groups and administration of LAIV is contraindicated:\npersons ing aspirin or other salicylates (because of the association of Reye syndrome with wild-type influenza virus infection); or pregnant women. - A moderate or severe illness with or without fever is a precaution for use of LAIV. GBS within 6 weeks following a previous dose of influenza vaccine is considered to be a precaution for use of influenza vaccines. LAIV should not be administered to close contacts of immunosuppressed persons who require a protected environment. ¶ Use of the term \"healthy\" in this recommendation refers to persons who do not have any of the underlying medical conditions that confer high risk for severe complications (see Contraindications and Precautions for Use of LAIV).\n\n# Personnel Who Can Administer LAIV\nLow-level introduction of vaccine viruses into the environment probably is unavoidable when administering LAIV. The risk for acquiring vaccine viruses from the environment is unknown but is probably low. Severely immunosuppressed persons should not administer LAIV. However, other persons at higher risk for influenza complications can administer LAIV. These include persons with underlying medical conditions placing them at higher risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged >50 years.\n\n# Concurrent Administration of Influenza Vaccine with other Vaccines\nUse of LAIV concurrently with measles, mumps, rubella (MMR) alone and MMR and varicella vaccine among children aged 12-15 months has been studied, and no interference with the immunogenicity to antigens in any of the vaccines was observed (261,388). Among adults aged >50 years, the safety and immunogenicity of zoster vaccine and TIV was similar whether administered simultaneously or spaced 4 weeks apart (389). In the absence of specific data indicating interference, following ACIP's general recommendations for vaccination is prudent (179). Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. Inactivated or live vaccines can be administered simultaneously with LAIV. However, after administration of a live vaccine, at least 4 weeks should pass before another live vaccine is administered.\n\n# Recommendations for Vaccination Administration and Vaccination Programs\nAlthough influenza vaccination levels increased substantially during the 1990s, little progress has been made since 2000 toward achieving national health objectives, and further improvements in vaccine coverage levels are needed to reduce the annual impact of influenza substantially. Strategies to improve vaccination levels, including using reminder/recall systems and standing orders programs (335,336,345), should be implemented whenever feasible. Vaccination efforts should begin as soon as vaccine is available and continue through the influenza season. Vaccination coverage can be increased by administering vaccine before and during the influenza season to persons during hospitalizations or routine health-care visits. Vaccinations can be provided in alternative settings (e.g., pharmacies, grocery stores, workplaces, or other locations in the community), thereby making special visits to physicians' offices or clinics unnecessary. Coordinated campaigns such as the National Influenza Vaccination Week (December 6-12, 2009) provide opportunities to refocus public attention on the benefits, safety, and availability of influenza vaccination throughout the influenza season. When educating patients about adverse events, clinicians should provide access to Vaccine Information Sheets (available at . gov/vaccines/pubs/vis), and emphasize that 1) TIV contains noninfectious killed viruses and cannot cause influenza, 2) LAIV contains weakened influenza viruses that cannot replicate outside the upper respiratory tract and are unlikely to infect others, and 3) concomitant symptoms or respiratory disease unrelated to vaccination with either TIV or LAIV can occur after vaccination. Adverse events after influenza vaccination should be reported promptly to VAERS at . gov even if the health-care professional is not certain that the vaccine caused the event.\n\n# Information About the Vaccines for Children Program\nThe Vaccines for Children (VFC) program supplies vaccine to all states, territories, and the District of Columbia for use by participating providers. These vaccines are to be provided to eligible children without vaccine cost to the patient or the provider, although the provider might charge a vaccine administration fee. All routine childhood vaccines recommended by ACIP are available through this program, including influenza vaccines. The program saves parents and providers out-ofpocket expenses for vaccine purchases and provides cost savings to states through CDC's vaccine contracts. The program results in lower vaccine prices and ensures that all states pay the same contract prices. Detailed information about the VFC program is available at / vfc/default.htm.\n\n# Influenza Vaccine Supply Considerations\nThe annual supply of influenza vaccine and the timing of its distribution cannot be guaranteed in any year. During the 2008-09 influenza season, 113 million doses of influenza vaccine were distributed in the United States. For the 2009-10 season, total production of seasonal influenza vaccine for the United States is anticipated to be >130 million doses, depending on demand and production yields. However, influenza vaccine distribution delays or vaccine shortages remain possible. One factor that affects production is the inherent critical time constraints in manufacturing the vaccine given the annual updating of the influenza vaccine strains. Multiple manufacturing and regulatory issues, including the anticipated need to produce a separate vaccine against novel influenza A (H1N1), also might affect the production schedule. To ensure optimal use of available doses of influenza vaccine, health-care providers, persons planning organized campaigns, and state and local public health agencies should develop plans for expanding outreach and infrastructure to vaccinate more persons in targeted groups and others who wish to reduce their risk for influenza. They also should develop contingency plans for the timing and prioritization of administering influenza vaccine if the supply of vaccine is delayed or reduced.\nIf supplies of TIV are not adequate, vaccination should be carried out in accordance with local circumstances of supply and demand based on the judgment of state and local health officials and health-care providers. Guidance for tiered use of TIV during prolonged distribution delays or supply short falls is available at and will be modified as needed in the event of shortage. CDC and other public health agencies will assess the vaccine supply on a continuing basis throughout the manufacturing period and will inform both providers and the general public if any indication exists of a substantial delay or an inadequate supply.\nBecause LAIV is recommended for use only in healthy nonpregnant persons aged 2-49 years, no recommendations for prioritization of LAIV use are made. Either LAIV or TIV can be used when considering vaccination of healthy, nonpregnant persons aged 2-49 years. However, during shortages of TIV, LAIV should be used preferentially when feasible for all healthy nonpregnant persons aged 2-49 years (including HCP) who desire or are recommended for vaccination to increase the availability of inactivated vaccine for persons at high risk.\n\n# timing of Vaccination\nVaccination efforts should be structured to ensure the vaccination of as many persons as possible over the course of several months, with emphasis on vaccinating before influenza activity in the community begins. Even if vaccine distribution begins before October, distribution probably will not be completed until December or January. The following recommendations reflect this phased distribution of vaccine.\nIn any given year, the optimal time to vaccinate patients cannot be determined precisely because influenza seasons vary in their timing and duration, and more than one outbreak might occur in a single community in a single year. In the United States, localized outbreaks that indicate the start of seasonal influenza activity can occur as early as October. However, in >80% of influenza seasons since 1976, peak influenza activity (which often is close to the midpoint of influenza activity for the season) has not occurred until January or later, and in >60% of seasons, the peak was in February or later (Figure 1). In general, health-care providers should begin offering vaccination soon after vaccine becomes available and if possible by October. To avoid missed opportunities for vaccination, providers should offer vaccination during routine health-care visits or during hospitalizations whenever vaccine is available. The potential for addition of a novel influenza A (H1N1) vaccine program to the current burden on vaccination programs and providers underscores the need for careful planning of seasonal vaccination programs. Beginning use of seasonal vaccine as soon as available, including in September or earlier, might reduce the overlap of seasonal and novel influenza vaccination efforts.\nVaccination efforts should continue throughout the season, because the duration of the influenza season varies, and influenza might not appear in certain communities until February or March. Providers should offer influenza vaccine routinely, and organized vaccination campaigns should continue throughout the influenza season, including after influenza activity has begun in the community. Vaccine administered in December or later, even if influenza activity has already begun, is likely to be beneficial in the majority of influenza seasons. The majority of adults have antibody protection against influenza virus infection within 2 weeks after vaccination (390,391).\nAll children aged 6 months-8 years who have not received vaccination against influenza previously should receive their first dose as soon after vaccine becomes available as is feasible and should receive the second dose >4 weeks later. This practice increases the opportunity for both doses to be administered before or shortly after the onset of influenza activity.\nVaccination clinics should be scheduled through December, and later if feasible, with attention to settings that serve children aged >6 months, pregnant women, other persons aged 50 years, HCP, and persons who are household contacts of children aged <59 months or other persons at high risk. Planners are encouraged to develop the capacity and flexibility to schedule at least one vaccination clinic in December. Guidelines for planning large-scale vaccination clinics are available at / vaccination/vax_clinic.htm.\nDuring a vaccine shortage or delay, substantial proportions of TIV doses might not be released and distributed until November and December or later. When the vaccine is substantially delayed or disease activity has not subsided, providers should consider offering vaccination clinics into January and beyond as long as vaccine supplies are available. Campaigns using LAIV also can extend into January and beyond.\n\n# Strategies for Implementing Vaccination Recommendations in Health-Care Settings\nSuccessful vaccination programs combine publicity and education for HCP and other potential vaccine recipients, a plan for identifying persons recommended for vaccination, use of reminder/recall systems, assessment of practice-level vaccination rates with feedback to staff, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs (336,392). The use of standing orders programs by long-term-care facilities (e.g., nursing homes and skilled nursing facilities), hospitals, and home health agencies ensures that vaccination is offered. Standing orders programs for influenza vaccination should be conducted under the supervision of a licensed practitioner according to a physician-approved facility or agency policy by HCP trained to screen patients for contraindications to vaccination, administer vaccine, and monitor for adverse events. The Centers for Medicare and Medicaid Services (CMS) has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term-care facilities, and home health agencies (393). To the extent allowed by local and state law, these facilities and agencies can implement standing orders for influenza and pneumococcal vaccination of Medicare-and Medicaideligible patients. Payment for influenza vaccine under Medicare Part B is available (394,395) Other settings (e.g., outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces) are encouraged to introduce standing orders programs (396). In addition, physician reminders (e.g., flagging charts) and patient reminders are recognized strategies for increasing rates of influenza vaccination. Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following sections.\n\n# outpatient Facilities Providing ongoing Care\nStaff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccination. Vaccine should be offered during visits throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the medical record or vaccination information system. Patients for whom vaccination is recommended and who do not have regularly scheduled visits during the fall should be reminded by mail, telephone, or other means of the need for vaccination.\n\n# outpatient Facilities Providing Episodic or Acute Care\nAcute health-care facilities (e.g., EDs and walk-in clinics) should offer vaccinations throughout the influenza season to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility.\n\n# nursing Homes and other Long-term-Care Facilities\nVaccination should be provided routinely to all residents of long-term-care facilities. If possible, all residents should be vaccinated at one time before influenza season. In the majority of seasons, TIV will become available to long-term-care facilities in October or November, and vaccination should commence as soon as vaccine is available. As soon as possible after admission to the facility, the benefits and risks of vaccination should be discussed and education materials provided (397). Signed consent is not required (398). Residents admitted after completion of the vaccination program at the facility should be vaccinated at the time of admission.\nSince October 2005, CMS has required nursing homes participating in the Medicare and Medicaid programs to offer all residents influenza and pneumococcal vaccines and to document the results. According to the requirements, each resident is to be vaccinated unless contraindicated medically, the resident or a legal representative refuses vaccination, or the vaccine is not available because of shortage. This information is to be reported as part of the CMS Minimum Data Set, which tracks nursing home health parameters (395,399).\n\n# Acute-Care Hospitals\nHospitals should serve as a key setting for identifying persons at increased risk for influenza complications. Unvaccinated persons of all ages (including children) with high-risk conditions and persons aged 6 months-18 years or >50 years who are hospitalized at any time during the period when vaccine is available should be offered and strongly encouraged to receive influenza vaccine before they are discharged. Standing orders to offer influenza vaccination to all hospitalized persons should be considered.\n\n# Visiting nurses and others Providing Home Care to Persons at High Risk\nNursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home if necessary as soon as influenza vaccine is available and throughout the influenza season. Caregivers and other persons in the household (including children) should be referred for vaccination.\n\n# other Facilities Providing Services to Persons Aged >50 Years\nFacilities providing services to persons aged >50 years (e.g., assisted living housing, retirement communities, and recreation centers) should offer unvaccinated residents, attendees, and staff annual on-site vaccination before the start of the influenza season. Continuing to offer vaccination throughout the fall and winter months is appropriate. Efforts to vaccinate newly admitted patients or new employees also should be continued, both to prevent illness and to avoid having these persons serve as a source of new influenza infections. Staff education should emphasize the benefits for self, staff and patients of protection from influenza through vaccination.\n\n# Health-Care Personnel\nHealth-care facilities should offer influenza vaccinations to all HCP, including night, weekend, and temporary staff. Particular emphasis should be placed on providing vaccinations to workers who provide direct care for persons at high risk for influenza complications. Efforts should be made to educate HCP regarding the benefits of vaccination and the potential health consequences of influenza illness for their patients, themselves, and their family members. All HCP should be provided convenient access to influenza vaccine at the work site, free of charge, as part of employee health programs (360,374,375).\n\n# Future Directions for Research and Recommendations Related to Influenza Vaccine\nAlthough available influenza vaccines are effective and safe, additional research is needed to improve prevention efforts. Most mortality from influenza occurs among persons aged >65 years (6), and more immunogenic influenza vaccines are needed for this age group and other groups at high risk for mortality. Additional research also is needed to understand potential biases in estimating the benefits of vaccination among older adults in reducing hospitalizations and deaths (82,175,400). Additional studies of the relative cost-effectiveness and cost utility of influenza vaccination among children and adults, especially those aged <65 years, are needed and should be designed to account for year-to-year variations in influenza attack rates, illness severity, hospitalization costs and rates, and vaccine effectiveness when evaluating the long-term costs and benefits of annual vaccination (401). Additional data on indirect effects of vaccination also are needed to quantify the benefits of influenza vaccination of HCP in protecting their patients (308) and the benefits of vaccinating children to reduce influenza complications among those at risk. Because expansions in ACIP recommendations for vaccination will lead to more persons being vaccinated, much larger research networks are needed that can identify and assess the causality of very rare events that occur after vaccination, including GBS. Ongoing studies of safety in pediatric populations with expanded recommendations are needed and are underway. These research networks also could provide a platform for effectiveness and safety studies in the event of a pandemic. A recent study showed that influenza vaccines contain structures that can induce anti-GM1 antibodies after inoculation into mice (402). Further research on potential biologic or genetic risk factors for GBS in humans also is needed (397). In addition, a better understanding is needed of how to motivate persons at risk to seek annual influenza vaccination.\nACIP continues to review new vaccination strategies to protect against influenza, including the possibility of expanding routine influenza vaccination recommendations toward universal vaccination or other approaches that will help reduce or prevent the transmission of influenza and reduce the burden of severe disease (403)(404)(405)(406)(407)(408). The 2009 ACIP expansion of annual vaccination recommendations to include all children aged 6 months-18 years will require a substantial increase in resources for epidemiologic research to develop long-term studies capable of assessing the possible effects on community-level transmission. Additional planning to improve surveillance systems capable of monitoring effectiveness, safety and vaccine coverage, and further development of implementation strategies will also be necessary. In addition, as noted by the National Vaccine Advisory Committee, strengthening the U.S. influenza vaccination system will require improving vaccine financing and demand and implementing systems to help better understand the burden of influenza in the United States (409). Vaccination programs capable of delivering annual influenza vaccination to a broad range of the population could potentially serve as a resilient and sustainable platform for delivering vaccines and monitoring outcomes for other urgently required public health interventions (e.g., vaccines for pandemic influenza or medications to prevent or treat illnesses caused by acts of terrorism).\n\n# Seasonal Influenza Vaccine and Influenza Viruses of Animal origin\nHuman infection with novel or nonhuman influenza A virus strains, including influenza A viruses of animal origin, is a nationally notifiable disease (410). Human infections with nonhuman or novel human influenza A virus should be identified quickly and investigated to determine possible sources of exposure, identify additional cases, and evaluate the possibility of human-to-human transmission because transmission patterns could change over time with variations in these influenza A viruses.\nSporadic severe and fatal human cases of infection with highly pathogenic avian influenza A (H5N1) virus have been identified in Asia, Africa, Europe, and the Middle East, primarily among persons who have had direct or close unprotected contact with sick or dead birds associated with the ongoing H5N1 panzootic among birds (411)(412)(413)(414)(415)(416)(417)(418)(419). Limited, nonsustained human-to-human transmission of H5N1 virus has likely occurred in some case clusters (420,421). To date, no evidence exists of genetic reassortment between human influenza A and H5N1 viruses. However, influenza viruses derived from strains circulating among poultry (e.g., the H5N1 virus that has caused outbreaks of avian influenza and occasionally have infected humans) have the potential to recombine with human influenza A viruses (422,423). To date, highly pathogenic H5N1 virus has not been identified in wild or domestic birds or in humans in the United States. Guidance for testing suspected cases of H5N1 virus infection among persons in the U.S. and follow-up of contacts is available (424,425).\nHuman illness from infection with different avian influenza A subtype viruses also have been documented, including infections with low pathogenic and highly pathogenic viruses. A range of clinical illness has been reported for human infection with low pathogenic avian influenza viruses, including conjunctivitis with influenza A (H7N7) virus in the United Kingdom, lower respiratory tract disease and conjunctivitis with influenza A (H7N2) virus in the United Kingdom, and uncomplicated ILI with influenza A (H9N2) virus in Hong Kong and China (426)(427)(428)(429)(430)(431)(432). Two human cases of infection with low pathogenic influenza A (H7N2) were reported in the United States (429). Although human infections with highly pathogenic A (H7N7) virus infections typically have ILI or conjunctivitis, severe infections, including one fatal case in the Netherlands, have been reported (433,434). Conjunctivitis also has been reported because of human infection with highly pathogenic influenza A (H7N3) virus in Canada and low pathogenic A (H7N3) in the United Kingdom (426,434). In contrast, sporadic infections with highly pathogenic avian influenza A (H5N1) virus have caused severe illness in many countries, with an overall case-fatality proportion of >60% (421,435).\nSwine influenza A (H1N1), A (H1N2), and A (H3N2) viruses, including reassortant viruses, are endemic among pig populations in the United States (436). Two clusters of influenza A (H2N3) virus infections among pigs have been reported recently (437). Outbreaks among pigs normally occur in colder weather months (late fall and winter) and sometimes with the introduction of new pigs into susceptible herds. An estimated 30% of the pig population in the United States has serologic evidence of having had swine influenza A (H1N1) virus infection. Sporadic human infections with a variety of swine influenza A viruses occur in the United States, but the incidence of these human infections is unknown (438)(439)(440)(441)(442)(443). Persons infected with swine influenza A viruses typically report direct contact with ill pigs or places where pigs have been present (e.g., agricultural fairs or farms), and have symptoms that are clinically indistinguishable from infection with other respiratory viruses (440,441,444,445). Clinicians should consider swine influenza A virus infection in the differential diagnosis of patients with ILI who have had recent contact with pigs. The sporadic cases identified in recent years have not resulted in sustained human-to-human transmission of swine influenza A viruses or community outbreaks (368,445). Although immunity to swine influenza A viruses appears to be low (<2%) in the overall human population, 10%-20% of persons exposed occupationally to pigs (e.g., pig farmers or pig veterinarians) have been documented in certain studies to have antibody evidence of prior swine influenza A (H1N1) virus infection (438,446).\nIn April 2009, a novel influenza A (H1N1) virus similar to influenza viruses previously identified in swine was determined to the cause of an influenza-like respiratory illness among humans that spread across North America and throughout most of the world by May 2009 (9,447). The epidemiology of influenza caused by this novel influenza virus is still being studied, and whether this virus will achieve long-term circulation among humans or even replace one of the other seasonal influenza viruses as the cause of annual epidemics is unknown.\nCurrent seasonal influenza vaccines are not expected to provide protection against human infection with avian influenza A viruses, including influenza A (H5N1) viruses, or to provide protection against currently circulating swine influenza A or the novel influenza A (H1N1) viruses (318,448). However, reducing seasonal influenza risk through influenza vaccination of persons who might be exposed to nonhuman influenza viruses (e.g., H5N1 virus) might reduce the theoretical risk for recombination of influenza A viruses of animal origin and human influenza A viruses by preventing seasonal influenza A virus infection within a human host.\nCDC has recommended that persons who are charged with responding to avian influenza outbreaks among poultry receive seasonal influenza vaccination (448,449). As part of preparedness activities, the Occupational Safety and Health Administration (OSHA) has issued an advisory notice regarding poultry worker safety that is intended for implementation in the event of a suspected or confirmed avian influenza outbreak at a poultry facility in the United States. OSHA guidelines recommend that poultry workers in an involved facility receive vaccination against seasonal influenza; OSHA also has recommended that HCP involved in the care of patients with documented or suspected avian influenza should be vaccinated with the most recent seasonal human influenza vaccine to reduce the risk for co-infection with human influenza A viruses (449).\n\n# Recommendations for Using Antiviral Agents for Seasonal Influenza\nAnnual vaccination is the primary strategy for preventing complications of influenza virus infections. Antiviral medications with activity against influenza viruses are useful adjuncts in the prevention of influenza, and effective when used early in the course of illness for treatment. Four influenza antiviral agents are licensed in the United States: amantadine, rimantadine, zanamivir, and oseltamivir.\nDuring the 2007-08 influenza season, influenza A (H1N1) viruses with a mutation that confers resistance to oseltamivir became more common in the United States and other countries (450)(451)(452). As of July 2009, in the United States, approximately 99% of human influenza A (H1N1) viruses tested, and none of the influenza A (H3N2) or influenza B viruses tested have been resistant to oseltamivir. As of July 2, 2009, with few exceptions, novel influenza A (H1N1) viruses that began circulating in April 2009 remained sensitive to oseltamivir (453). Oseltamivir resistance among circulating seasonal influenza A (H1N1) virus strains presents challenges for the selection of antiviral medications for treatment and chemoprophylaxis of influenza, and provides additional reasons for clinicians to test patients for influenza virus infection and to consult surveillance data when evaluating persons with acute respiratory illnesses during influenza season. CDC has published interim guidelines to provide options for treatment or chemoprophylaxis of influenza in the United States if oseltamivir-resistant seasonal influenza A (H1N1) viruses are circulating widely in a community or if the prevalence of oseltamivir-resistant influenza A (H1N1) viruses is uncertain (8). Updated guidance on antiviral use will be available from ACIP before the start of the 2009-10 influenza season. This guidance will include a summary of antiviral resistance data from the 2008-09 influenza season, and will be published separately from the vaccination recommendations. Until the ACIP recommendations for use of antivirals against influenza are published, CDC's previously published recommendations for use of influenza antiviral medications should be consulted for guidance on antiviral use (8). New guidance on clinical management of influenza, including use of antivirals, also is available from the Infectious Diseases Society of America (454).\n\n# Sources of Information Regarding Influenza and its Surveillance\nInformation regarding influenza surveillance, prevention, detection, and control is available at . During October-May, surveillance information is updated weekly. In addition, periodic updates regarding influenza are published in MMWR (). Additional information regarding influenza vaccine can be obtained by calling 1-800-CDC-INFO (1-800-232-4636). State and local health departments should be consulted about availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, reporting of influenza outbreaks and influenza-related pediatric deaths, and advice concerning outbreak control.\n\n# Vaccine Adverse Event Reporting System (VAERS)\nAdverse events after influenza vaccination should be reported promptly to VAERS at , even if the reporter is unsure whether vaccine caused the event. Clinically significant adverse events that follow vaccination should be reported to VAERS at . Reports may be filed securely online or by telephone at 1-800-822-7967 to request reporting forms or other assistance.\n\n# national Vaccine Injury Compensation Program\nThe National Vaccine Injury Compensation Program (VICP), established by the National Childhood Vaccine Injury Act of 1986, as amended, provides a mechanism through which compensation can be paid on behalf of a person determined to have been injured or to have died as a result of receiving a vaccine covered by VICP. The Vaccine Injury Table lists the vaccines covered by VICP and the injuries and conditions (including death) for which compensation might be paid. If the injury or condition is not on the Table, or does not occur within the specified time period on the Table, persons must prove that the vaccine caused the injury or condition.\nFor a person to be eligible for compensation, the general filing deadlines for injuries require claims to be filed within 3 years after the first symptom of the vaccine injury; for a death, claims must be filed within 2 years of the vaccine-related death and not more than 4 years after the start of the first symptom of the vaccine-related injury from which the death occurred. When a new vaccine is covered by VICP or when a new injury/ condition is added to the Table, claims that do not meet the general filing deadlines must be filed within 2 years from the date the vaccine or injury/condition is added to the Table for injuries or deaths that occurred up to 8 years before the Table change. Persons of all ages who receive a VICP-covered vaccine might be eligible to file a claim. Both the intranasal (LAIV) and injectable (TIV) trivalent influenza vaccines are covered under VICP. Additional information about VICP is available at http//www.hrsa.gov/vaccinecompensation or by calling 1-800-338-2382.\n\n# Additional Information Regarding Influenza Virus Infection Control Among Specific Populations\nEach year, ACIP provides general, annually updated information regarding control and prevention of influenza. Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised persons, HCP, hospital patients, pregnant women, children, and travelers) also are available in the following publications: CDC."},"raw_text":{"kind":"string","value":"This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2008;57[No. RR-7]). Information on vaccination issues related to the recently identified novel influenza A H1N1 virus will be published later in 2009. The 2009 seasonal influenza recommendations include new and updated information. Highlights of the 2009 recommendations include 1) a recommendation that annual vaccination be administered to all children aged 6 months-18 years for the 2009-10 influenza season; 2) a recommendation that vaccines containing the 2009-10 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)like, A/Brisbane/10/2007 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; and 3) a notice that recommendations for influenza diagnosis and antiviral use will be published before the start of the 2009-10 influenza season. Vaccination efforts should begin as soon as vaccine is available and continue through the influenza season. Approximately 83% of the United States population is specifically recommended for annual vaccination against seasonal influenza; however, <40% of the U.S. population received the 2008-09 influenza vaccine. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/ flu); any updates or supplements that might be required during the 2009-10 influenza season also can be found at this website. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.# Introduction\nIn the United States, annual epidemics of seasonal influenza occur typically during the late fall through early spring. Influenza viruses can cause disease among persons in any age group, but rates of infection are highest among children (1)(2)(3). Rates of serious illness and death are highest among persons aged >65 years, children aged <2 years, and persons of any age who have medical conditions that place them at increased risk for complications from influenza (1,4,5). An annual average of approximately 36,000 deaths during 1990-1999 and 226,000 hospitalizations during 1979-2001 have been associated with influenza epidemics (6,7).\nAnnual influenza vaccination is the most effective method for preventing influenza virus infection and its complications. Influenza vaccine can be administered to any person aged >6 months who does not have contraindications to vaccination to reduce the likelihood of becoming ill with influenza or of transmitting influenza to others. Trivalent inactivated influenza vaccine (TIV) can be used for any person aged >6 months, including those with high-risk conditions (Boxes 1 and 2). Live, attenuated influenza vaccine (LAIV) may be used for healthy, nonpregnant persons aged 2-49 years. No preference All children aged 6 months-18 years should be vaccinated annually.\nChildren and adolescents at higher risk for influenza complications should continue to be a focus of vaccination efforts as providers and programs transition to routinely vaccinating all children and adolescents, including those who:\nare aged 6 months-4 years ( • 59 months); have chronic pulmonary (including asthma), cardiovas-• cular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematological or metabolic disorders (including diabetes mellitus); are immunosuppressed (including immunosuppression • caused by medications or by human immunodeficiency virus); are receiving long-term aspirin therapy and therefore • might be at risk for experiencing Reye syndrome after influenza virus infection; are residents of long-term care facilities; and • will be pregnant during the influenza season. • Note: Children aged <6 months cannot receive influenza vaccination. Household and other close contacts (e.g., daycare providers) of children aged <6 months, including older children and adolescents, should be vaccinated. is indicated for LAIV or TIV when considering vaccination of healthy, nonpregnant persons aged 2-49 years. Because the safety or effectiveness of LAIV has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications, these persons should be vaccinated only with TIV. Influenza viruses undergo frequent antigenic change (i.e., antigenic drift); to gain immunity against viruses in circulation, patients must receive an annual vaccination against the influenza viruses that are predicted on the basis of viral surveillance data. . Although vaccination coverage has increased in recent years for many groups targeted for routine vaccination, coverage remains low among most of these groups, and strategies to improve vaccination coverage, including use of reminder/recall systems and standing orders programs, should be implemented or expanded.\nAntiviral medications are an adjunct to vaccination and are effective when administered as treatment and when used for chemoprophylaxis after an exposure to influenza virus. However, the emergence since 2005 of resistance to one or more of the four licensed antiviral agents (oseltamivir, zanamivir, amantadine and rimantadine) among circulating strains Annual vaccination against influenza is recommended for any adult who wants to reduce the risk of becoming ill with influenza or of transmitting it to others. Vaccination is recommended for all adults without contraindications in the following groups, because these persons either are at higher risk for influenza complications, or are close contacts of persons at higher risk has complicated antiviral treatment and chemoprophylaxis recommendations. Updated antiviral treatment and chemoprophylaxis recommendations will be provided in a separate set of guidelines later in 2009. CDC has issued interim recommendations for antiviral treatment and chemoprophylaxis of influenza (8), and these guidelines should be consulted pending issuance of new recommendations.\nIn April 2009, a novel influenza A (H1N1) virus that is similar to influenza viruses previously identified in swine was determined to be the cause of an influenza respiratory illness that spread across North America and was identified in many areas of the world by May 2009. The symptoms of novel influenza A (H1N1) virus infection are similar to those of seasonal influenza, and specific diagnostic testing is required to distinguish novel influenza A (H1N1) virus infection from seasonal influenza (9). The epidemiology of this illness is still being studied and prevention issues related to this newly emerging influenza virus will be published separately.\n# Methods\nCDC's Advisory Committee on Immunization Practices (ACIP) provides annual recommendations for the prevention and control of influenza. The ACIP Influenza Vaccine Working Group* meets monthly throughout the year to discuss newly published studies, review current guidelines, and consider revisions to the recommendations. As they review the annual recommendations for ACIP consideration of the full committee, members of the working group consider a variety of issues, including burden of influenza illness, vaccine effectiveness, safety, and coverage in groups recommended for vaccination, feasibility, cost-effectiveness, and anticipated vaccine supply. Working group members also request periodic updates on vaccine and antiviral production, supply, safety and efficacy from vaccinologists, epidemiologists, and manufacturers. State and local vaccination program representatives are consulted. CDC's Influenza Division (available at http://www.cdc.gov/ flu) provides influenza surveillance and antiviral resistance data. The Vaccines and Related Biological Products Advisory Committee provides advice on vaccine strain selection to the Food and Drug Administration (FDA), which selects the viral strains to be used in the annual trivalent influenza vaccines.\nPublished, peer-reviewed studies are the primary source of data used by ACIP in making recommendations for the prevention and control of influenza, but unpublished data that are relevant to issues under discussion also might be considered. Among studies discussed or cited, those of greatest scientific quality and those that measured influenza-specific outcomes are the most influential. For example, population-based estimates that use outcomes associated with laboratory-confirmed influenza virus infection outcomes contribute the most specific data for estimates of influenza burden. The best evidence for vaccine or antiviral efficacy and effectiveness comes from randomized controlled trials that assess laboratory-confirmed influenza infections as an outcome measure and consider factors such as timing and intensity of influenza circulation and degree of match between vaccine strains and wild circulating strains (10,11). Randomized, placebo-controlled trials cannot be performed ethically in populations for which vaccination already is recommended, but observational studies that assess outcomes associated with laboratory-confirmed influenza infection can provide important vaccine or antiviral effectiveness data. Randomized, placebo-controlled clinical trials are the best source of vaccine and antiviral safety data for common adverse events; however, such studies do not have the statistical power to identify rare but potentially serious adverse events. The frequency of rare adverse events that might be associated with vaccination is best assessed by reviewing computerized medical records from large linked clinical databases and medical charts of persons who are identified as having a potential adverse event after vaccination (12,13). Vaccine coverage data from a nationally representative, randomly selected population that includes verification of vaccination through health-care record review are superior to coverage data derived from limited populations or without verification of vaccination; however, these data rarely are available for older children or adults (14). Finally, studies that assess vaccination program practices that improve vaccination coverage are most influential in formulating recommendations if the study design includes a nonintervention comparison group. In cited studies that included statistical comparisons, a difference was considered to be statistically significant if the p-value was <0.05 or the 95% confidence interval (CI) around an estimate of effect allowed rejection of the null hypothesis (i.e., no effect).\nThese recommendations were presented to the full ACIP and approved in February 2009. Modifications were made to the ACIP statement during the subsequent review process at CDC to update and clarify wording in the document. Vaccine recommendations apply only to persons who do not have contraindications to vaccine use (see Contraindications and Precautions for use of TIV and Contraindications and Precautions for use of LAIV). Data presented in this report were current as of July 17, 2009. Further updates, if needed, will be posted at CDC's influenza website (http://www.cdc. gov/flu).\n# Primary Changes and Updates in the Recommendations\nThe 2009 recommendations include three principal changes or updates:\nAnnual vaccination of all children aged 6 months-18 • years should begin as soon as the 2009-10 influenza vaccine is available. Annual vaccination of all children aged 6 months-4 years (59 months) and older children with conditions that place them at increased risk for complications from influenza should continue to be a primary focus of vaccination efforts as providers and programs transition to routinely vaccinating all children. from the United States and other countries are now resistant to oseltamivir. Recommendations for influenza diagnosis and antiviral use will be published later in 2009. CDC issued interim recommendations for antiviral treatment and chemoprophylaxis of influenza in December 2008, and these should be consulted for guidance pending recommendations from the ACIP (8).\n# Background and Epidemiology\n\n# Biology of Influenza\nInfluenza A and B are the two types of influenza viruses that cause epidemic human disease. Influenza A viruses are categorized into subtypes on the basis of two surface antigens: hemagglutinin and neuraminidase. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have circulated globally. Influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses also have been identified in some influenza seasons. In April 2009, human infections with a novel influenza A (H1N1) virus were identified; as of June 2009, infections with the novel influenza A (H1N1) virus have been reported worldwide. This novel virus is derived partly from influenza A viruses that circulate in swine and is antigenically distinct from human influenza A (H1N1) viruses in circulation since 1977. Influenza A subtypes and B viruses are further separated into groups on the basis of antigenic similarities. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations and recombination events that occur during viral replication (15). Recent studies have begun to shed some light on the complex molecular evolution and epidemiologic dynamics of influenza A viruses (16)(17)(18).\nCurrently circulating influenza B viruses are separated into two distinct genetic lineages (Yamagata and Victoria) but are not categorized into subtypes. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. Influenza B viruses from both lineages have circulated in most recent influenza seasons (19).\nImmunity to the surface antigens, particularly the hemagglutinin, reduces the likelihood of infection (20). Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza virus. Furthermore, antibody to one antigenic type or subtype of influenza virus might not protect against infection with a new antigenic variant of the same type or subtype (21). Frequent emergence of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and is the reason for annually reassessing the need to change one or more of the recommended strains for influenza vaccines.\nMore dramatic changes, or antigenic shifts, occur less frequently. Antigenic shift occurs when a new subtype of influenza A virus appears and can result in the emergence of a novel influenza A virus with the potential to cause a pandemic. New influenza A subtypes have the potential to cause a pandemic when they are able to cause human illness and demonstrate efficient human-to-human transmission and little or no previously existing immunity has been identified among humans (15). Novel influenza A (H1N1) virus is not a new subtype, but because the large majority of humans appear to have no pre-existing antibody to key novel influenza A (H1N1) virus hemagglutinin epitopes, substantial potential exists for widespread infection (16).\n# Health-Care Use, Hospitalizations, and Deaths Attributed to Influenza\nIn the United States, annual epidemics of influenza typically occur during the fall or winter months, but the peak of influenza activity can occur as late as April or May (Figure 1). Influenza-related complications requiring urgent medical care, including hospitalizations or deaths, can result from the direct effects of influenza virus infection, from complications associated with age or pregnancy, or from complications of underlying cardiopulmonary conditions or other chronic diseases. Studies that have measured rates of a clinical outcome without a laboratory confirmation of influenza virus infection (e.g., respiratory illness requiring hospitalization during influenza season) to assess the effect of influenza can be difficult to interpret because of circulation of other respiratory pathogens (e.g., respiratory syncytial virus) during the same time as influenza viruses (22)(23)(24). However, increases in healthcare provider visits for acute febrile respiratory illness occur each year during the time when influenza viruses circulate. Data from the U.S. Outpatient Influenza-like Illness Surveillance Network (ILINet) demonstrate the annual increase in physician visits for influenza-like illness (ILI) † and for each influenza season; for 2009, the data also indicate the recent resurgence of respiratory illness associated with circulation of novel influenza A (H1N1) virus (Figure 2) (25,26).\nDuring seasonal influenza epidemics from 1979-1980 through 2000-2001, the estimated annual overall number of influenza-associated hospitalizations in the United States ranged from approximately 55,000 to 431,000 per annual epidemic (mean: 226,000) (7). The estimated annual number of deaths attributed to influenza from the 1990-91 influenza season through the 1998-99 season ranged from 17,000 to 51,000 per epidemic (mean: 36,000) (6). In the United States, the estimated number of influenza-associated deaths 53; therefore the week 53 data point for those seasons is an average of weeks 52 and 1. ¶ The national baseline is the mean percentage of visits for ILI during noninfluenza weeks for the previous three seasons plus two standard deviations. A noninfluenza week is a week during which <10% of specimens tested positive for influenza. increased during 1990-1999. This increase was attributed in part to the substantial increase in the number of persons aged >65 years who were at increased risk for death from influenza complications (6). In one study, an average of approximately 19,000 influenza-associated pulmonary and circulatory deaths per influenza season occurred during 1976-1990 compared with an average of approximately 36,000 deaths per season during 1990-1999 (6). In addition, influenza A (H3N2) viruses, which have been associated with higher mortality (27), predominated in 90% of influenza seasons during 1990-1999 compared with compared with 57% of seasons during 1976-1990 (6).\nInfluenza viruses cause disease among persons in all age groups (1)(2)(3)(4)(5). Rates of infection are highest among children, but the risks for complications, hospitalizations, and deaths from influenza are higher among persons aged >65 years, young children, and persons of any age who have medical conditions that place them at increased risk for complications from influenza (1,4,5,(28)(29)(30)(31). Estimated rates of influenzaassociated hospitalizations and deaths varied substantially by age group in studies conducted during different influenza epidemics. During 1990-1999, estimated average rates of influenza-associated pulmonary and circulatory deaths per 100,000 persons were 0.4-0.6 among persons aged 0-49 years, 7.5 among persons aged 50-64 years, and 98.3 among persons aged >65 years (6).\n# Children\nAmong children aged <5 years, influenza-related illness is a common cause of visits to medical practices and emergency departments (EDs). During two influenza seasons (2002-03 and 2003-04), the percentage of visits among children aged <5 years with acute respiratory illness or fever caused by laboratory-confirmed influenza ranged from 10%-19% of medical office visits to 6%-29% of EDs visits during the influenza season. On the basis of these data, the rate of visits to medical clinics for influenza was estimated to be 50-95 per 1,000 children, and the rate of visits to EDs was estimated to be 6-27 per 1,000 children (32). A multiyear study in New York City used viral surveillance data to estimate influenza strain-specific illness rates among ED visits. In addition to the expected variation by season and age group, influenza B epidemics were found to be an important cause of illness among school-aged children in several seasons, and annual epidemics of both influenza A and B peaked among school-aged children before other age groups (33). Retrospective studies using medical records data have demonstrated similar rates of illness among children aged <5 years during other influenza seasons (29,34,35). During the influenza season, an estimated 7-12 additional outpatient visits and 5-7 additional antibiotic prescriptions per 100 children aged <15 years have been documented when compared with periods when influenza viruses are not circulating, with rates decreasing with increasing age of the child (35). During 1993During -2004 in the Boston area, the rate of ED visits for respiratory illness that was attributed to influenza virus based on viral surveillance data among children aged <7 years during the winter respiratory illness season ranged from 22.0 per 1,000 children aged 6-23 months to 5.4 per 1,000 children aged 5-7 years (36).\nRates of influenza-associated hospitalization are substantially higher among infants and young children than among older children when influenza viruses are in circulation and are similar to rates for other groups considered at high risk for influenza-related complications (37)(38)(39)(40)(41)(42), including persons aged >65 years (35,39). During 1979-2001, on the basis of data from a national sample of hospital discharges of influenzaassociated hospitalizations among children aged <5 years, the estimated rate of influenza-associated hospitalizations in the United States was 108 hospitalizations per 100,000 personyears (7). Recent population-based studies that measured hospitalization rates for laboratory-confirmed influenza in young children have documented hospitalization rates that are similar to or higher than rates derived from studies that analyzed hospital discharge data (32,34,41,43,44). Annual hospitalization rates for laboratory-confirmed influenza decrease with increasing age, ranging from 240-720 per 100,000 children aged <6 months to approximately 20 per 100,000 children aged 2-5 years (32). Hospitalization rates for children aged <5 years with high-risk medical conditions are approximately 250-500 per 100,000 children (29,31,45).\nInfluenza-associated deaths are uncommon among children. An estimated annual average of 92 influenza-related deaths (0.4 deaths per 100,000 persons) occurred among children aged <5 years during the 1990s compared with 32,651 deaths (98.3 per 100,000 persons) among adults aged >65 years (6). Of 153 laboratory-confirmed influenza-related pediatric deaths reported during the 2003-04 influenza season, 96 (63%) deaths occurred among children aged <5 years and 61 (40%) among children aged <2 years. Among the 149 children who died and for whom information on underlying health status was available, 100 (67%) did not have an underlying medical condition that was an indication for vaccination at that time (46). In California during the 2003-04 and 2004-05 influenza seasons, 51% of children with laboratory-confirmed influenza who died and 40% of those who required admission to an intensive care unit had no underlying medical conditions (47). These data indicate that although children with risk factors for influenza complications are at higher risk for death, the majority of pediatric deaths occur among children with no known high-risk conditions. The annual number of influenza-associated deaths among children reported to CDC for the past four influenza seasons has ranged from 44 during 2004-05 to 84 during 2007-08 (48). As of July 8, 2009, a total of 17 deaths caused by novel influenza A (H1N1) virus infection have occurred in 2009 among children in the United States (CDC, unpublished data, 2009). Death associated with laboratory-confirmed influenza virus infection among children (defined as persons aged <18 years) is a nationally reportable condition. Deaths among children that have been attributed to co-infection with influenza and Staphylococcus aureus, particularly methicillin-resistant S. aureus (MRSA), have increased during the preceding four influenza seasons (26,49). The reason for this increase is not established but might reflect an increasing prevalence within the general population of colonization with MRSA strains, some of which carry certain virulence factors (50,51).\n# Adults\nHospitalization rates during the influenza season are substantially increased for persons aged >65 years. One retrospective analysis based on data from managed-care organizations collected during 1996-2000 estimated that the risk during influenza season among persons aged >65 years with underlying conditions that put them at risk for influenza-related complications (i.e., one or more of the conditions listed as indications for vaccination) was approximately 560 influenzaassociated hospitalizations per 100,000 persons compared with approximately 190 per 100,000 healthy persons. Persons aged 50-64 years with underlying medical conditions also were at substantially increased risk for hospitalizations during influenza season compared with healthy adults aged 50-64 years. No increased risk for influenza-related hospitalizations was demonstrated among healthy adults aged 50-64 years or among those aged 19-49 years, regardless of underlying medical conditions (28).\nInfluenza is an important contributor to the annual increase in deaths attributed to pneumonia and influenza that is observed during the winter months (Figure 3). During 1976-2001, an estimated yearly average of 32,651 (90%) influenza-related deaths occurred among adults aged >65 years (6). Risk for influenza-related death was highest among the oldest elderly, with persons aged >85 years 16 times more likely to die from an influenza-related illness than persons aged 65-69 years (6).\nThe duration of influenza symptoms is prolonged and the severity of influenza illness increased among persons with human immunodeficiency virus (HIV) infection (52)(53)(54)(55)(56). A retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program determined that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than it was either before or after influenza was circulating. The risk for hospitalization was higher for HIV-infected women than it was for women with other underlying medical conditions (57). Another study estimated that the risk for influenza- * Each week, the vital statistics offices of 122 cities report the total number of death certificates received and the number of those for which pneumonia or influenza (P&I) was listed as the underlying or contributing cause of death by age group. The percentage of all deaths attributable to P&I are compared with a seasonal baseline and epidemic threshold value calculated for each week. † An increase of 1.645 standard deviations above the seasonal baseline deaths is considered the \"epidemic threshold,\" i.e., the point at which the observed proportion of deaths attributed to pneumonia or influenza was significantly higher than would be expected at that time of the year in the absence of substantial influenza-related mortality. § The seasonal baseline of P&I deaths is calculated using a periodic regression model that incorporates a robust regression procedure applied to data from the previous 5 years. related death was 94-146 deaths per 100,000 persons with acquired immunodeficiency syndrome (AIDS) compared with 0.9-1.0 deaths per 100,000 persons aged 25-54 years and 64-70 deaths per 100,000 persons aged >65 years in the general population (58).\nInfluenza-related excess deaths among pregnant women were reported during the pandemics of 1918-1919 and 1957-1958 (59-63). Case reports and several epidemiologic studies also indicate that pregnancy increases the risk for influenza complications (64-69) for the mother. The majority of studies that have attempted to assess the effect of influenza on pregnant women have measured changes in excess hospitalizations for respiratory illness during influenza season but not laboratoryconfirmed influenza hospitalizations. Pregnant women have an increased number of medical visits for respiratory illnesses during influenza season compared with nonpregnant women (70). Hospitalized pregnant women with respiratory illness during influenza season have increased lengths of stay compared with hospitalized pregnant women without respiratory illness. Rates of hospitalization for respiratory illness were twice as common during influenza season (71). A retrospective cohort study of approximately 134,000 pregnant women conducted in Nova Scotia during 1990-2002 compared medical record data for pregnant women to data from the same women during the year before pregnancy. Among pregnant women, 0.4% were hospitalized and 25% visited a clinician during pregnancy for a respiratory illness. The rate of third-trimester hospital admissions during the influenza season was five times higher than the rate during the influenza season in the year before pregnancy and more than twice as high as the rate during the noninfluenza season. An excess of 1,210 hospital admissions in the third trimester per 100,000 pregnant women with comorbidities and 68 admissions per 100,000 women without comorbidities was reported (72). In one study, pregnant women with respiratory hospitalizations did not have an increase in adverse perinatal outcomes or delivery complications (73); another study indicated an increase in delivery complications, including fetal distress, preterm labor, and cesarean delivery. However, infants born to women with laboratory-confirmed influenza during pregnancy do not have higher rates of low birth weight, congenital abnormalities, or lower Apgar scores compared with infants born to uninfected women (64,74).\n# options for Controlling Influenza\nThe most effective strategy for preventing influenza is annual vaccination (10,15). Strategies that focus on providing routine vaccination to persons at higher risk for influenza complications have long been recommended, although coverage among the majority of these groups remains low. Routine vaccination of certain persons (e.g., children, contacts of persons at risk for influenza complications, and health-care personnel [HCP]) who serve as a source of influenza virus transmission might provide additional protection to persons at risk for influenza complications and reduce the overall influenza burden. However, coverage levels among these persons need to be increased before effects on transmission can be measured reliably. Antiviral drugs used for chemoprophylaxis or treatment of influenza are adjuncts to vaccine but are not substitutes for annual vaccination. However, antiviral drugs might be underused among those hospitalized with influenza (75). Nonpharmacologic interventions (e.g., advising frequent handwashing and improved respiratory hygiene) are reasonable and inexpensive; these strategies have been demonstrated to reduce respiratory diseases; reductions in detectable influenza A viruses on hands after handwashing also have been demonstrated (76)(77)(78). Few data are available to assess the effects of community-level respiratory disease mitigation strategies (e.g., closing schools, avoiding mass gatherings, or using respiratory protection) on reducing influenza virus transmission during typical seasonal influenza epidemics (79,80).\n# Influenza Vaccine Efficacy, Effectiveness, and Safety Evaluating Influenza Vaccine Efficacy and Effectiveness Studies\nThe efficacy (i.e., prevention of illness among vaccinated persons in controlled trials) and effectiveness (i.e., prevention of illness in vaccinated populations) of influenza vaccines depend in part on the age and immunocompetence of the vaccine recipient, the degree of similarity between the viruses in the vaccine and those in circulation (see Effectiveness of Influenza Vaccination when Circulating Influenza Virus Strains Differ from Vaccine Strains), and the outcome being measured. Influenza vaccine efficacy and effectiveness studies have used multiple possible outcome measures, including the prevention of medically attended acute respiratory illness (MAARI), prevention of laboratory-confirmed influenza virus illness, prevention of influenza or pneumonia-associated hospitalizations or deaths, or prevention of seroconversion to circulating influenza virus strains. Efficacy or effectiveness for more specific outcomes such as laboratory-confirmed influenza typically will be higher than for less specific outcomes such as MAARI because the causes of MAARI include infections with other pathogens that influenza vaccination would not be expected to prevent (81). Observational studies that compare less-specific outcomes among vaccinated populations to those among unvaccinated populations are subject to biases that are difficult to control for during analyses. For example, an observational study that determines that influenza vaccination reduces overall mortality might be biased if healthier persons in the study are more likely to be vaccinated (82,83). Randomized controlled trials that measure laboratory-confirmed influenza virus infections as the outcome are the most persuasive evidence of vaccine efficacy, but such trials cannot be conducted ethically among groups recommended to receive vaccine annually.\n# Influenza Vaccine Composition\nBoth LAIV and TIV contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one influenza A (H1N1) virus, and one influenza B virus. Each year, one or more virus strains in the vaccine might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains. For the 2009-10 influenza season, the influenza B vaccine virus strain was changed to B/Brisbane/60/2008, a representative of the B/Victoria lineage) compared with the 2008-09 season. The influenza A (H1N1 and H3N2 vaccine virus strains were not changed (84). Viruses for both types of currently licensed vaccines are grown in eggs. Both vaccines are administered annually to provide optimal protection against influenza virus infection (Table 1). Both TIV and LAIV are widely available in the United States. Although both types of vaccines are expected to be effective, the vaccines differ in several respects (Table 1).\n# Major Differences Between tIV and LAIV\nDuring the preparation of TIV, the vaccine viruses are made noninfectious (i.e., inactivated or killed) (15). Only subvirion and purified surface antigen preparations of TIV (often referred to as \"split\" and subunit vaccines, respectively) are available in the United States. TIV contains killed viruses and thus cannot cause influenza. LAIV contains live, attenuated influenza viruses that have the potential to cause mild signs or symptoms (e.g., runny nose, nasal congestion, fever, or sore throat). LAIV is administered intranasally by sprayer, whereas TIV is administered intramuscularly by injection. LAIV is licensed for use among nonpregnant persons aged 2-49 years; safety has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications. TIV is licensed for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions (Table 1).\n# Correlates of Protection after Vaccination\nImmune correlates of protection against influenza infection after vaccination include serum hemagglutination inhibition antibody and neutralizing antibody (20,85). Increased levels of antibody induced by vaccination decrease the risk for illness caused by strains that are antigenically similar to those strains of the same type or subtype included in the vaccine (86)(87)(88)(89). The majority of healthy children and adults have high titers of antibody after vaccination (87,90). Although immune correlates such as achievement of certain antibody titers after vaccination correlate well with immunity on a population level, the significance of reaching or failing to reach a certain antibody threshold is not well understood on the individual level. Other immunologic correlates of protection that might best indicate clinical protection after receipt of an intranasal vaccine such as LAIV (e.g., mucosal antibody) are more difficult to measure (91,92). Laboratory measurements that correlate with protective immunity induced by LAIV have been described, including measurement of cell-mediated immunity with ELISPOT assays that measure gamma-interferon (89). If not simultaneously administered, can be administered within 4 wks of an inactivated vaccine Yes Yes * Children aged 6 months-8 years who have never received influenza vaccine before should receive 2 doses. Those who only receive 1 dose in their first year of vaccination should receive 2 doses in the following year, spaced 4 weeks apart. † Persons at higher risk for complications of influenza infection because of underlying medical conditions should not receive LAIV. Persons at higher risk for complications of influenza infection because of underlying medical conditions include adults and children with chronic disorders of the pulmonary or cardiovascular systems; adults and children with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunnosuppression; children and adolescents receiving long-term aspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); persons who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration; pregnant women; and residents of nursing homes and other chronic-care facilities that house persons with chronic medical conditions. § Clinicians and immunization programs should screen for possible reactive airways diseases when considering use of LAIV for children aged 2-4 years and should avoid use of this vaccine in children with asthma or a recent wheezing episode. Health-care providers should consult the medical record, when available, to identify children aged 2-4 years with asthma or recurrent wheezing that might indicate asthma. In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving LAIV, parents or caregivers of children aged 2-4 years should be asked: \"In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?\" Children whose parents or caregivers answer \"yes\" to this question and children who have asthma or who had a wheezing episode noted in the medical record during the preceding 12 months should not receive LAIV. ¶ LAIV coadministration has been evaluated systematically only among children aged 12-15 months who received measles, mumps, and rubella vaccine or varicella vaccine. ** TIV coadministration has been evaluated systematically only among adults who received pneumococcal polysaccharide or zoster vaccine.\n# Immunogenicity, Efficacy, and Effectiveness of tIV Children\nChildren aged >6 months typically have protective levels of anti-influenza antibody against specific influenza virus strains after receiving the recommended number of doses of influenza vaccine (85 90 93-97). In most seasons, one or more vaccine antigens are changed compared with the previous season. In consecutive years when vaccine antigens change, children aged <9 years who received only 1 dose of vaccine in their first year of vaccination are less likely to have protective antibody responses when administered only a single dose during their second year of vaccination compared with children who received 2 doses in their first year of vaccination (98)(99)(100).\nWhen the vaccine antigens do not change from one season to the next, priming children aged 6-23 months with a single dose of vaccine in the spring followed by a dose in the fall engenders similar antibody responses compared with a regimen of 2 doses in the fall (101). However, one study conducted during a season when the vaccine antigens did not change compared with the previous season estimated 62% effectiveness against ILI for healthy children who had received only 1 dose in the previous influenza season and only 1 dose in the study season compared with 82% for those who received 2 doses separated by >4 weeks during the study season (102).\nThe antibody response among children at higher risk for influenza-related complications (e.g., children with chronic medical conditions) might be lower than those reported typically among healthy children (103,104). However, antibody responses among children with asthma are similar to those of healthy children and are not substantially altered during asthma exacerbations requiring short-term prednisone treatment (105).\nVaccine effectiveness studies also have indicated that 2 doses are needed to provide adequate protection during the first season that young children are vaccinated. Among children aged <5 years who have never received influenza vaccine previously or who received only 1 dose of influenza vaccine in their first year of vaccination, vaccine effectiveness is lower compared with children who received 2 doses in their first year of being vaccinated. Two large retrospective studies of young children who had received only 1 dose of TIV in their first year of being vaccinated determined that no decrease was observed in ILI-related office visits compared with unvaccinated children (102,106). Similar results were reported in a case-control study of children aged 6-59 months (107). These results, along with the immunogenicity data indicating that antibody responses are significantly higher when young children are given 2 doses, are the basis for the recommendation that all children aged <9 years who are being vaccinated for the first time should receive 2 vaccine doses separated by at least 4 weeks.\nEstimates of vaccine efficacy or effectiveness among children aged >6 months have varied by season and study design. In a randomized trial conducted during five influenza seasons (1985)(1986)(1987)(1988)(1989)(1990) in the United States among children aged 1-15 years, annual vaccination reduced laboratory-confirmed influenza A substantially (77%-91%) (87). A limited 1-year placebo-controlled study reported vaccine efficacy against laboratory-confirmed influenza illness of 56% among healthy children aged 3-9 years and 100% among healthy children and adolescents aged 10-18 years (108). A randomized, double-blind, placebo-controlled trial conducted during two influenza seasons among children aged 6-24 months indicated that efficacy was 66% against culture-confirmed influenza illness during the 1999-00 influenza season but did not reduce culture-confirmed influenza illness significantly during the 2000-20 influenza season (109).\nA case-control study conducted during the 2003-04 season found vaccine effectiveness of 49% against laboratory-confirmed influenza (107). An observational study among children aged 6-59 months with laboratory-confirmed influenza compared with children who tested negative for influenza reported vaccine effectiveness of 44% in the 2003-04 influenza season and 57% during the 2004-05 season (110). Partial vaccination (only 1 dose for children being vaccinated for the first time) was not effective in either study. During an influenza season (2003-04) with a suboptimal vaccine match, a retrospective cohort study conducted among approximately 30,000 children aged 6 months-8 years indicated vaccine effectiveness of 51% against medically attended, clinically diagnosed pneumonia or influenza (i.e., no laboratory confirmation of influenza) among fully vaccinated children and 49% among approximately 5,000 children aged 6-23 months (106). Another retrospective cohort study of similar size conducted during the same influenza season in Denver but limited to healthy children aged 6-21 months estimated clinical effectiveness of 2 TIV doses to be 87% against pneumonia or influenza-related office visits (102). Among children, TIV effectiveness might increase with age (87,111). A systematic review of published studies estimated vaccine effectiveness at 59% for children aged >2 years but concluded that additional evidence was needed to demonstrate effectiveness among children aged 6 months-2 years (112).\nBecause of the recognized influenza-related disease burden among children with other chronic diseases or immunosuppression and the long-standing recommendation for vaccination of these children, randomized placebo-controlled studies to study efficacy in these children have not been conducted. In a nonrandomized controlled trial among children aged 2-6 years and 7-14 years who had asthma, vaccine efficacy was 54% and 78% against laboratory-confirmed influenza type A infection and 22% and 60% against laboratory-confirmed influenza type B infection, respectively. Vaccinated children aged 2-6 years with asthma did not have substantially fewer type B influenza virus infections compared with the control group in this study (113). The association between vaccination and prevention of asthma exacerbations is unclear. One study suggested that vaccination might provide protection against asthma exacerbations (114); however, other studies of children with asthma have not demonstrated decreased exacerbations (115).\nTIV has been demonstrated to reduce acute otitis media in some studies. Two studies have reported that TIV decreases the risk for influenza-related otitis media by approximately 30% among children with mean ages of 20 and 27 months, respectively (116,117). However, a large study conducted among children with a mean age of 14 months indicated that TIV was not effective against acute otitis media (109). Influenza vaccine effectiveness against a nonspecific clinical outcome such as acute otitis media, which is caused by a variety of pathogens and is not typically diagnosed using influenza virus culture, would be expected to be relatively low.\n# Adults Aged <65 Years\nOne dose of TIV is highly immunogenic in healthy adults aged <65 years. Limited or no increase in antibody response is reported among adults when a second dose is administered during the same season (118)(119)(120). When the vaccine and circulating viruses are antigenically similar, TIV prevents laboratory-confirmed influenza illness among approximately 70%-90% of healthy adults aged <65 years in randomized controlled trials (121)(122)(123)(124). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources, including use of antibiotics, when the vaccine and circulating viruses are well-matched (121)(122)(123). Efficacy or effectiveness against laboratory-confirmed influenza illness was 47%-77% in studies conducted during different influenza seasons when the vaccine strains were antigenically dissimilar to the majority of circulating strains (117,119,(121)(122)(123)(124). However, effectiveness among healthy adults against influenza-related hospitalization, measured in the most recent of these studies, was 90% (125).\nIn certain studies, persons with certain chronic diseases have lower serum antibody responses after vaccination compared with healthy young adults and can remain susceptible to influenza virus infection and influenza-related upper respiratory tract illness (126,127). Vaccine effectiveness among adults aged <65 years who are at higher risk for influenza complications typically is lower than that reported for healthy adults. In a case-control study conducted during the 2003-04 influenza season, when the vaccine was a suboptimal antigenic match to many circulating virus strains, effectiveness for prevention of laboratory-confirmed influenza illness among adults aged 50-64 years with high-risk conditions was 48% compared with 60% for healthy adults (125). Effectiveness against hospitalization among adults aged 50-64 years with high-risk conditions was 36% compared with 90% effectiveness among healthy adults in that age range (125). A randomized controlled trial among adults in Thailand with chronic obstructive pulmonary disease (median age: 68 years) indicated a vaccine effectiveness of 76% in preventing laboratory-confirmed influenza during a season when viruses were well-matched to vaccine viruses. Effectiveness did not decrease with increasing severity of underlying lung disease (128).\nFew randomized controlled trials have studied the effect of influenza vaccination on noninfluenza outcomes. A randomized controlled trial conducted in Argentina among 301 adults hospitalized with myocardial infarction or undergoing angioplasty for cardiovascular disease (56% of whom were aged >65 years) found that a significantly lower percentage (6%) of cardiovascular deaths occurred among vaccinated persons at 1 year after vaccination compared with unvaccinated persons (17%) (129). A randomized, double-blind, placebo-controlled study conducted in Poland among 658 persons with coronary artery disease indicated that significantly fewer vaccinated persons vaccinated persons had a cardiac ischemic event during the 9 months of follow up compared with unvaccinated persons (p <0.05) (130).\nObservational studies that have measured clinical endpoints without laboratory confirmation of influenza virus infection, typically have demonstrated substantial reductions in hospitalizations or deaths among adults with risk factors for influenza complications. In a case-control study conducted during 1999-2000 in Denmark among adults aged <65 years with underlying medical conditions, vaccination reduced deaths attributable to any cause 78% and reduced hospitalizations attributable to respiratory infections or cardiopulmonary diseases 87% (131). A benefit was reported after the first vaccination and increased with subsequent vaccinations in subsequent years (132). Among patients with diabetes mellitus, vaccination was associated with a 56% reduction in any complication, a 54% reduction in hospitalizations, and a 58% reduction in deaths (133). Certain experts have noted that the substantial effects on morbidity and mortality among those who received influenza vaccination in these observational studies should be interpreted with caution because of the difficulties in ensuring that those who received vaccination had similar baseline health status as those who did not (82,83). One meta-analysis of published studies concluded that evidence was insufficient to demonstrate that persons with asthma benefit from vaccination (134). However, a meta-analysis that examined effectiveness among persons with chronic obstructive pulmonary disease identified evidence of benefit from vaccination (135).\n# Immunocompromised Persons\nTIV produces adequate antibody concentrations against influenza among vaccinated HIV-infected persons who have minimal AIDS-related symptoms and normal or near-normal CD4+ T-lymphocyte cell counts (136)(137)(138). Among persons who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, TIV might not induce protective antibody titers (138,139); a second dose of vaccine does not improve the immune response in these persons (139,140). A randomized, placebo-controlled trial determined that TIV was highly effective in preventing symptomatic, laboratory-confirmed influenza virus infection among HIV-infected persons with a mean of 400 CD4+ T-lymphocyte cells/mm3; however, a limited number of persons with CD4+ T-lymphocyte cell counts of <200 were included in that study (140). A nonrandomized study of HIV-infected persons determined that influenza vaccination was most effective among persons with >100 CD4+ cells and among those with <30,000 viral copies of HIV type-1/mL (53).\nOn the basis of certain limited studies, immunogenicity for persons with solid organ transplants varies according to transplant type. Among persons with kidney or heart transplants, the proportion who developed seroprotective antibody concentrations was similar or slightly reduced compared with healthy persons (141)(142)(143). However, a study among persons with liver transplants indicated reduced immunologic responses to influenza vaccination (144)(145)(146), especially if vaccination occurred within the 4 months after the transplant procedure (144).\n# Pregnant Women and neonates\nPregnant women have protective levels of anti-influenza antibodies after vaccination (147,148). Passive transfer of anti-influenza antibodies that might provide protection from vaccinated women to neonates has been reported (147,(149)(150)(151). A retrospective, clinic-based study conducted during 1998-2003 documented a nonsignificant trend toward fewer episodes of MAARI during one influenza season among vaccinated pregnant women compared with unvaccinated pregnant women and substantially fewer episodes of MAARI during the peak influenza season (148). However, a retrospective study conducted during 1997-2002 that used clinical records data did not indicate a reduction in ILI among vaccinated pregnant women or their infants (152). In another study conducted during 1995-2001, medical visits for respiratory illness among the infants were not substantially reduced (153). One randomized controlled trial conducted in Bangladesh that provided vaccination to pregnant women during the third trimester demonstrated a 29% reduction in respiratory illness with fever and a 36% reduction in respiratory illness with fever among their infants during the first 6 months after birth. In addition, infants born to vaccinated women had a 63% reduction in laboratory-confirmed influenza illness during the first 6 months of life (154). All women in this trial breastfed their infants (mean duration: 14 weeks).\n# older Adults\nAdults aged >65 years typically have a diminished immune response to influenza vaccination compared with young healthy adults, suggesting that immunity might be of shorter duration (although still extending through one influenza season) (155,156). However, a review of the published literature concluded that no clear evidence existed that immunity declined more rapidly in the elderly (157), and additional vaccine doses during the same season do not increase the antibody response (118,120). Infections among the vaccinated elderly might be associated with an age-related reduction in ability to respond to vaccination rather than reduced duration of immunity (127,128). One prospective cohort study found that immunogenicity among hospitalized persons who were either aged >65 years or who were aged 18-64 years and had one or more chronic medical conditions was similar compared with outpatients (158).\nThe only randomized controlled trial among communitydwelling persons aged >60 years reported a vaccine efficacy of 58% (CI = 26%-77%) against laboratory-confirmed influenza illness during a season when the vaccine strains were considered to be well-matched to circulating strains (159). Additional information from this trial published separately indicated that efficacy among those aged >70 years was 57% (CI = -36%-87%), similar to younger persons. However, few persons aged >75 years participated in this study, and the wide confidence interval for the estimate of efficacy among participants aged >70 years included 0 (160). Influenza vaccine effectiveness in preventing MAARI among the elderly in nursing homes has been estimated at 20%-40% (161,162), and reported outbreaks among well-vaccinated nursing home populations have suggested that vaccination might not have any significant effectiveness when circulating strains are drifted from vaccine strains (163,164). In contrast, some studies have indicated that vaccination can be up to 80% effective in preventing influenzarelated death (161,(165)(166)(167). Among elderly persons not living in nursing homes or similar long-term-care facilities, influenza vaccine is 27%-70% effective in preventing hospitalization for pneumonia and influenza (168)(169)(170). Influenza vaccination reduces the frequency of secondary complications and reduces the risk for influenza-related hospitalization and death among community-dwelling adults aged >65 years with and without high-risk medical conditions (e.g., heart disease and diabetes) (169)(170)(171)(172)(173)(174). However, studies demonstrating large reductions in hospitalizations and deaths among the vaccinated elderly have been conducted using medical record databases and have not measured reductions in laboratory-confirmed influenza illness. These studies have been challenged because of concerns that they have not adequately controlled for differences in the propensity for healthier persons to be more likely than less healthy persons to receive vaccination (82,83,166,(175)(176)(177).\n# tIV Dosage, Administration, and Storage\nThe composition of TIV varies according to manufacturer, and package inserts should be consulted. TIV formulations in multidose vials contain the vaccine preservative thimerosal; preservative-free, single-dose preparations also are available. TIV should be stored at 35°F-46°F (2°C-8°C) and should not be frozen. TIV that has been frozen should be discarded. Dosage recommendations and schedules vary according to age group (Table 2). Vaccine prepared for a previous influenza season should not be administered to provide protection for any subsequent season.\nThe intramuscular route is recommended for TIV. Adults and older children should be vaccinated in the deltoid muscle. A needle length of >1 inch (>25 mm) should be considered for persons in these age groups because needles of <1 inch might be of insufficient length to penetrate muscle tissue in certain adults and older children (178). When injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8-1.25 inches is recommended (179).\nInfants and young children should be vaccinated in the anterolateral aspect of the thigh. A needle length of 7/8-1 inch should be used for children aged <12 months. In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving FluMist, parents or caregivers of children aged 2-4 years should be asked: \"In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?\" Children whose parents or caregivers answer \"yes\" to this question and children who have asthma or who had a wheezing episode noted in the medical record during the preceding 12 months should not receive FluMist. † † Two doses administered at least 4 weeks apart are recommended for children aged 2-8 years who are receiving LAIV for the first time, and those who only received 1 dose in their first year of vaccination should receive 2 doses in the following year.\n# Adverse Events After Receipt of tIV Children\nStudies support the safety of annual TIV in children and adolescents. The largest published postlicensure populationbased study assessed TIV safety in 251,600 children aged <18 years, (including 8,476 vaccinations in children aged 6-23 months) through the Vaccine Safety Datalink (VSD), who were enrolled in one of five health maintenance organizations (HMOs) during 1993-1999. This study indicated no increase in clinically important medically attended events during the 2 weeks after inactivated influenza vaccination compared with control periods 3-4 weeks before and after vaccination (180). A retrospective cohort study using VSD medical records data from 45,356 children aged 6-23 months provided additional evidence supporting overall safety of TIV in this age group. During the 2 weeks after vaccination, TIV was not associated with statistically significant increases in any clinically important medically attended events other than gastritis/duodenitis, and 13 diagnoses, including acute upper respiratory illness, otitis media and asthma, were significantly less common (181). On chart review, most children with a diagnosis of gastritis/duodenitis had self-limited vomiting or diarrhea. The positive or negative associations between TIV and any of these diagnoses do not necessarily indicate a causal relationship (181).\nIn a study of 791 healthy children aged 1-15 years, postvaccination fever was noted among 12% of those aged 1-5 years, 5% among those aged 6-10 years, and 5% among those aged 11-15 years (87). Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with inactivated vaccine most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children) (182,183). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Data about potential adverse events among children after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). Because of the limitations of passive reporting systems, determining causality for specific types of adverse events usually is not possible using VAERS data alone.\nPublished reviews of VAERS reports submitted after administration of TIV to children aged 6-23 months indicated that the most frequently reported adverse events were fever, rash, injection-site reactions, and seizures; the majority of the limited number of reported seizures appeared to be febrile (184,185). Seizure and fever were the leading serious adverse events (SAEs), defined using standard criteria, reported to VAERS in these studies (184,185); further investigation in VSD did not confirm an association with febrile seizures as identified in VAERS (181).\n# Adults\nIn placebo-controlled studies among adults, the most frequent side effect of vaccination was soreness at the vaccination site (affecting 10%-64% of patients) that lasted <2 days (186,187). These local reactions typically were mild and rarely interfered with the recipients' ability to conduct usual daily activities. Placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of TIV is not associated with higher rates for systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (121,134,(186)(187)(188). One prospective cohort study found that the rate of adverse events was similar among hospitalized persons who either were aged >65 years or were aged 18-64 years and had one or more chronic medical conditions compared with outpatients (158). Adverse events in adults aged >18 years reported to VAERS during 1990-2005 were analyzed. The most common adverse events reported to VAERS in adults included injection-site reactions, pain, fever, myalgia, and headache. The VAERS review identified no new safety concerns. In clinical trials, SAEs were reported to occur after vaccination with TIV at a rate of <1%. A small proportion (14%) of the TIV VAERS reports in adults were classified as SAEs, without assessment of causality. The most common SAE reported after TIV in VAERS in adults was Guillain-Barré Syndrome (GBS) (189). The potential association between TIV and GBS has been an area of ongoing research (see Guillain-Barré Syndrome and TIV).\n# Pregnant Women and neonates\nFDA has classified TIV as a \"Pregnancy Category C\" medication, indicating that adequate animal reproduction studies have not been conducted.. Available data indicate that influenza vaccine does not cause fetal harm when administered to a pregnant woman or affect reproductive capacity. One study of approximately 2,000 pregnant women who received TIV during pregnancy demonstrated no adverse fetal effects and no adverse effects during infancy or early childhood (190). A matched case-control study of 252 pregnant women who received TIV within the 6 months before delivery determined no adverse events after vaccination among pregnant women and no difference in pregnancy outcomes compared with 826 pregnant women who were not vaccinated (148). During 2000-2003, an estimated 2 million pregnant women were vaccinated, and only 20 adverse events among women who received TIV were reported to VAERS during this time, including nine injection-site reactions and eight systemic reactions (e.g., fever, headache, and myalgias). In addition, three miscarriages were reported, but these were not known to be causally related to vaccination (191). Similar results have been reported in certain smaller studies (147,149,192), and a recent international review of data on the safety of TIV concluded that no evidence exists to suggest harm to the fetus (193). The rate of adverse events associated with TIV was similar to the rate of adverse events among pregnant women who received pneumococcal polysaccharide vaccine in one small randomized controlled trial in Bangladesh, and no severe adverse events were reported in any study group (154).\n# Persons with Chronic Medical Conditions\nIn a randomized cross-over study of children and adults with asthma, no increase in asthma exacerbations was reported for either age group (194), and two additional studies also have indicated no increase in wheezing among vaccinated asthmatic children (114) or adults (195). One study reported that 20%-28% of children with asthma aged 9 months-18 years had local pain and swelling at the site of influenza vaccination ( 104), and another study reported that 23% of children aged 6 months-4 years with chronic heart or lung disease had local reactions (93). A blinded, randomized, cross-over study of 1,952 adults and children with asthma demonstrated that only self-reported \"body aches\" were reported more frequently after TIV (25%) than placebo-injection (21%) (194). However, a placebo-controlled trial of TIV indicated no difference in local reactions among 53 children aged 6 months-6 years with high-risk medical conditions or among 305 healthy children aged 3-12 years (97).\nAmong children with high-risk medical conditions, one study of 52 children aged 6 months-3 years reported fever among 27% and irritability and insomnia among 25% (93); and a study among 33 children aged 6-18 months reported that one child had irritability and one had a fever and seizure after vaccination (196). No placebo comparison group was used in these studies.\n# Immunocompromised Persons\nData demonstrating safety of TIV for HIV-infected persons are limited, but no evidence exists that vaccination has a clinically important impact on HIV infection or immunocompetence. One study demonstrated a transient (i.e., 2-4 week) increase in HIV RNA (ribonucleic acid) levels in one HIV-infected person after influenza virus infection (197). Studies have demonstrated a transient increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (138,198). However, more recent and better-designed studies have not documented a substantial increase in the replication of HIV (199)(200)(201)(202). CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated to change substantially after influenza vaccination among HIV-infected persons compared with unvaccinated HIV-infected persons (138,203). Limited information is available about the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza virus infection or influenza vaccination (52,204).\nData are similarly limited for persons with other immunocompromising conditions. In small studies, vaccination did not affect allograft function or cause rejection episodes in recipients of kidney transplants (141,142), heart transplants (143), or liver transplants (144).\n# Immediate Hypersensitivity Reactions after Influenza Vaccines\nVaccine components can rarely cause allergic reactions, also called immediate hypersensitivity reactions, among certain recipients. Immediate hypersensitivity reactions are mediated by preformed immunoglobulin E (IgE) antibodies against a vaccine component and usually occur within minutes to hours of exposure (205). Symptoms of immediate hypersensitivity range from mild urticaria (hives) and angioedema to anaphylaxis. Anaphylaxis is a severe life-threatening reaction that involves multiple organ systems and can progress rapidly. Symptoms and signs of anaphylaxis can include but are not limited to generalized urticaria, wheezing, swelling of the mouth and throat, difficulty breathing, vomiting, hypotension, decreased level of consciousness, and shock. Minor symptoms such as red eyes or hoarse voice also might be present (179,(205)(206)(207)(208).\nAllergic reactions might be caused by the vaccine antigen, residual animal protein, antimicrobial agents, preservatives, stabilizers, or other vaccine components (209). Manufacturers use a variety of compounds to inactivate influenza viruses and add antibiotics to prevent bacterial growth. Package inserts for specific vaccines of interest should be consulted for additional information. ACIP has recommended that all vaccine providers should be familiar with the office emergency plan and be certified in cardiopulmonary resuscitation (179). The Clinical Immunization Safety Assessment (CISA) network, a collaboration between CDC and six medical research centers with expertise in vaccination safety, has developed an algorithm to guide evaluation and revaccination decisions for persons with suspected immediate hypersensitivity after vaccination (205).\nImmediate hypersensitivity reaction after TIV and LAIV are rare. A VSD study of children aged <18 years in four HMOs during 1991-1997 estimated the overall risk of postvaccination anaphylaxis to be less than 1 case per 500,000 doses administered and in this study no cases were identified in TIV recipients (210). Reports of anaphylaxis occurring after receipt of TIV and LAIV in adults have rarely been reported to VAERS (189). Some immediate hypersensitivity reactions after TIV or LAIV are caused by the presence of residual egg protein in the vaccines (211). Although influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Asking persons if they can eat eggs without adverse effects is a reasonable way to determine who might be at risk for allergic reactions from receiving influenza vaccines (179). Persons who have had symptoms such as hives or swelling of the lips or tongue, or who have experienced acute respiratory distress after eating eggs, should consult a physician for appropriate evaluation to help determine if future influenza vaccine should be administered. Persons who have documented (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma related to egg exposure or other allergic responses to egg protein, also might be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician before vaccination should be considered (212)(213)(214). A regimen has been developed for administering influenza vaccine to asthmatic children with severe disease and egg hypersensitivity (213).\nHypersensitivity reactions to other vaccine components also can rarely occur. Although exposure to vaccines containing thimerosal can lead to hypersensitivity (215), the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (216,217). When reported, hypersensitivity to thimerosal typically has consisted of local delayed hypersensitivity reactions (216).\n# ocular and Respiratory Symptoms after tIV\nOcular or respiratory symptoms have occasionally been reported within 24 hours after TIV administration, but these symptoms typically are mild and resolve quickly without specific treatment. In some trials conducted in the United States, ocular or respiratory symptoms included red eyes (<1%-6%), cough (1%-7%), wheezing (1%), and chest tightness (1%-3%) (207,208,(218)(219)(220). However, most of these trials were not placebo-controlled, and causality cannot be determined. In addition, ocular and respiratory symptoms are features of a variety of respiratory illnesses and seasonal allergies that would be expected to occur coincidentally among vaccine recipients unrelated to vaccination. A placebo-controlled vaccine effectiveness study among young adults found that 2% of persons who received the 2006-07 formulation of Fluzone (Sanofi Pasteur) reported red eyes compared with none of the controls (p = 0.03) (221). A similar trial conducted during the 2005-06 influenza season found that 3% of Fluzone recipients reported red eyes compared with 1% of placebo recipients; however the difference was not statistically significant (222) .\nOculorespiratory syndrome (ORS), an acute, self-limited reaction to TIV with prominent ocular and respiratory symptoms, was first described during the 2000-01 influenza season in Canada. The initial case-definition for ORS was the onset of one or more of the following within 2-24 hours after receiving TIV: bilateral red eyes and/or facial edema and/or respiratory symptoms (coughing, wheezing, chest tightness, difficulty breathing, sore throat, hoarseness or difficulty swallowing, cough, wheeze, chest tightness, difficulty breathing, sore throat, or facial swelling) (223). ORS was first described in Canada and strongly associated with one vaccine preparation (Fluviral S/F, Shire Biologics, Quebec, Canada) not available in the United States during the 2000-01 influenza season (224). Subsequent investigations identified persons with ocular or respiratory symptoms meeting an ORS case-definition in safety monitoring systems and trials that had been conducted before 2000 in Canada, the United States, and several European countries (225)(226)(227).\nThe cause of ORS has not been established; however studies suggest the reaction is not IgE-mediated (228). After changes in the manufacturing process of the vaccine preparation associated with ORS during 2000-01, the incidence of ORS in Canada was greatly reduced (226). In one placebo-controlled study, only hoarseness, cough, and itchy or sore eyes (but not red eyes) were significantly associated with a reformulated Fluviral preparation. These findings indicated that ORS symptoms following use of the reformulated vaccine were mild, resolved within 24 hours, and might not typically be of sufficient concern to cause vaccine recipients to seek medical care (229).\nOcular and respiratory symptoms reported after TIV administration, including ORS, have some similarities with immediate hypersensitivity reactions. One study indicated that the risk for ORS recurrence with subsequent vaccination is low, and persons with ocular or respiratory symptoms (e.g., bilateral red eyes, cough, sore throat, or hoarseness) after TIV that did not involve the lower respiratory tract have been revaccinated without reports of SAEs after subsequent exposure to TIV (230). VAERS routinely monitors for adverse events such as ocular or respiratory symptoms after receipt of TIV.\n# Contraindications and Precautions for Use of tIV\nTIV is contraindicated and should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine unless the recipient has been desensitized. Prophylactic use of antiviral agents is an option for preventing influenza among such persons. Information about vaccine components is located in package inserts from each manufacturer. Persons with moderate to severe acute febrile illness usually should not be vaccinated until their symptoms have abated. Moderate or severe acute illness with or without fever is a precaution § for TIV. GBS within 6 weeks following a previous dose of influenza vaccine is considered to be a precaution for use of influenza vaccines.\n# Revaccination in Persons Who Experienced ocular or Respiratory Symptoms After tIV\nWhen assessing whether a patient who experienced ocular and respiratory symptoms should be revaccinated, providers should determine if concerning signs and symptoms of Ig-E mediated immediate hypersensitivity are present (see Immediate Hypersensitivity after Influenza Vaccines). Healthcare providers who are unsure whether symptoms reported or observed after TIV represent an IgE-mediated hypersensitivity immune response should seek advice from an allergist/immunologist. Persons with symptoms of possible IgE-mediated hypersensitivity after TIV should not receive influenza vaccination unless hypersensitivity is ruled out or revaccination is administered under close medical supervision (205).\nOcular or respiratory symptoms observed after TIV often are coincidental and unrelated to TIV administration, as observed among placebo recipients in some randomized controlled studies. Determining whether ocular or respiratory symptoms are coincidental or related to possible ORS might not be possible. Persons who have had red eyes, mild upper facial swelling, or mild respiratory symptoms (e.g., sore throat, cough, or hoarseness) after TIV without other concerning signs or symptoms of hypersensitivity can receive TIV in subsequent seasons without further evaluation. Two studies showed that persons who had symptoms of ORS after TIV were at a higher risk for ORS after subsequent TIV administration; however, these events usually were milder than the first episode (230,231).\n# Guillain-Barré Syndrome and tIV\nThe annual incidence of GBS is 10-20 cases per 1 million adults (232). Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni gastrointestinal infections and upper respiratory tract infections, are associated with GBS (233)(234)(235). A recent study identified serologically confirmed influenza virus infection as a trigger of GBS, with time from onset of influenza illness to GBS of 3-30 days. The estimated frequency of influenza-related GBS was four to seven times higher than the frequency that has been estimated for influenza-vaccine-associated GBS (236).\nThe 1976 swine influenza vaccine was associated with an increased frequency of GBS, estimated at one additional case of GBS per 100,000 persons vaccinated (237,238). The risk for influenza-vaccine-associated GBS was higher among persons aged >25 years than among persons aged <25 years (239). However, obtaining epidemiologic evidence for a small increase in risk for a rare condition with multiple causes is difficult, and no evidence consistently exists for a causal relation between subsequent vaccines prepared from other influenza viruses and GBS.\nNone of the studies conducted using influenza vaccines other than the 1976 swine influenza vaccine has demonstrated a substantial increase in GBS associated with influenza vaccines. During three of four influenza seasons studied during 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were not statistically significant in any of these studies (240)(241)(242). However, in a study of the 1992-93 and 1993-94 seasons, the overall relative risk for GBS was 1.7 (CI = 1.0-2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately one additional case of GBS per 1 million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination (238). Results of a study that examined health-care data from Ontario, Canada, during 1992-2004 demonstrated a small but statistically significant temporal association between receiving influenza vaccination and subsequent hospital admission for GBS. However, no increase in cases of GBS at the population level was reported after introduction of a mass public influenza vaccination program in Ontario beginning in 2000 (243). Data from VAERS have documented decreased reporting of GBS occurring after vaccination across age groups over time, despite overall increased reporting of other non-GBS conditions occurring after administration of influenza vaccine (237). Published data from the United Kingdom's General Practice Research Database (GPRD) found influenza vaccine to be associated with a decreased risk for GBS, although whether this was associated with protection against influenza or confounding because of a \"healthy vaccinee\" (e.g., healthier persons might be more likely to be vaccinated and also be at lower risk for GBS) (244) is unclear. A separate GPRD analysis found no association between vaccination and GBS for a 9-year period; only three cases of GBS occurred within 6 weeks after administration of influenza vaccine (245). A third GPRD analysis found that GBS was associated with recent ILI, but not influenza vaccination (246). § A precaution is a condition in a recipient that might increase the risk for a serious adverse reaction or that might compromise the ability of the vaccine to produce immunity (179).\nThe estimated risk for GBS (on the basis of the few studies that have demonstrated an association between vaccination and GBS) is low (i.e., approximately one additional case per 1 million persons vaccinated). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh these estimates of risk for vaccine-associated GBS. No evidence indicates that the casefatality ratio for GBS differs among vaccinated persons and those not vaccinated.\n# Use of tIV Among Patients with a History of GBS\nThe incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (232). Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown. Among 311 patients with GBS who responded to a survey, 11 (4%) reported some worsening of symptoms after influenza vaccination; however, some of these patients had received other vaccines at the same time, and recurring symptoms were generally mild (247). However, as a precaution, persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks generally should not be vaccinated. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. Although data are limited, the established benefits of influenza vaccination might outweigh the risks for many persons who have a history of GBS and who also are at high risk for severe complications from influenza.\n# Vaccine Preservative (thimerosal) in Multidose Vials of tIV\nThimerosal, a mercury-containing antibacterial compound, has been used as a preservative in vaccines and other medications since the 1930s (248) and is used in multidose vial preparations of TIV to reduce the likelihood of bacterial growth. No scientific evidence indicates that thimerosal in vaccines, including influenza vaccines, is a cause of adverse events other than occasional local hypersensitivity reactions in vaccine recipients. In addition, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received vaccine during pregnancy. The weight of accumulating evidence does not suggest an increased risk for neurodevelopment disorders from exposure to thimerosal-containing vaccines (249)(250)(251)(252)(253)(254)(255)(256)(257)(258). The U.S. Public Health Service and other organizations have recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines as part of a strategy to reduce mercury exposures from all sources (249,250,259) Also, continuing public concerns about exposure to mercury in vaccines has been viewed as a potential barrier to achieving higher vaccine coverage levels and reducing the burden of vaccine-preventable diseases. Since mid-2001, vaccines routinely recommended for infants aged <6 months in the United States have been manufactured either without or with greatly reduced (trace) amounts of thimerosal. As a result, a substantial reduction in the total mercury exposure from vaccines for infants and children already has been achieved ( 179)). ACIP and other federal agencies and professional medical organizations continue to support efforts to provide thimerosal-preservative-free vaccine options.\nThe benefits of influenza vaccination for all recommended groups, including pregnant women and young children, outweigh concerns on the basis of a theoretical risk from thimerosal exposure through vaccination. The risks for severe illness from influenza virus infection are elevated among both young children and pregnant women, and vaccination has been demonstrated to reduce the risk for severe influenza illness and subsequent medical complications. In contrast, no scientifically conclusive evidence has demonstrated harm from exposure to vaccine containing thimerosal preservative. For these reasons, persons recommended to receive TIV may receive any age-and risk factor-appropriate vaccine preparation, depending on availability. An analysis of VAERS reports found no difference in the safety profile of preservative-containing compared with preservative-free TIV vaccines in infants aged 6-23 months (184).\nNonetheless, as of May 2009, some states have enacted legislation banning the administration of vaccines containing mercury; the provisions defining mercury content vary (260). LAIV and many of the single-dose vial or syringe preparations of TIV are thimerosal-free, and the number of influenza vaccine doses that do not contain thimerosal as a preservative is expected to increase (Table 2). However, these laws might present a barrier to vaccination unless influenza vaccines that do not contain thimerosal as a preservative are easily available in those states.\nThe U.S. vaccine supply for infants and pregnant women is in a period of transition as manufacturers expand the availability of thimerosal-reduced or thimerosal-free vaccine to reduce the cumulative exposure of infants to mercury. Other environmental sources of mercury exposure are more difficult or impossible to avoid or eliminate (249).\n# LAIV Dosage, Administration, and Storage\nEach dose of LAIV contains the same three vaccine antigens used in TIV. However, the antigens are constituted as live, attenuated, cold-adapted, temperature-sensitive vaccine viruses. Providers should refer to the package insert, which contains additional information about the formulation of this vaccine and other vaccine components. LAIV does not contain thimerosal. LAIV is made from attenuated viruses that are able to replicate efficiently only at temperatures present in the nasal mucosa. LAIV does not cause systemic symptoms of influenza in vaccine recipients, although a minority of recipients experience nasal congestion or fever, which is probably a result of effects of intranasal vaccine administration or local viral replication or fever (261).\nLAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route. LAIV is not licensed for vaccination of children aged <2 years or adults aged >49 years. LAIV is supplied in a prefilled, single-use sprayer containing 0.2 mL of vaccine. Approximately 0.1 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril. LAIV is shipped at 35°F-46°F (2°C-8°C). LAIV should be stored at 35°F-46°F (2°C-8°C) on receipt and can remain at that temperature until the expiration date is reached (261). Vaccine prepared for a previous influenza season should not be administered to provide protection for any subsequent season.\n# Shedding, transmission, and Stability of Vaccine Viruses\nAvailable data indicate that both children and adults vaccinated with LAIV can shed vaccine viruses after vaccination, although in lower amounts than occur typically with shedding of wild-type influenza viruses. In rare instances, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated persons. However, serious illnesses have not been reported among unvaccinated persons who have been infected inadvertently with vaccine viruses.\nOne study of 197 children aged 8-36 months in a child care center assessed transmissibility of vaccine viruses from 98 vaccinated children to the other 99 unvaccinated children; 80% of vaccine recipients shed one or more virus strains (mean duration: 7.6 days). One influenza type B vaccine strain isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the coldadapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient who was in the same play group. The placebo recipient from whom the influenza type B vaccine strain was isolated had symptoms of a mild upper respiratory illness but did not experience any serious clinical events. The estimated probability of acquiring vaccine virus after close contact with a single LAIV recipient in this child care population was 1%-2% (262).\nStudies assessing whether vaccine viruses are shed have been based on viral cultures or PCR detection of vaccine viruses in nasal aspirates from persons who have received LAIV. Among 345 subjects aged 5-49 years, 30% had detectable virus in nasal secretions obtained by nasal swabbing after receiving LAIV. The duration of virus shedding and the amount of virus shed was inversely correlated with age, and maximal shedding occurred within 2 days of vaccination. Symptoms reported after vaccination, including runny nose, headache, and sore throat, did not correlate with virus shedding (263). Other smaller studies have reported similar findings (264,265). Vaccine strain virus was detected from nasal secretions in one (2%) of 57 HIV-infected adults who received LAIV, none of 54 HIV-negative participants (266), and three (13%) of 23 HIV-infected children compared with seven (28%) of 25 children who were not HIV-infected (267). No participants in these studies had detectable virus beyond 10 days after receipt of LAIV. The possibility of person-to-person transmission of vaccine viruses was not assessed in these studies (264)(265)(266)(267).\nIn clinical trials, viruses isolated from vaccine recipients have retained attenuated phenotypes. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt (268). Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes. A study conducted in a child care setting demonstrated that limited genetic change occurred in the LAIV strains following replication in the vaccine recipients (269).\n# Immunogenicity, Efficacy, and Effectiveness of LAIV\nLAIV virus strains replicate primarily in nasopharyngeal epithelial cells. The protective mechanisms induced by vaccination with LAIV are not understood completely but appear to involve both serum and nasal secretory antibodies. The immunogenic-ity of the approved LAIV has been assessed in multiple studies conducted among children and adults (270)(271)(272)(273)(274)(275)(276).\n# Healthy Children\nA randomized, double-blind, placebo-controlled trial among 1,602 healthy children aged 15-71 months assessed the efficacy of LAIV against culture-confirmed influenza during two seasons (277,278). This trial included a subset of children aged 60-71 months who received 2 doses in the first season. During season one (1996-97), when vaccine and circulating virus strains were well-matched, efficacy against culture-confirmed influenza was 94% for participants who received 2 doses of LAIV separated by >6 weeks, and 89% for those who received 1 dose. During season two (1997-98), when the A (H3N2) component in the vaccine was not well-matched with circulating virus strains, efficacy (1 dose) was 86%, for an overall efficacy for two influenza seasons of 92%. Receipt of LAIV also resulted in 21% fewer febrile illnesses and a significant decrease in acute otitis media requiring antibiotics (277,279). Other randomized, placebo-controlled trials demonstrating the efficacy of LAIV in young children against culture-confirmed influenza include a study conducted among children aged 6-35 months attending child care centers during consecutive influenza seasons (280) in which 85%-89% efficacy was observed, and a study conducted among children aged 12-36 months living in Asia during consecutive influenza seasons in which 64%-70% efficacy was documented (281). In one community-based, nonrandomized open-label study, reductions in MAARI were observed among children who received 1 dose of LAIV during the 1990-00 and 2000-01 influenza seasons even though antigenically drifted influenza A/H1N1 and B viruses were circulating during that season (282). LAIV efficacy in preventing laboratory-confirmed influenza also has been demonstrated in studies comparing the efficacy of LAIV with TIV rather than with a placebo (see Comparisons of LAIV and TIV Efficacy or Effectiveness).\n# Healthy Adults\nA randomized, double-blind, placebo-controlled trial of LAIV effectiveness among 4,561 healthy working adults aged 18-64 years assessed multiple endpoints, including reductions in self-reported respiratory tract illness without laboratory confirmation, work loss, health-care visits, and medication use during influenza outbreak periods . The study was conducted during the 1997-98 influenza season, when the vaccine and circulating A (H3N2) strains were not well-matched. The frequency of febrile illnesses was not significantly decreased among LAIV recipients compared with those who received placebo. However, vaccine recipients had significantly fewer severe febrile illnesses (19% reduction) and febrile upper respiratory tract illnesses (24% reduction), and significant reductions in days of illness, days of work lost, days with health-care-provider visits, and use of prescription antibiotics and over-the-counter medications (283). Efficacy against culture-confirmed influenza in a randomized, placebo-controlled study was 57% in the 2004-05 influenza season and 43% in the 2005-06 influenza season, although efficacy in these studies was not demonstrated to be significantly greater than placebo (221,222).\n# Adverse Events after Receipt of LAIV Healthy Children Aged 2-18 Years\nIn a subset of healthy children aged 60-71 months from one clinical trial, certain signs and symptoms were reported more often after the first dose among LAIV recipients (n = 214) than among placebo recipients (n = 95), including runny nose (48% and 44%, respectively); headache (18% and 12%, respectively); vomiting (5% and 3%, respectively); and myalgias (6% and 4%, respectively) (277). However, these differences were not statistically significant. In other trials, signs and symptoms reported after LAIV administration have included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0-26%), vomiting (3%-13%), abdominal pain (2%), and myalgias (0-21%) (270,272,273,280,(284)(285)(286)(287). These symptoms were associated more often with the first dose and were self-limited. A placebo-controlled trial in 9,689 children aged 1-17 years assessed prespecified medically attended outcomes during the 42 days after vaccination (286). Following >1,500 statistical analyses in the 42 days after LAIV, elevated risks that were biologically plausible were observed for the following conditions: asthma, upper respiratory infection, musculoskeletal pain, otitis media with effusion, and adenitis/ adenopathy. The increased risk for wheezing events after LAIV was observed among children aged 18-35 months (RR: 4.06; 90% CI = 1.3-17.9). In this study, the rate of SAEs was 0.2% in LAIV and placebo recipients; none of the SAEs was judged to be related to the vaccine by the study investigators (286).\nIn a randomized trial published in 2007, LAIV and TIV were compared among children aged 6-59 months (288). Children with medically diagnosed or treated wheezing within 42 days before enrollment or with a history of severe asthma were excluded from this study. Among children aged 24-59 months who received LAIV, the rate of medically significant wheezing, using a prespecified definition, was not greater compared with those who received TIV (288). Wheezing was observed more frequently among younger LAIV recipients aged 6-23 months in this study; LAIV is not licensed for this age group. In a previous randomized placebo-controlled safety trial among children aged 12 months-17 years without a history of asthma by parental report, an elevated risk for asthma events (RR: 4.1; CI = 1.3-17.9) was documented among 728 children aged 18-35 months who received LAIV. Of the 16 children with asthma-related events in this study, seven had a history of asthma on the basis of subsequent medical record review. None required hospitalization, and elevated risks for asthma were not observed in other age groups (286).\nAnother study was conducted among >11,000 children aged 18 months-18 years in which 18,780 doses of vaccine were administered for 4 years. For children aged 18 months-4 years, no increase was reported in asthma visits 0-15 days after vaccination compared with the prevaccination period. A significant increase in asthma events was reported 15-42 days after vaccination, but only in vaccine year 1 (289). A 4-year, open-label field trial study assessed LAIV safety of more than 2000 doses administered to children aged 18 months-18 years with a history of intermittent wheeze who were otherwise healthy. Among these children, no increased risk was reported for medically attended acute respiratory illnesses, including acute asthma exacerbation, during the 0-14 or 0-42 days after LAIV compared with the pre-and postvaccination reference periods (290).\nInitial data from VAERS during 2007-2008, following ACIP's recommendation for LAIV use in healthy children aged 2-4 years, did not suggest a concern for wheezing after LAIV in young children. However data also suggest uptake of LAIV was limited, and safety monitoring for wheezing events after LAIV is ongoing (CDC, unpublished data, 2008).\n# Adults Aged 19-49 Years\nAmong adults, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients (277,291). In one clinical trial among a subset of healthy adults aged 18-49 years, signs and symptoms reported significantly more often (p<0.05) among LAIV recipients (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (14% and 11%, respectively), runny nose (45% and 27%, respectively), sore throat (28% and 17%, respectively), chills (9% and 6%, respectively), and tiredness/weakness (26% and 22%, respectively) (92). A review of 460 reports to VAERS after distribution of approximately 2.5 million doses during the 2003-04 and 2004-05 influenza seasons did not indicate any new safety concerns (292). Few of the LAIV VAERS reports (9%) were SAEs; respiratory events were the most common conditions reported.\n# Persons at Higher Risk for Influenza-Related Complications\nLimited data assessing the safety of LAIV use for certain groups at higher risk for influenza-related complications are available. In one study of 54 HIV-infected persons aged 18-58 years and with CD4+ counts >200 cells/mm 3 who received LAIV, no SAEs were reported during a 1-month follow-up period (266). Similarly, one study demonstrated no significant difference in the frequency of adverse events or viral shedding among HIV-infected children aged 1-8 years on effective antiretroviral therapy who were administered LAIV compared with HIV-uninfected children receiving LAIV (267). LAIV was well-tolerated among adults aged >65 years with chronic medical conditions (293). These findings suggest that persons at risk for influenza complications who have inadvertent exposure to LAIV would not have significant adverse events or prolonged viral shedding and that persons who have contact with persons at higher risk for influenza-related complications may receive LAIV.\n# Comparisons of LAIV and tIV Efficacy or Effectiveness\nBoth TIV and LAIV have been demonstrated to be effective in children and adults. However, data directly comparing the efficacy or effectiveness of these two types of influenza vaccines are limited and insufficient to identify whether one vaccine might offer a clear advantage over the other in certain settings or populations. Studies comparing the efficacy of TIV to that of LAIV have been conducted in a variety of settings and populations using several different outcomes. One randomized, double-blind, placebo-controlled challenge study that was conducted among 92 healthy adults aged 18-41 years assessed the efficacy of both LAIV and TIV in preventing influenza infection when challenged with wild-type strains that were antigenically similar to vaccine strains (294). The overall efficacy in preventing laboratory-documented influenza from all three influenza strains combined was 85% and 71%, respectively, when challenged 28 days after vaccination by viruses to which study participants were susceptible before vaccination. The difference in efficacy between the two vaccines was not statistically significant in this limited study. No additional challenges were conducted to assess efficacy at time points later than 28 days (294). In a randomized, double-blind, placebo-controlled trial that was conducted among young adults during the 2004-05 influenza season, when the majority of circulating H3N2 viruses were antigenically drifted from that season's vaccine viruses, the efficacy of LAIV and TIV against culture-confirmed influenza was 57% and 77%, respectively. The difference in efficacy was not statistically significant and was attributable primarily to a difference in efficacy against influenza B (222). A similar study conducted during the 2005-06 influenza season found no significant difference in vaccine efficacy (221).\nA randomized controlled clinical trial conducted among children aged 6-59 months during the 2004-05 influenza season demonstrated a 55% reduction in cases of culture-confirmed influenza among children who received LAIV compared with those who received TIV (288). In this study, LAIV efficacy was higher compared with TIV against antigenically drifted viruses and well-matched viruses (288). An open-label, nonrandomized, community-based influenza vaccine trial conducted during an influenza season when circulating H3N2 strains were poorly matched with strains contained in the vaccine also indicated that LAIV, but not TIV, was effective against antigenically drifted H3N2 strains during that influenza season. In this study, children aged 5-18 years who received LAIV had significant protection against laboratory-confirmed influenza (37%) and pneumonia and influenza events (50%) (295). A recent observational study conducted among military personnel aged 17-49 years over three influenza seasons indicated that persons who received TIV had a significantly lower incidence of health-care encounters resulting in diagnostic coding for pneumonia and influenza compared with those who received LAIV. However, among new recruits being vaccinated for the first time, the incidence of pneumonia-and influenza-coded health-care encounters among those received LAIV was similar to those receiving TIV (296).\nAlthough LAIV is not licensed for use in persons with risk factors for influenza complications, certain studies have compared the efficacy of LAIV to TIV in these groups. LAIV provided 32% increased protection in preventing culture-confirmed influenza compared with TIV in one study conducted among children aged >6 years and adolescents with asthma (297) and 52% increased protection compared with TIV among children aged 6-71 months with recurrent respiratory tract infections (298).\n# Effectiveness of Vaccination for Decreasing transmission to Contacts\nDecreasing transmission of influenza from caregivers and household contacts to persons at high risk might reduce ILI and complications among persons at high risk. Influenza virus infection and ILI are common among HCP (299-301). Influenza outbreaks have been attributed to low vaccination rates among HCP in hospitals and long-term-care facilities (302)(303)(304). One serosurvey demonstrated that 23% of HCP had serologic evidence of influenza virus infection during a single influenza season; the majority had mild illness or subclinical infection (299). Observational studies have demonstrated that vaccination of HCP is associated with decreased deaths among nursing home patients (305,306). In one clusterrandomized controlled trial that included 2,604 residents of 44 nursing homes, significant decreases in mortality, ILI, and medical visits for ILI care were demonstrated among residents in nursing homes in which staff were offered influenza vaccination (coverage rate: 48%) compared with nursing homes in which staff were not provided with vaccination (coverage rate: 6%) (307). A review concluded that vaccination of HCP in settings in which patients also were vaccinated provided significant reductions in deaths among elderly patients from all causes and deaths from pneumonia (308).\nEpidemiologic studies of community outbreaks of influenza demonstrate that school-aged children typically have the highest influenza illness attack rates, suggesting routine universal vaccination of children might reduce transmission to their household contacts and possibly others in the community. Results from certain studies have indicated that the benefits of vaccinating children might extend to protection of their adult contacts and to persons at risk for influenza complications in the community. However, these data are limited, and studies have not used laboratory-confirmed influenza as an outcome measure. A single-blinded, randomized controlled study conducted as part of a 1996-1997 vaccine effectiveness study demonstrated that vaccinating preschool-aged children with TIV reduced influenza-related morbidity among some household contacts (309). A randomized, placebo-controlled trial among children with recurrent respiratory tract infections demonstrated that members of families with children who had received LAIV were significantly less likely to have respiratory tract infections and reported significantly fewer workdays lost compared with families with children who received placebo (310). In nonrandomized community-based studies, administration of LAIV has been demonstrated to reduce MAARI (311,312) and ILI-related economic and medical consequences (e.g., workdays lost and number of health-care provider visits) among contacts of vaccine recipients (312). Households with children attending schools in which school-based LAIV vaccination programs had been established reported less ILI and fewer physician visits during peak influenza season compared with households with children in schools in which no LAIV vaccination had been offered. However a decrease in the overall rate of school absenteeism was not reported in communities in which LAIV vaccination was offered (312). During an influenza outbreak during the 2005-06 influenza season, countywide school-based influenza vaccination was associated with reduced absenteeism among elementary and high school students in one county that implemented a school based vaccination program compared with another county without such a program (313). These community-based studies have not used laboratory-confirmed influenza as an outcome.\nSome studies also have documented reductions in influenza illness among persons living in communities where focused programs for vaccinating children have been conducted. A community-based observational study conducted during the 1968 pandemic using a univalent inactivated vaccine reported that a vaccination program targeting school-aged children (coverage rate: 86%) in one community reduced influenza rates within the community among all age groups compared with another community in which aggressive vaccination was not conducted among school-aged children (314). An observational study conducted in Russia demonstrated reductions in ILI among the community-dwelling elderly after implementation of a vaccination program using TIV for children aged 3-6 years (57% coverage achieved) and children and adolescents aged 7-17 years (72% coverage achieved) (315). In a nonrandomized community-based study conducted over three influenza seasons, 8%-18% reductions in the incidence of MAARI during the influenza season among adults aged >35 years were observed in communities in which LAIV was offered to all children aged >18 months (estimated coverage rate: 20%-25%) compared with communities that did not provide routine influenza vaccination programs for all children (311). In a subsequent influenza season, the same investigators documented a 9% reduction in MAARI rates during the influenza season among persons aged 35-44 years in intervention communities, where coverage was estimated at 31% among school children. However, MAARI rates among persons aged >45 years were lower in the intervention communities regardless of the presence of influenza in the community, suggesting that lower rates could not be attributed to vaccination of school children against influenza (295).\nThe largest study to examine the community effects of increasing overall vaccine coverage was an ecologic study that described the experience in Ontario, Canada, which was the only province to implement a universal influenza vaccination program beginning in 2000. On the basis of models developed from administrative and viral surveillance data, influenzarelated mortality, hospitalizations, ED use, and physicians' office visits decreased significantly more in Ontario after program introduction than in other provinces, with the largest reductions observed in younger age groups (316).\n# Effectiveness of Influenza Vaccination When Circulating Influenza Virus Strains Differ from Vaccine Strains\nManufacturing trivalent influenza virus vaccines is a challenging process that takes 6-8 months to complete. Vaccination can provide reduced but substantial cross-protection against drifted strains in some seasons, including reductions in severe outcomes such as hospitalization. Usually one or more circulating viruses with antigenic changes compared with the vaccine strains are identified in each influenza season. In addition, two distinct lineages of influenza B viruses have co-circulated in recent years, and limited cross-protection is observed against the lineage not represented in the vaccine (48). However, assessment of the clinical effectiveness of influenza vaccines cannot be determined solely by laboratory evaluation of the degree of antigenic match between vaccine and circulating strains. In some influenza seasons, circulating influenza viruses with significant antigenic differences predominate, and reductions in vaccine effectiveness sometimes are observed compared with seasons when vaccine and circulating strains are wellmatched, (107,121,125,173,222). However, even during years when vaccine strains were not antigenically well matched to circulating strains (the result of antigenic drift), substantial protection has been observed against severe outcomes, presumably because of vaccine-induced cross-reacting antibodies (121,125,222,283). For example, in one study conducted during the 2003-04 influenza season, when the predominant circulating strain was an influenza A (H3N2) virus that was antigenically different from that season's vaccine strain, effectiveness against laboratory-confirmed influenza illness among persons aged 50-64 years was 60% among healthy persons and 48% among persons with medical conditions that increased the risk for influenza complications (125). An interim, withinseason analysis during the 2007-08 influenza season indicated that vaccine effectiveness was 44% overall, 54% among healthy persons aged 5-49 years, and 58% against influenza A, despite the finding that viruses circulating in the study area were predominately a drifted influenza A (H3N2) and an influenza B strain from a different lineage compared with vaccine strains (317). Among children, both TIV and LAIV provide protection against infection even in seasons when vaccines and circulating strains are not well-matched. Vaccine effectiveness against ILI was 49%-69% in two observational studies, and 49% against medically attended, laboratory-confirmed influenza in a case-control study conducted among young children during the 2003-04 influenza season, when a drifted influenza A (H3N2) strain predominated, based on viral surveillance data (102,106). However, continued improvements in collecting representative circulating viruses and use of surveillance data to forecast antigenic drift are needed. Shortening manufacturing time to increase the time to identify good vaccine candidate strains from among the most recent circulating strains also is important. Data from multiple seasons that are collected in a consistent manner are needed to better understand vaccine effectiveness during seasons when circulating and vaccine virus strains are not well-matched.\nSeasonal influenza vaccines are not expected to provide protection against novel influenza A (H1N1) virus infection because this novel strain hemagglutinin is substantially different from seasonal influenza A (H1N1). Preliminary immunologic data indicate that few persons have antibody that shows evidence of cross-reactivity against novel influenza A (H1N1) virus, and few show increases in antibody titer to novel influenza A (H1N1) virus after vaccination with the 2007-08 or the 2008-09 seasonal influenza vaccines (318). Vaccines currently are being developed that are specific to novel influenza A (H1N1) virus.\n# Cost-Effectiveness of Influenza Vaccination\nEconomic studies of influenza vaccination are difficult to compare because they have used different measures of both costs and benefits (e.g., cost-only, cost-effectiveness, costbenefit, or cost-utility). However, most studies find that vaccination reduces or minimizes health care, societal, and individual costs and the productivity losses and absenteeism associated with influenza illness. One national study estimated the annual economic burden of seasonal influenza in the United States (using 2003 population and dollars) to be $87.1 billion, including $10.4 billion in direct medical costs (319).\nStudies of influenza vaccination in the United States among persons aged >65 years have estimated substantial reductions in hospitalizations and deaths and overall societal cost savings (168,169). Studies comparing adults in different age groups also find that vaccination is economically beneficial. One study that compared the economic impact of vaccination among persons aged >65 years with those aged 15-64 years indicated that vaccination resulted in a net savings per quality-adjusted life year (QALY) and that the Medicare program saved costs of treating illness by paying for vaccination (320). A study of a larger population comparing persons aged 50-64 years with those aged >65 years estimated the cost-effectiveness of influenza vaccination to be $28,000 per QALY saved (in 2000 dollars) in persons aged 50-64 years compared with $980 per QALY saved among persons aged >65 years (321).\nEconomic analyses among adults aged <65 years have reported mixed results regarding influenza vaccination. Two studies in the United States found that vaccination can reduce both direct medical costs and indirect costs from work absenteeism and reduced productivity (322,323). However, another U.S. study indicated no productivity and absentee savings in a strategy to vaccinate healthy working adults, although vaccination was still estimated to be cost-effective (324).\nCost analyses have documented the considerable financial burden of illness among children. In a study of 727 children conducted at a medical center during 2000-2004, the mean total cost of hospitalization for influenza-related illness was $13,159 ($39,792 for patients admitted to an intensive care unit and $7,030 for patients cared for exclusively on the wards) (325). A strategy that focuses on vaccinating children with medical conditions that confer a higher risk for influenza complications are more cost-effective than a strategy of vaccinating all children (324). An analysis that compared the costs of vaccinating children of varying ages with TIV and LAIV indicated that costs per QALY saved increased with age for both vaccines. In 2003 dollars per QALY saved, costs for routine vaccination using TIV were $12,000 for healthy children aged 6-23 months and $119,000 for healthy adolescents aged 12-17 years compared with $9,000 and $109,000 using LAIV, respectively (326). Economic evaluations of vaccinating children have demonstrated a wide range of cost estimates, but have generally found this strategy to be either cost-saving or cost-beneficial (327)(328)(329)(330).\nEconomic analyses are sensitive to the vaccination venue, with vaccination in medical care settings incurring higher projected costs. In a published model, the mean cost (year 2004 values) of vaccination was lower in mass vaccination ($17.04) and pharmacy ($11.57) settings than in scheduled doctor's office visits ($28.67) (331). Vaccination in nonmedical settings was projected to be cost saving for healthy adults aged >50 years and for high-risk adults of all ages. For healthy adults aged 18-49 years, preventing an episode of influenza would cost $90 if vaccination were delivered in a pharmacy setting, $210 in a mass vaccination setting, and $870 during a scheduled doctor's office visit (331). Medicare payment rates in recent years have been less than the costs associated with providing vaccination in a medical practice (332).\n# Vaccination Coverage Levels\nContinued annual monitoring is needed to determine the effects on vaccination coverage of vaccine supply delays and shortages, changes in influenza vaccination recommendations and target groups for vaccination, reimbursement rates for vaccine and vaccine administration, and other factors related to vaccination coverage among adults and children. One of the Healthy People 2010 objectives (objective no. 14-29a) includes achieving an influenza vaccination coverage level of 90% for persons aged >65 years and among nursing home residents (333,334); new strategies to improve coverage are needed to achieve this objective (335,336). Increasing vaccination coverage among persons who have high-risk conditions and are aged <65 years, including children at high risk, is the highest priority for expanding influenza vaccine use.\nOn 3) and are only slightly lower than coverage levels observed before the 2004-05 vaccine shortage year (337)(338)(339). In the 2006-07 and 2007-08 influenza seasons, estimated vaccination coverage levels among adults with high-risk conditions aged 18-49 years were 25% and 30%, respectively, substantially lower than the Healthy People 2000 and Healthy People 2010 objectives of 60% (Table 3) (333,334).\nStudies conducted among children and adults indicate that opportunities to vaccinate persons at risk for influenza complications (e.g., during hospitalizations for other causes) often are missed. In one study, 23% of children hospitalized with influenza and a comorbidity had a previous hospitalization during the preceding influenza vaccination season (340). In a study of hospitalized Medicare patients, only 31.6% were vaccinated before admission, 1.9% during admission, and 10.6% after admission (341). A study in New York City conducted during 2001-2005 among 7,063 children aged 6-23 months indicated that 2-dose vaccine coverage increased from 1.6% to 23.7% over time; however, although the average number of medical visits during which an opportunity to be vaccinated decreased during the course of the study from 2.9 to 2.0 per child, 55% of all visits during the final year of the study still represented a missed vaccination opportunity (342). Using standing orders in hospitals increases vaccination rates among hospitalized persons (343), and vaccination of hospitalized patients is safe and stimulates an appropriate immune response (158). In one survey, the strongest predictor of receiving vaccination was the survey respondent's belief that he or she was in a high-risk group, based on data from one survey; however, many persons in high-risk groups did not know that they were in a group recommended for vaccination (344).\nReducing racial/ethnic health disparities, including disparities in influenza vaccination coverage, is an overarching national goal that is not being met (334). Estimated vaccination coverage levels in 2007 among persons aged >65 years were 70% for non-Hispanic whites, 58% for non-Hispanic blacks, and 54% for Hispanics (345). Among Medicare beneficiaries, other key factors that contribute to disparities in coverage include variations in the propensity of patients to actively seek vaccination and variations in the likelihood that providers recommend vaccination (346,347). One study estimated that eliminating these disparities in vaccination coverage would have an impact on mortality similar to the impact of eliminating deaths attributable to kidney disease among blacks or liver disease among Hispanics (348).\nReported vaccination levels are low among children at increased risk for influenza complications. Coverage among children aged 2-17 years with asthma for the 2004-05 influenza season was estimated to be 29% (349). One study reported 79% vaccination coverage among children attending a cystic fibrosis treatment center (350). During the first season for which ACIP recommended that all children aged 6 months-23 months receive vaccination, 33% received 1 or more doses of influenza vaccine, and 18% received 2 doses if they were unvaccinated previously (351). Among children enrolled in HMOs who had received a first dose during 2001-2004, second dose coverage varied from 29% to 44% among children aged 6-23 months and from 12% to 24% among children aged 2-8 years (352). A rapid analysis of influenza vaccination coverage levels among members of an HMO in Northern California demonstrated that during the 2004-05 influenza season, the first year of the recommendation for vaccination of children aged 6-23 months, 1-dose coverage was 57% (353). During the 2006-07 influenza season, the second season for which ACIP recommended that all children aged 6 months-23 months receive vaccination, coverage remained low and did not increase substantially from the 2004-05 season. Data collected in 2007 by the National Immunization Survey indicated that for the 2006-07 season, 32% of children aged 6-23 months received at least 1 dose of influenza vaccine and 21% were fully vaccinated (i.e., received 1 or 2 doses depending on previous vaccination history); however, results varied substantially among states (354). As has been reported for older adults, a physician recommendation for vaccination and the perception that having a child be vaccinated \"is a smart idea\" were associated positively with likelihood of vaccination of children aged 6-23 months (355). Similarly, children with asthma were more likely to be vaccinated if their parents recalled a physician recommendation to be vaccinated or believed that the vaccine worked well (356). Implementation of a reminder/recall system in a pediatric clinic increased the percentage of children with asthma receiving vaccination from 5% to 32% (357).\nAlthough annual vaccination is recommended for HCP and is a high priority for reducing morbidity associated with influenza in health-care settings and for expanding influenza vaccine use (358)(359)(360), national survey data demonstrated a vaccination coverage level of only 42% among HCP during the 2005-06 season, and 44% during the 2006-07 season (Table † † Adults categorized as being at high risk for influenza-related complications self-reported one or more of the following: 1) ever being told by a physician they had diabetes, emphysema, coronary heart disease, angina, heart attack, or other heart condition; 2) having a diagnosis of cancer during the previous 12 months (excluding nonmelanoma skin cancer) or ever being told by a physician they have lymphoma, leukemia, or blood cancer during the previous 12 months (post coding for a cancer diagnosis was not yet completed at the time of this publication so this diagnosis was not include in the 2006-07 season data.); 3) being told by a physician they have chronic bronchitis or weak or failing kidneys; or 4) reporting an asthma episode or attack during the preceding 12 months. For children aged <18 years, high-risk conditions included ever having been told by a physician of having diabetes, cystic fibrosis, sickle cell anemia, congenital heart disease, other heart disease, or neuromuscular conditions (seizures, cerebral palsy, and muscular dystrophy), or having an asthma episode or attack during the preceding 12 months. § § Aged 18-44 years, pregnant at the time of the survey and without high-risk conditions. ¶ ¶ Adults were classified as health-care workers if they were employed in a health-care occupation or in a health-care-industry setting, on the basis of standard occupation and industry categories recoded in groups by CDC's National Center for Health Statistics. *** Interviewed sample child or adult in each household containing at least one of the following: a child aged <5 years, an adult aged ≥65 years, or any person aged 5-17 years at high risk (see previous footnote † † ). To obtain information on household composition and high-risk status of household members, the sampled adult, child, and person files from NHIS were merged. Interviewed adults who were health-care workers or who had high-risk conditions were excluded. Information could not be assessed regarding high-risk status of other adults aged 18-64 years in the household; therefore, certain adults aged 18-64 years who lived with an adult aged 18-64 years at high risk were not included in the analysis. Also note that although the recommendation for children aged 2-4 years was not in place during the 2005-06 season, children aged 2-4 years in these calculations were considered to have an indication for vaccination to facilitate comparison of coverage data for subsequent years.\n3). Vaccination of HCP has been associated with reduced work absenteeism (300) and with fewer deaths among nursing home patients (305,307) and elderly hospitalized patients (308). Factors associated with a higher rate of influenza vaccination among HCP include older age, being a hospital employee, having employer-provided health-care insurance, having had pneumococcal or hepatitis B vaccination in the past, or having visited a health-care professional during the preceding year. Non-Hispanic black HCP were less likely than non-Hispanic white HCP to be vaccinated (361). HCP who decline vaccination frequently express doubts about the risk for influenza and the need for vaccination, are concerned about vaccine effectiveness and side effects, and dislike injections (362).\nVaccine coverage among pregnant women increased during the 2007-08 influenza season with 24% of pregnant women reporting vaccination, excluding pregnant women who reported diabetes, heart disease, lung disease, and other selected high-risk conditions (Table 3). However, the sample size is small, and the increase in coverage compared with previous seasons was not statistically significant. In a study of influenza vaccine acceptance by pregnant women, 71% of those who were offered the vaccine chose to be vaccinated (363). However, a 1999 survey of obstetricians and gynecologists determined that only 39% administered influenza vaccine to obstetric patients in their practices, although 86% agreed that pregnant women's risk for influenza-related morbidity and mortality increases during the last two trimesters (364).\nInfluenza vaccination coverage in all groups recommended for vaccination remains suboptimal. Despite the timing of the peak of influenza disease, administration of vaccine decreases substantially after November. According to results from the NHIS regarding the two most recent influenza seasons for which these data are available, approximately 84% of all influenza vaccination were administered during September-November. Among persons aged >65 years, the percentage of September-November vaccinations was 92% (365). Because many persons recommended for vaccination remain unvaccinated at the end of November, CDC encourages public health partners and health-care providers to conduct vaccination clinics and other activities that promote seasonal influenza vaccination annually during National Influenza Vaccination Week (December 6-12, 2009) and throughout the remainder of the influenza season.\nSelf-report of influenza vaccination among adults compared with determining vaccination status from the medical record, is a sensitive and specific source of information (366,367). Patient self-reports should be accepted as evidence of influenza vaccination in clinical practice (367). However, information on the validity of parents' reports of pediatric influenza vaccination is not yet available.\n# Recommendations for Using tIV and LAIV During the 2009-10 Influenza Season\nBoth TIV and LAIV prepared for the 2009-10 season will include A/Brisbane/59/2007 (H1N1)-like, A/ Brisbane/10/2007 (H3N2)-like, and B/Brisbane/60/2008-like antigens. The influenza B virus component of the 2009-10 vaccine is from the Victoria lineage (368). These viruses will be used because they are representative of seasonal influenza viruses that are predicted to be circulating in the United States during the 2009-10 influenza season and have favorable growth properties in eggs. Seasonal influenza vaccines are not expected to provide substantial protection against infection with the recently identified novel influenza A (H1N1) (318), and guidance for the prevention of infection against this virus will be published separately.\nTIV and LAIV can be used to reduce the risk for influenza virus infection and its complications. Vaccination providers should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza or transmitting influenza to others should they become infected.\nHealthy, nonpregnant persons aged 2-49 years can choose to receive either vaccine. Some TIV formulations are FDAlicensed for use in persons as young as age 6 months (see Recommended Vaccines for Different Age Groups). TIV is licensed for use in persons with high-risk conditions (Table 2). LAIV is FDA-licensed for use only for persons aged 2-49 years. In addition, FDA has indicated that the safety of LAIV has not been established in persons with underlying medical conditions that confer a higher risk for influenza complications. All children aged 6 months-8 years who have not been vaccinated previously at any time with at least 1 dose of either LAIV (if appropriate) or TIV should receive 2 doses of ageappropriate vaccine in the same season, with a single dose during subsequent seasons.\n# target Groups for Protection through Vaccination\nInfluenza vaccine should be provided to all persons who want to reduce the risk for becoming ill with influenza or of transmitting it to others. However, emphasis on providing routine vaccination annually to certain groups at higher risk for influenza infection or complications is advised, including all children aged 6 months-18 years, all persons aged >50 years, and other adults at risk for medical complications from influenza. In addition, all persons who live with or care for persons at high risk for influenza-related complications, including contacts of children aged <6 months, should receive influenza vaccine annually (Boxes 1 and 2). Approximately 85% of the U.S. population is included in one or more of these target groups; however, <40% of the U.S. population received an influenza vaccination during the 2008-09 influenza season.\n# Children Aged 6 Months-18 Years\nBeginning with the 2008-09 influenza season, annual vaccination for all children aged 6 months-18 years was recommended. Children and adolescents at high risk for influenza complications should continue to be a focus of vaccination efforts as providers and programs transition to routinely vaccinating all children.\nHealthy children aged 2-18 years can receive either LAIV or TIV. Children aged 6-23 months, and those aged 2-4 years who have evidence of asthma wheezing or who have medical conditions that put them at higher risk for influenza complications should receive TIV (see Considerations When Using LAIV). All children aged 6 months-8 years who have not received vaccination against influenza previously should receive 2 doses of vaccine the first year they are vaccinated.\n# Persons at Risk for Medical Complications\nVaccination to prevent influenza is particularly important for the following persons, who are at increased risk for severe complications from influenza, or at higher risk for influenzarelated outpatient, ED, or hospital visits: all children aged 6 months- facilities. For children, the risk for severe complications from seasonal influenza is highest among those aged <2 years, who have much higher rates of hospitalization for influenza-related complications compared with older children (7,32,39). Medical care and ED visits attributable to influenza are increased among children aged <5 years compared with older children (32).\nChronic neurologic and neuromuscular conditions include any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration (30).\n# Persons Who Live With or Care for Persons at High Risk for Influenza-Related Complications\nTo prevent transmission to persons identified above, vaccination with TIV or LAIV (unless contraindicated) also is recommended for the following persons. When vaccine supply is limited, vaccination efforts should focus on delivering vaccination to these persons: HCP; • household contacts (including children) and caregivers • of children aged <59 months (i.e., aged <5 years) and adults aged >50 years; and household contacts (including children) and caregivers • of persons with medical conditions that put them at higher risk for severe complications from influenza.\n# Children Aged <6 Months\nChildren aged <6 months are not recommended for vaccination, and antivirals are not licensed for use among infants. Protection of young infants, who have hospitalization rates similar to those observed among the elderly, depends on vaccination of the infants' close contacts. A recent study conducted in Bangladesh demonstrated that infants born to vaccinated women have significant protection from laboratory-confirmed influenza, either through transfer of influenza-specific maternal antibodies or by reducing the risk for exposure to influenza that might occur through vaccination of the mother (154). All household contacts, health-care and day care providers, and other close contacts of young infants should be vaccinated.\n# Vaccination of Specific Populations Children Aged 6 Months-18 Years\nAll children aged 6 months-18 years should be vaccinated against influenza annually. In 2004, ACIP recommended routine vaccination for all children aged 6-23 months, and in 2006, ACIP expanded the recommendation to include all children aged 24-59 months. Recommendations to provide routine influenza vaccination to all children and adolescents aged 6 months-18 years are made on the basis of 1) accumulated evidence that influenza vaccine is effective and safe for children (see Influenza Vaccine Efficacy, Effectiveness, and Safety); 2) increased evidence that influenza has substantial adverse impacts among children and their contacts (e.g., school absenteeism, increased antibiotic use, medical care visits, and parental work loss) (see Health-Care Use, Hospitalizations, and Deaths Attributed to Influenza); and 3) an expectation that a simplified age-based influenza vaccine recommendation for all children and adolescents will improve vaccine coverage levels among children who already have a risk-or contact-based indication for annual influenza vaccination.\nChildren typically have the highest attack rates during community outbreaks of influenza and serve as a major source of transmission within communities (1,2). If sufficient vaccination coverage among children can be achieved, potential benefits include the indirect effect of reducing influenza among persons who have close contact with children and reducing overall transmission within communities. Achieving and sustaining community-level reductions in influenza will require mobilization of community resources and development of sustainable annual vaccination campaigns to assist health-care providers and vaccination programs in providing influenza vaccination services to children of all ages. In many areas, innovative community-based efforts, which might include mass vaccination programs in school or other community settings, will be needed to supplement vaccination services provided in health-care providers' offices or public health clinics. In nonrandomized community-based controlled trials, reductions in ILI-related symptoms and medical visits among household contacts have been demonstrated in communities where vaccination programs among school-aged children were established compared with communities without such vaccination programs (295,314,315).Reducing influenza-related illness among children who are at high risk for influenza complications should continue to be a primary focus of influenza-prevention efforts. Children who should be vaccinated because they are at high risk for influenza complications include all children aged 6-59 months, children with certain medical conditions, children who are contacts of children aged <5 years (60 months) or of persons aged >50 years, and children who are contacts of persons at high risk for influenza complications because of medical conditions.\nAll children aged 6 months-8 years who have not received vaccination against influenza previously should receive 2 doses of vaccine the first influenza season that they are vaccinated. The second dose should be administered 4 or more weeks after the initial dose. When only 1 dose is administered to children aged 6 months-8 years during their first year of vaccination, 2 doses should be administered in the following season. However, 2 doses should only be administered in the first season of vaccination, or in the season that immediately follows if only 1 dose is administered in the first season. For example, children aged 6 months-8 years who were vaccinated for the first time with the 2008-09 influenza vaccine but received only 1 dose should receive 2 doses of the 2009-10 influenza vaccine. All other children aged 6 months-8 years who have previously received 1 or more doses of influenza vaccine at any time should receive 1 dose of the 2009-10 influenza vaccine. Children aged 6 months-8 years who received only a single vaccination during a season before 2007-08 should receive 1 dose of the 2009-10 influenza vaccine. If possible, both doses should be administered before onset of influenza season. However, vaccination, including the second dose, is recommended even after influenza virus begins to circulate in a community.\n# HCP and other Persons Who Can transmit Influenza to those at High Risk\nHealthy persons who are infected with influenza virus, including those with subclinical infection, can transmit influenza virus to persons at higher risk for complications from influenza. In addition to HCP, groups that can transmit influenza to high-risk persons and that should be vaccinated include employees of assisted living and other residences for All HCP and persons in training for health-care professions should be vaccinated annually against influenza. Persons working in health-care settings who should be vaccinated include physicians, nurses, and other workers in both hospital and outpatient-care settings, medical emergency-response workers (e.g., paramedics and emergency medical technicians), employees of nursing home and long-term-care facilities who have contact with patients or residents, and students in these professions who will have contact with patients (359,360,371).\nFacilities that employ HCP should provide vaccine to workers by using approaches that have been demonstrated to be effective in increasing vaccination coverage. Health-care administrators should consider the level of vaccination coverage among HCP to be one measure of a patient safety quality program and consider obtaining signed declinations from personnel who decline influenza vaccination for reasons other than medical contraindications (360,372,373). Influenza vaccination rates among HCP within facilities should be regularly measured and reported, and ward-, unit-, and specialty-specific coverage rates should be provided to staff and administration (360). Studies have demonstrated that organized campaigns can attain higher rates of vaccination among HCP with moderate effort and by using strategies that increase vaccine acceptance (358,360,374).\nEfforts to increase vaccination coverage among HCP are supported by various national accrediting and professional organizations and in certain states by statute. The Joint Commission on Accreditation of Health-Care Organizations has approved an infection-control standard that requires accredited organizations to offer influenza vaccinations to staff, including volunteers and licensed independent practitioners with close patient contact. The standard became an accreditation requirement beginning January 1, 2007 (375). In addition, the Infectious Diseases Society of America has recommended mandatory vaccination for HCP, with a provision for declination of vaccination based on religious or medical reasons (376). Some states have regulations regarding vaccination of HCP in long-term-care facilities (377), require that health-care facilities offer influenza vaccination to HCP, or require that HCP either receive influenza vaccination or indicate a religious, medical, or philosophic reason for not being vaccinated (378,379).\n# Close Contacts of Immunocompromised Persons\nImmunocompromised persons are at risk for influenza complications but might have inadequate protection after vaccination. Close contacts of immunocompromised persons, including HCP, should be vaccinated to reduce the risk for influenza transmission. TIV is recommended for vaccinating household members, HCP, and others who have close contact with severely immunosuppressed persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunosuppressed person requires care in a protective environment (typically defined as a specialized patient-care area with a positive airflow relative to the cor-ridor, high-efficiency particulate air filtration, and frequent air changes) (360,380).\nLAIV transmission from a recently vaccinated person causing clinically important illness in an immunocompromised contact has not been reported. The rationale for avoiding use of LAIV among HCP or other close contacts of severely immunocompromised patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunosuppressed person. As a precautionary measure, HCP who receive LAIV should avoid providing care for severely immunosuppressed patients requiring a protected environment for 7 days after vaccination. Hospital visitors who have received LAIV should avoid contact with severely immunosuppressed persons in protected environments for 7 days after vaccination but should not be restricted from visiting less severely immunosuppressed patients.\nNo preference is indicated for TIV use by persons who have close contact with persons with lesser degrees of immunosuppression (e.g., persons with diabetes, persons with asthma who take corticosteroids, persons who have recently received chemotherapy or radiation but who are not being cared for in a protective environment as defined above, or persons infected with HIV) or for TIV use by HCP or other healthy nonpregnant persons aged 2-49 years in close contact with persons in all other groups at high risk.\n# Pregnant Women\nPregnant women and newborns are at risk for influenza complications, and all women who are pregnant or will be pregnant during influenza season should be vaccinated. The American College of Obstetricians and Gynecologists and the American Academy of Family Physicians also have recommended routine vaccination of all pregnant women (381). No preference is indicated for use of TIV that does not contain thimerosal as a preservative (see Vaccine Preservative [Thimerosal] in Multidose Vials of TIV) for any group recommended for vaccination, including pregnant women. LAIV is not licensed for use in pregnant women. However, pregnant women do not need to avoid contact with persons recently vaccinated with LAIV.\n# Breastfeeding Mothers\nVaccination is recommended for all persons, including breastfeeding women, who are contacts of infants or children aged <5 years because infants and young children are at high risk for influenza complications and are more likely to require medical care or hospitalization if infected. Breastfeeding does not affect the immune response adversely and is not a con-traindication for vaccination (179). Unless contraindicated because of other medical conditions, women who are breastfeeding can receive either TIV or LAIV. In one randomized controlled trial conducted in Bangladesh, infants born to women vaccinated during pregnancy had a lower risk for laboratory-confirmed influenza. However, the contribution to protection from influenza of breastfeeding compared with passive transfer of maternal antibodies during pregnancy was not determined (154).\n# travelers\nThe risk for exposure to influenza during travel depends on the time of year and destination. In the temperate regions of the Southern Hemisphere, influenza activity occurs typically during April-September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large tourist groups (e.g., on cruise ships) that include persons from areas of the world in which influenza viruses are circulating (382,383). In the tropics, influenza occurs throughout the year. In a study among Swiss travelers to tropical and subtropical countries, influenza was the most frequently acquired vaccine-preventable disease (384).\nAny traveler who wants to reduce the risk for influenza infection should consider influenza vaccination, preferably at least 2 weeks before departure. In particular, persons at high risk for complications of influenza and who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to travel to the tropics, • with organized tourist groups at any time of year, or • to the Southern Hemisphere during April-September. • No information is available about the benefits of revaccinating persons before summer travel who already were vaccinated during the preceding fall, and revaccination is not recommended. Persons at high risk who receive the previous season's vaccine before travel should be revaccinated with the current vaccine the following fall or winter. Persons at higher risk for influenza complications should consult with their health-care practitioner to discuss the risk for influenza or other travel-related diseases before embarking on travel during the summer.\n# General Population\nVaccination is recommended for any persons who wish to reduce the likelihood of their becoming ill with influenza or transmitting influenza to others should they become infected. Healthy, nonpregnant persons aged 2-49 years might choose to receive either TIV or LAIV. All other persons aged >6 months should receive TIV. Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories or correctional facilities) should be encouraged to receive vaccine to minimize morbidity and the disruption of routine activities during influenza epidemics (385,386).\n# Recommended Vaccines for Different Age Groups\nWhen vaccinating children aged 6-35 months with TIV, health-care providers should use TIV that has been licensed by the FDA for this age group (i.e., TIV manufactured by Sanofi Pasteur [FluZone]) (219). TIV from Novartis (Fluvirin) is FDA-approved in the United States for use among persons aged >4 years (220). TIV from GlaxoSmithKline (Fluarix and FluLaval) or CSL Biotherapies (Afluria) is labeled for use in persons aged >18 years because data to demonstrate immunogenicity or efficacy among younger persons have not been provided to FDA (207,208,218). LAIV from MedImmune (FluMist) is recommended for use by healthy nonpregnant persons aged 2-49 years (Table 2) (291). If a pediatric vaccine dose (0.25mL) is administered to an adult, an additional pediatric dose (0.25 mL) should be given to provide a full adult dose (0.5mL). If the error is discovered later (after the patient has left the vaccination setting), an adult dose should be administered as soon as the patient can return. No action needs to be taken if an adult dose is administered to a child. Several new vaccine formulations are being evaluated in immunogenicity and efficacy trials; when licensed, these new products will increase the influenza vaccine supply and provide additional vaccine choices for practitioners and their patients.\n# Influenza Vaccines and Use of Influenza Antiviral Medications\nUnvaccinated persons who are receiving antiviral medications for treatment or chemoprophylaxis often also are recommended for vaccination. Administration of TIV to persons receiving influenza antivirals is acceptable. The effect on safety and effectiveness of LAIV coadministration with influenza antiviral medications has not been studied. However, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV. Persons receiving antivirals within the period 2 days before to 14 days after vaccination with LAIV should be revaccinated at a later date with any approved vaccine formulation (179,291).\n# Considerations When Using LAIV\nLAIV is an option for vaccination of healthy, nonpregnant persons aged 2-49 years, including HCP and other close contacts of high-risk persons (excepting severely immunocompromised persons who require care in a protected environment). No preference is indicated for LAIV or TIV when considering vaccination of healthy, ¶ nonpregnant persons aged 2-49 years. Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response in children, its ease of administration, and the possibly increased acceptability of an intranasal rather than intramuscular route of administration.\nIf the vaccine recipient sneezes after administration, the dose should not be repeated. However, if nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness, or TIV should be administered instead. No data exist about concomitant use of nasal corticosteroids or other intranasal medications (261).\nAlthough FDA licensure of LAIV excludes children aged 2-4 years with a history of asthma or recurrent wheezing, the precise risk, if any, of wheezing caused by LAIV among these children is unknown because experience with LAIV among these young children is limited. Young children might not have a history of recurrent wheezing if their exposure to respiratory viruses has been limited because of their age. Certain children might have a history of wheezing with respiratory illnesses but have not had asthma diagnosed.\nThe following screening recommendations should be used to assist persons who administer influenza vaccines in providing the appropriate vaccine for children aged 2-4 years.\nClinicians and vaccination programs should screen • for asthma or wheezing illness (or history of wheezing illness) when considering use of LAIV for children aged 2-4 years, and should avoid use of this vaccine in children with asthma or a recent wheezing episode within the previous 12 months. Health-care providers should consult the medical record, when available, to identify children aged 2-4 years with asthma or recurrent wheezing that might indicate asthma. In addition, to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving LAIV, parents or caregivers of children aged 2-4 years should be asked: \"In the past 12 months, has a health-care provider ever told you that your child had wheezing or asthma?\" Children whose parents or caregivers answer \"yes\" to this question and children who have asthma or who had a wheezing episode noted in the medical record during the preceding 12 months should not receive LAIV. TIV is available for use in children with asthma or wheezing (387).LAIV can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infection with or without fever). However, if nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness.\n# Contraindications and Precautions for Use of LAIV\nThe effectiveness or safety of LAIV is not known for the following groups and administration of LAIV is contraindicated:\npersons ing aspirin or other salicylates (because of the association of Reye syndrome with wild-type influenza virus infection); or pregnant women. • A moderate or severe illness with or without fever is a precaution for use of LAIV. GBS within 6 weeks following a previous dose of influenza vaccine is considered to be a precaution for use of influenza vaccines. LAIV should not be administered to close contacts of immunosuppressed persons who require a protected environment. ¶ Use of the term \"healthy\" in this recommendation refers to persons who do not have any of the underlying medical conditions that confer high risk for severe complications (see Contraindications and Precautions for Use of LAIV).\n# Personnel Who Can Administer LAIV\nLow-level introduction of vaccine viruses into the environment probably is unavoidable when administering LAIV. The risk for acquiring vaccine viruses from the environment is unknown but is probably low. Severely immunosuppressed persons should not administer LAIV. However, other persons at higher risk for influenza complications can administer LAIV. These include persons with underlying medical conditions placing them at higher risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged >50 years.\n# Concurrent Administration of Influenza Vaccine with other Vaccines\nUse of LAIV concurrently with measles, mumps, rubella (MMR) alone and MMR and varicella vaccine among children aged 12-15 months has been studied, and no interference with the immunogenicity to antigens in any of the vaccines was observed (261,388). Among adults aged >50 years, the safety and immunogenicity of zoster vaccine and TIV was similar whether administered simultaneously or spaced 4 weeks apart (389). In the absence of specific data indicating interference, following ACIP's general recommendations for vaccination is prudent (179). Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. Inactivated or live vaccines can be administered simultaneously with LAIV. However, after administration of a live vaccine, at least 4 weeks should pass before another live vaccine is administered.\n# Recommendations for Vaccination Administration and Vaccination Programs\nAlthough influenza vaccination levels increased substantially during the 1990s, little progress has been made since 2000 toward achieving national health objectives, and further improvements in vaccine coverage levels are needed to reduce the annual impact of influenza substantially. Strategies to improve vaccination levels, including using reminder/recall systems and standing orders programs (335,336,345), should be implemented whenever feasible. Vaccination efforts should begin as soon as vaccine is available and continue through the influenza season. Vaccination coverage can be increased by administering vaccine before and during the influenza season to persons during hospitalizations or routine health-care visits. Vaccinations can be provided in alternative settings (e.g., pharmacies, grocery stores, workplaces, or other locations in the community), thereby making special visits to physicians' offices or clinics unnecessary. Coordinated campaigns such as the National Influenza Vaccination Week (December 6-12, 2009) provide opportunities to refocus public attention on the benefits, safety, and availability of influenza vaccination throughout the influenza season. When educating patients about adverse events, clinicians should provide access to Vaccine Information Sheets (available at http://www.cdc. gov/vaccines/pubs/vis), and emphasize that 1) TIV contains noninfectious killed viruses and cannot cause influenza, 2) LAIV contains weakened influenza viruses that cannot replicate outside the upper respiratory tract and are unlikely to infect others, and 3) concomitant symptoms or respiratory disease unrelated to vaccination with either TIV or LAIV can occur after vaccination. Adverse events after influenza vaccination should be reported promptly to VAERS at http://vaers.hhs. gov even if the health-care professional is not certain that the vaccine caused the event.\n# Information About the Vaccines for Children Program\nThe Vaccines for Children (VFC) program supplies vaccine to all states, territories, and the District of Columbia for use by participating providers. These vaccines are to be provided to eligible children without vaccine cost to the patient or the provider, although the provider might charge a vaccine administration fee. All routine childhood vaccines recommended by ACIP are available through this program, including influenza vaccines. The program saves parents and providers out-ofpocket expenses for vaccine purchases and provides cost savings to states through CDC's vaccine contracts. The program results in lower vaccine prices and ensures that all states pay the same contract prices. Detailed information about the VFC program is available at http://www.cdc.gov/vaccines/programs/ vfc/default.htm.\n# Influenza Vaccine Supply Considerations\nThe annual supply of influenza vaccine and the timing of its distribution cannot be guaranteed in any year. During the 2008-09 influenza season, 113 million doses of influenza vaccine were distributed in the United States. For the 2009-10 season, total production of seasonal influenza vaccine for the United States is anticipated to be >130 million doses, depending on demand and production yields. However, influenza vaccine distribution delays or vaccine shortages remain possible. One factor that affects production is the inherent critical time constraints in manufacturing the vaccine given the annual updating of the influenza vaccine strains. Multiple manufacturing and regulatory issues, including the anticipated need to produce a separate vaccine against novel influenza A (H1N1), also might affect the production schedule. To ensure optimal use of available doses of influenza vaccine, health-care providers, persons planning organized campaigns, and state and local public health agencies should develop plans for expanding outreach and infrastructure to vaccinate more persons in targeted groups and others who wish to reduce their risk for influenza. They also should develop contingency plans for the timing and prioritization of administering influenza vaccine if the supply of vaccine is delayed or reduced.\nIf supplies of TIV are not adequate, vaccination should be carried out in accordance with local circumstances of supply and demand based on the judgment of state and local health officials and health-care providers. Guidance for tiered use of TIV during prolonged distribution delays or supply short falls is available at http://www.cdc.gov/flu/professionals/vaccination/vax_priority.htm and will be modified as needed in the event of shortage. CDC and other public health agencies will assess the vaccine supply on a continuing basis throughout the manufacturing period and will inform both providers and the general public if any indication exists of a substantial delay or an inadequate supply.\nBecause LAIV is recommended for use only in healthy nonpregnant persons aged 2-49 years, no recommendations for prioritization of LAIV use are made. Either LAIV or TIV can be used when considering vaccination of healthy, nonpregnant persons aged 2-49 years. However, during shortages of TIV, LAIV should be used preferentially when feasible for all healthy nonpregnant persons aged 2-49 years (including HCP) who desire or are recommended for vaccination to increase the availability of inactivated vaccine for persons at high risk.\n# timing of Vaccination\nVaccination efforts should be structured to ensure the vaccination of as many persons as possible over the course of several months, with emphasis on vaccinating before influenza activity in the community begins. Even if vaccine distribution begins before October, distribution probably will not be completed until December or January. The following recommendations reflect this phased distribution of vaccine.\nIn any given year, the optimal time to vaccinate patients cannot be determined precisely because influenza seasons vary in their timing and duration, and more than one outbreak might occur in a single community in a single year. In the United States, localized outbreaks that indicate the start of seasonal influenza activity can occur as early as October. However, in >80% of influenza seasons since 1976, peak influenza activity (which often is close to the midpoint of influenza activity for the season) has not occurred until January or later, and in >60% of seasons, the peak was in February or later (Figure 1). In general, health-care providers should begin offering vaccination soon after vaccine becomes available and if possible by October. To avoid missed opportunities for vaccination, providers should offer vaccination during routine health-care visits or during hospitalizations whenever vaccine is available. The potential for addition of a novel influenza A (H1N1) vaccine program to the current burden on vaccination programs and providers underscores the need for careful planning of seasonal vaccination programs. Beginning use of seasonal vaccine as soon as available, including in September or earlier, might reduce the overlap of seasonal and novel influenza vaccination efforts.\nVaccination efforts should continue throughout the season, because the duration of the influenza season varies, and influenza might not appear in certain communities until February or March. Providers should offer influenza vaccine routinely, and organized vaccination campaigns should continue throughout the influenza season, including after influenza activity has begun in the community. Vaccine administered in December or later, even if influenza activity has already begun, is likely to be beneficial in the majority of influenza seasons. The majority of adults have antibody protection against influenza virus infection within 2 weeks after vaccination (390,391).\nAll children aged 6 months-8 years who have not received vaccination against influenza previously should receive their first dose as soon after vaccine becomes available as is feasible and should receive the second dose >4 weeks later. This practice increases the opportunity for both doses to be administered before or shortly after the onset of influenza activity.\nVaccination clinics should be scheduled through December, and later if feasible, with attention to settings that serve children aged >6 months, pregnant women, other persons aged <50 years at increased risk for influenza-related complications, persons aged >50 years, HCP, and persons who are household contacts of children aged <59 months or other persons at high risk. Planners are encouraged to develop the capacity and flexibility to schedule at least one vaccination clinic in December. Guidelines for planning large-scale vaccination clinics are available at http://www.cdc.gov/flu/professionals/ vaccination/vax_clinic.htm.\nDuring a vaccine shortage or delay, substantial proportions of TIV doses might not be released and distributed until November and December or later. When the vaccine is substantially delayed or disease activity has not subsided, providers should consider offering vaccination clinics into January and beyond as long as vaccine supplies are available. Campaigns using LAIV also can extend into January and beyond.\n# Strategies for Implementing Vaccination Recommendations in Health-Care Settings\nSuccessful vaccination programs combine publicity and education for HCP and other potential vaccine recipients, a plan for identifying persons recommended for vaccination, use of reminder/recall systems, assessment of practice-level vaccination rates with feedback to staff, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs (336,392). The use of standing orders programs by long-term-care facilities (e.g., nursing homes and skilled nursing facilities), hospitals, and home health agencies ensures that vaccination is offered. Standing orders programs for influenza vaccination should be conducted under the supervision of a licensed practitioner according to a physician-approved facility or agency policy by HCP trained to screen patients for contraindications to vaccination, administer vaccine, and monitor for adverse events. The Centers for Medicare and Medicaid Services (CMS) has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term-care facilities, and home health agencies (393). To the extent allowed by local and state law, these facilities and agencies can implement standing orders for influenza and pneumococcal vaccination of Medicare-and Medicaideligible patients. Payment for influenza vaccine under Medicare Part B is available (394,395) Other settings (e.g., outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces) are encouraged to introduce standing orders programs (396). In addition, physician reminders (e.g., flagging charts) and patient reminders are recognized strategies for increasing rates of influenza vaccination. Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following sections.\n# outpatient Facilities Providing ongoing Care\nStaff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccination. Vaccine should be offered during visits throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the medical record or vaccination information system. Patients for whom vaccination is recommended and who do not have regularly scheduled visits during the fall should be reminded by mail, telephone, or other means of the need for vaccination.\n# outpatient Facilities Providing Episodic or Acute Care\nAcute health-care facilities (e.g., EDs and walk-in clinics) should offer vaccinations throughout the influenza season to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility.\n# nursing Homes and other Long-term-Care Facilities\nVaccination should be provided routinely to all residents of long-term-care facilities. If possible, all residents should be vaccinated at one time before influenza season. In the majority of seasons, TIV will become available to long-term-care facilities in October or November, and vaccination should commence as soon as vaccine is available. As soon as possible after admission to the facility, the benefits and risks of vaccination should be discussed and education materials provided (397). Signed consent is not required (398). Residents admitted after completion of the vaccination program at the facility should be vaccinated at the time of admission.\nSince October 2005, CMS has required nursing homes participating in the Medicare and Medicaid programs to offer all residents influenza and pneumococcal vaccines and to document the results. According to the requirements, each resident is to be vaccinated unless contraindicated medically, the resident or a legal representative refuses vaccination, or the vaccine is not available because of shortage. This information is to be reported as part of the CMS Minimum Data Set, which tracks nursing home health parameters (395,399).\n# Acute-Care Hospitals\nHospitals should serve as a key setting for identifying persons at increased risk for influenza complications. Unvaccinated persons of all ages (including children) with high-risk conditions and persons aged 6 months-18 years or >50 years who are hospitalized at any time during the period when vaccine is available should be offered and strongly encouraged to receive influenza vaccine before they are discharged. Standing orders to offer influenza vaccination to all hospitalized persons should be considered.\n# Visiting nurses and others Providing Home Care to Persons at High Risk\nNursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home if necessary as soon as influenza vaccine is available and throughout the influenza season. Caregivers and other persons in the household (including children) should be referred for vaccination.\n# other Facilities Providing Services to Persons Aged >50 Years\nFacilities providing services to persons aged >50 years (e.g., assisted living housing, retirement communities, and recreation centers) should offer unvaccinated residents, attendees, and staff annual on-site vaccination before the start of the influenza season. Continuing to offer vaccination throughout the fall and winter months is appropriate. Efforts to vaccinate newly admitted patients or new employees also should be continued, both to prevent illness and to avoid having these persons serve as a source of new influenza infections. Staff education should emphasize the benefits for self, staff and patients of protection from influenza through vaccination.\n# Health-Care Personnel\nHealth-care facilities should offer influenza vaccinations to all HCP, including night, weekend, and temporary staff. Particular emphasis should be placed on providing vaccinations to workers who provide direct care for persons at high risk for influenza complications. Efforts should be made to educate HCP regarding the benefits of vaccination and the potential health consequences of influenza illness for their patients, themselves, and their family members. All HCP should be provided convenient access to influenza vaccine at the work site, free of charge, as part of employee health programs (360,374,375).\n# Future Directions for Research and Recommendations Related to Influenza Vaccine\nAlthough available influenza vaccines are effective and safe, additional research is needed to improve prevention efforts. Most mortality from influenza occurs among persons aged >65 years (6), and more immunogenic influenza vaccines are needed for this age group and other groups at high risk for mortality. Additional research also is needed to understand potential biases in estimating the benefits of vaccination among older adults in reducing hospitalizations and deaths (82,175,400). Additional studies of the relative cost-effectiveness and cost utility of influenza vaccination among children and adults, especially those aged <65 years, are needed and should be designed to account for year-to-year variations in influenza attack rates, illness severity, hospitalization costs and rates, and vaccine effectiveness when evaluating the long-term costs and benefits of annual vaccination (401). Additional data on indirect effects of vaccination also are needed to quantify the benefits of influenza vaccination of HCP in protecting their patients (308) and the benefits of vaccinating children to reduce influenza complications among those at risk. Because expansions in ACIP recommendations for vaccination will lead to more persons being vaccinated, much larger research networks are needed that can identify and assess the causality of very rare events that occur after vaccination, including GBS. Ongoing studies of safety in pediatric populations with expanded recommendations are needed and are underway. These research networks also could provide a platform for effectiveness and safety studies in the event of a pandemic. A recent study showed that influenza vaccines contain structures that can induce anti-GM1 antibodies after inoculation into mice (402). Further research on potential biologic or genetic risk factors for GBS in humans also is needed (397). In addition, a better understanding is needed of how to motivate persons at risk to seek annual influenza vaccination.\nACIP continues to review new vaccination strategies to protect against influenza, including the possibility of expanding routine influenza vaccination recommendations toward universal vaccination or other approaches that will help reduce or prevent the transmission of influenza and reduce the burden of severe disease (403)(404)(405)(406)(407)(408). The 2009 ACIP expansion of annual vaccination recommendations to include all children aged 6 months-18 years will require a substantial increase in resources for epidemiologic research to develop long-term studies capable of assessing the possible effects on community-level transmission. Additional planning to improve surveillance systems capable of monitoring effectiveness, safety and vaccine coverage, and further development of implementation strategies will also be necessary. In addition, as noted by the National Vaccine Advisory Committee, strengthening the U.S. influenza vaccination system will require improving vaccine financing and demand and implementing systems to help better understand the burden of influenza in the United States (409). Vaccination programs capable of delivering annual influenza vaccination to a broad range of the population could potentially serve as a resilient and sustainable platform for delivering vaccines and monitoring outcomes for other urgently required public health interventions (e.g., vaccines for pandemic influenza or medications to prevent or treat illnesses caused by acts of terrorism).\n# Seasonal Influenza Vaccine and Influenza Viruses of Animal origin\nHuman infection with novel or nonhuman influenza A virus strains, including influenza A viruses of animal origin, is a nationally notifiable disease (410). Human infections with nonhuman or novel human influenza A virus should be identified quickly and investigated to determine possible sources of exposure, identify additional cases, and evaluate the possibility of human-to-human transmission because transmission patterns could change over time with variations in these influenza A viruses.\nSporadic severe and fatal human cases of infection with highly pathogenic avian influenza A (H5N1) virus have been identified in Asia, Africa, Europe, and the Middle East, primarily among persons who have had direct or close unprotected contact with sick or dead birds associated with the ongoing H5N1 panzootic among birds (411)(412)(413)(414)(415)(416)(417)(418)(419). Limited, nonsustained human-to-human transmission of H5N1 virus has likely occurred in some case clusters (420,421). To date, no evidence exists of genetic reassortment between human influenza A and H5N1 viruses. However, influenza viruses derived from strains circulating among poultry (e.g., the H5N1 virus that has caused outbreaks of avian influenza and occasionally have infected humans) have the potential to recombine with human influenza A viruses (422,423). To date, highly pathogenic H5N1 virus has not been identified in wild or domestic birds or in humans in the United States. Guidance for testing suspected cases of H5N1 virus infection among persons in the U.S. and follow-up of contacts is available (424,425).\nHuman illness from infection with different avian influenza A subtype viruses also have been documented, including infections with low pathogenic and highly pathogenic viruses. A range of clinical illness has been reported for human infection with low pathogenic avian influenza viruses, including conjunctivitis with influenza A (H7N7) virus in the United Kingdom, lower respiratory tract disease and conjunctivitis with influenza A (H7N2) virus in the United Kingdom, and uncomplicated ILI with influenza A (H9N2) virus in Hong Kong and China (426)(427)(428)(429)(430)(431)(432). Two human cases of infection with low pathogenic influenza A (H7N2) were reported in the United States (429). Although human infections with highly pathogenic A (H7N7) virus infections typically have ILI or conjunctivitis, severe infections, including one fatal case in the Netherlands, have been reported (433,434). Conjunctivitis also has been reported because of human infection with highly pathogenic influenza A (H7N3) virus in Canada and low pathogenic A (H7N3) in the United Kingdom (426,434). In contrast, sporadic infections with highly pathogenic avian influenza A (H5N1) virus have caused severe illness in many countries, with an overall case-fatality proportion of >60% (421,435).\nSwine influenza A (H1N1), A (H1N2), and A (H3N2) viruses, including reassortant viruses, are endemic among pig populations in the United States (436). Two clusters of influenza A (H2N3) virus infections among pigs have been reported recently (437). Outbreaks among pigs normally occur in colder weather months (late fall and winter) and sometimes with the introduction of new pigs into susceptible herds. An estimated 30% of the pig population in the United States has serologic evidence of having had swine influenza A (H1N1) virus infection. Sporadic human infections with a variety of swine influenza A viruses occur in the United States, but the incidence of these human infections is unknown (438)(439)(440)(441)(442)(443). Persons infected with swine influenza A viruses typically report direct contact with ill pigs or places where pigs have been present (e.g., agricultural fairs or farms), and have symptoms that are clinically indistinguishable from infection with other respiratory viruses (440,441,444,445). Clinicians should consider swine influenza A virus infection in the differential diagnosis of patients with ILI who have had recent contact with pigs. The sporadic cases identified in recent years have not resulted in sustained human-to-human transmission of swine influenza A viruses or community outbreaks (368,445). Although immunity to swine influenza A viruses appears to be low (<2%) in the overall human population, 10%-20% of persons exposed occupationally to pigs (e.g., pig farmers or pig veterinarians) have been documented in certain studies to have antibody evidence of prior swine influenza A (H1N1) virus infection (438,446).\nIn April 2009, a novel influenza A (H1N1) virus similar to influenza viruses previously identified in swine was determined to the cause of an influenza-like respiratory illness among humans that spread across North America and throughout most of the world by May 2009 (9,447). The epidemiology of influenza caused by this novel influenza virus is still being studied, and whether this virus will achieve long-term circulation among humans or even replace one of the other seasonal influenza viruses as the cause of annual epidemics is unknown.\nCurrent seasonal influenza vaccines are not expected to provide protection against human infection with avian influenza A viruses, including influenza A (H5N1) viruses, or to provide protection against currently circulating swine influenza A or the novel influenza A (H1N1) viruses (318,448). However, reducing seasonal influenza risk through influenza vaccination of persons who might be exposed to nonhuman influenza viruses (e.g., H5N1 virus) might reduce the theoretical risk for recombination of influenza A viruses of animal origin and human influenza A viruses by preventing seasonal influenza A virus infection within a human host.\nCDC has recommended that persons who are charged with responding to avian influenza outbreaks among poultry receive seasonal influenza vaccination (448,449). As part of preparedness activities, the Occupational Safety and Health Administration (OSHA) has issued an advisory notice regarding poultry worker safety that is intended for implementation in the event of a suspected or confirmed avian influenza outbreak at a poultry facility in the United States. OSHA guidelines recommend that poultry workers in an involved facility receive vaccination against seasonal influenza; OSHA also has recommended that HCP involved in the care of patients with documented or suspected avian influenza should be vaccinated with the most recent seasonal human influenza vaccine to reduce the risk for co-infection with human influenza A viruses (449).\n# Recommendations for Using Antiviral Agents for Seasonal Influenza\nAnnual vaccination is the primary strategy for preventing complications of influenza virus infections. Antiviral medications with activity against influenza viruses are useful adjuncts in the prevention of influenza, and effective when used early in the course of illness for treatment. Four influenza antiviral agents are licensed in the United States: amantadine, rimantadine, zanamivir, and oseltamivir.\nDuring the 2007-08 influenza season, influenza A (H1N1) viruses with a mutation that confers resistance to oseltamivir became more common in the United States and other countries (450)(451)(452). As of July 2009, in the United States, approximately 99% of human influenza A (H1N1) viruses tested, and none of the influenza A (H3N2) or influenza B viruses tested have been resistant to oseltamivir. As of July 2, 2009, with few exceptions, novel influenza A (H1N1) viruses that began circulating in April 2009 remained sensitive to oseltamivir (453). Oseltamivir resistance among circulating seasonal influenza A (H1N1) virus strains presents challenges for the selection of antiviral medications for treatment and chemoprophylaxis of influenza, and provides additional reasons for clinicians to test patients for influenza virus infection and to consult surveillance data when evaluating persons with acute respiratory illnesses during influenza season. CDC has published interim guidelines to provide options for treatment or chemoprophylaxis of influenza in the United States if oseltamivir-resistant seasonal influenza A (H1N1) viruses are circulating widely in a community or if the prevalence of oseltamivir-resistant influenza A (H1N1) viruses is uncertain (8). Updated guidance on antiviral use will be available from ACIP before the start of the 2009-10 influenza season. This guidance will include a summary of antiviral resistance data from the 2008-09 influenza season, and will be published separately from the vaccination recommendations. Until the ACIP recommendations for use of antivirals against influenza are published, CDC's previously published recommendations for use of influenza antiviral medications should be consulted for guidance on antiviral use (8). New guidance on clinical management of influenza, including use of antivirals, also is available from the Infectious Diseases Society of America (454).\n# Sources of Information Regarding Influenza and its Surveillance\nInformation regarding influenza surveillance, prevention, detection, and control is available at http://www.cdc.gov/flu. During October-May, surveillance information is updated weekly. In addition, periodic updates regarding influenza are published in MMWR (http://www.cdc.gov/mmwr). Additional information regarding influenza vaccine can be obtained by calling 1-800-CDC-INFO (1-800-232-4636). State and local health departments should be consulted about availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, reporting of influenza outbreaks and influenza-related pediatric deaths, and advice concerning outbreak control.\n# Vaccine Adverse Event Reporting System (VAERS)\nAdverse events after influenza vaccination should be reported promptly to VAERS at http://vaers.hhs.gov, even if the reporter is unsure whether vaccine caused the event. Clinically significant adverse events that follow vaccination should be reported to VAERS at http://www.vaers.hhs.gov. Reports may be filed securely online or by telephone at 1-800-822-7967 to request reporting forms or other assistance.\n# national Vaccine Injury Compensation Program\nThe National Vaccine Injury Compensation Program (VICP), established by the National Childhood Vaccine Injury Act of 1986, as amended, provides a mechanism through which compensation can be paid on behalf of a person determined to have been injured or to have died as a result of receiving a vaccine covered by VICP. The Vaccine Injury Table lists the vaccines covered by VICP and the injuries and conditions (including death) for which compensation might be paid. If the injury or condition is not on the Table, or does not occur within the specified time period on the Table, persons must prove that the vaccine caused the injury or condition.\nFor a person to be eligible for compensation, the general filing deadlines for injuries require claims to be filed within 3 years after the first symptom of the vaccine injury; for a death, claims must be filed within 2 years of the vaccine-related death and not more than 4 years after the start of the first symptom of the vaccine-related injury from which the death occurred. When a new vaccine is covered by VICP or when a new injury/ condition is added to the Table, claims that do not meet the general filing deadlines must be filed within 2 years from the date the vaccine or injury/condition is added to the Table for injuries or deaths that occurred up to 8 years before the Table change. Persons of all ages who receive a VICP-covered vaccine might be eligible to file a claim. Both the intranasal (LAIV) and injectable (TIV) trivalent influenza vaccines are covered under VICP. Additional information about VICP is available at http//www.hrsa.gov/vaccinecompensation or by calling 1-800-338-2382.\n# Additional Information Regarding Influenza Virus Infection Control Among Specific Populations\nEach year, ACIP provides general, annually updated information regarding control and prevention of influenza. Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised persons, HCP, hospital patients, pregnant women, children, and travelers) also are available in the following publications: CDC. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":274,"cells":{"id":{"kind":"string","value":"513f1be5e7056f2af22339a8a068ae820c67bd5b"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"CDC convened a workshop in Atlanta on March 26-28, 1991, to discuss chlamydia prevention. The following persons participated in the workshop and provided expert technical and scientific review:# INTRODUCTION\nChlamydia trachomatis infections are common in sexually active adolescents and young adults in the United States (CDC, unpublished review ). More than 4 million chlamydial infections occur annually (2,3 ). Infection by this organism is insidioussymptoms are absent or minor among most infected women and many men. This large group of asymptomatic and infectious persons sustains transmission within a community. In addition, these persons are at risk for acute illness and serious longterm sequelae. The direct and indirect costs of chlamydial illness exceed $2.4 billion annually (2-4 )*.\nUntil recently, chlamydia prevention and patient care were impeded by the lack of suitable laboratory tests for screening and diagnosis. Such tests are now available. Through education, screening, partner referral, and proper patient care, public health workers and health-care practitioners can combine efforts to decrease the morbidity and costs resulting from this infection.\n\n# Prevalence of Chlamydial Infection\nAdolescents and young adults are at substantial risk of becoming infected with chlamydia. Unrecognized infection is highly prevalent in this group (CDC, unpublished review ).\nIn the United States, published studies of sexually active females screened during visits to health-care providers indicate that age is the sociodemographic factor most strongly associated with chlamydial infection. Prevalence has been highest (>10%) among sexually active, adolescent females (CDC, unpublished review ). The prevalence of chlamydial infection also has been higher among those patients who live in inner cities, have a lower socioeconomic status, or are black (5)(6)(7)(8)(9)(10)(11). Although prevalences have been higher in these subgroups, with few exceptions prevalences are ≥5% regardless of region of the country, urban/rural location of provider, or race/ethnicity (CDC, unpublished review ).\nFewer screening studies have been reported for men, but prevalences have been >5% among young men seeking health care for reasons other than genitourinary tract problems. Published reports of these studies from North America and Europe have included male high school students (12 ), military personnel (13,14 ), semen donors (15,16 ), adolescents in detention centers (17)(18)(19)(20), and teens attending adolescent clinics (17,20 ), adolescents attending university health centers (20,21 ), and chemical dependency units (22 ).\n\n# Clinical Spectrum of Chlamydial Infection Among Nonpregnant Women\nPelvic inflammatory disease (PID) accounts for most of the serious acute illness, morbidity, and economic cost resulting from chlamydial infection. Treating women with acute, symptomatic PID is not a sufficient prevention strategy because treatment does not always prevent sequelae and because many women with tubal infection have symptoms too mild or too nonspecific for them to seek treatment.\nA woman's exposure to chlamydia is usually a result of sexual intercourse. The site of initial infection is most often the cervix; the urethra and the rectum may also be infected (23)(24)(25)(26)(27)(28). Chlamydia causes symptoms in a minority of infected women (9,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). When symptoms occur, they include vaginal discharge and dysuria (9,23,(25)(26)(27)(29)(30)(31)(32)(33)(35)(36)(37)(38). The ascension of lower, genitourinary tract infection to the endometrium and fallopian tubes may cause lower abdominal pain and menstrual abnormalities. Untreated infections among women often persist for months (7,34,(39)(40)(41). During this period, complications may develop, and many of these women transmit their infection to others.\nThe proportion of women with chlamydial infection who develop infection of the upper reproductive tract (endometritis, salpingitis, and pelvic peritonitis) is uncertain; however, an estimated 8% of women with chlamydia also had overt salpingitis (42). A second study of women with dual gonococcal and chlamydial infections, but who were treated only for gonorrhea, revealed that 30% developed salpingitis during follow-up (43 ). Chlamydia, alone or with other microorganisms, has been isolated from 5% to 50% of women seeking care for symptoms of PID (CDC, unpublished review). Symptomatic PID prompts 2.5 million outpatient visits to physicians annually (44,45 ). More than 275,000 women are hospitalized and more than 100,000 surgical procedures are performed yearly because of PID (45 ). Both the diagnosis and the treatment of PID are unsatisfactory: approximately 17% of women treated for PID will be infertile; an equal proportion will experience chronic pelvic pain as a result of infection (46,47 ); and 10% who do conceive will have an ectopic pregnancy (48 ).\nThe importance of undetected, untreated fallopian tube infections as a cause of infertility and ectopic pregnancy is clear. In two studies of chlamydia and PID in infertile women, PID was the cause of the infertility in half of the women, and anti-chlamydial antibody was strongly associated with a tubal etiology for infertility (49,50 ). Of concern in these studies was the small proportion of women with tubalfactor infertility who reported a past history of salpingitis. Other studies indicate that many of these women may have had salpingitis, but were not treated because symptoms were absent or nonspecific (49,(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Unrecognized PID also may be a contributor to the occurrence of ectopic pregnancies (60,61 ). Because chlamydial infections are not usually associated with overt symptoms, prevention of infection is the most effective means of preventing sequelae.\nPregnant women with chlamydial infection are at risk for postpartum PID. Postpartum and perinatal disease are preventable by treating infected pregnant women and their sex partners. Endometritis, and possibly salpingitis, developed among 10%-28% of pregnant women with untreated chlamydial infection who underwent induced abortions (27,(62)(63)(64). Similarly, endometritis may develop during the late postpartum period among 19%-34% of infected pregnant women who deliver vaginally and atterm (65,66 ).\n\n# Clinical Spectrum of Chlamydial Infection Among Infants\nNearly two-thirds of the infants born vaginally to mothers with chlamydial infection become infected during delivery (67,68 ). Even after ophthalmia prophylaxis with silver nitrate or antibiotic ointment, 15%-25% of infants exposed to chlamydia developed chlamydia conjunctivitis, and 3%-16% developed chlamydia pneumonia (41,(68)(69)(70)(71)(72)(73). C. trachomatis is the most common cause of neonatal conjunctivitis (72,(74)(75)(76)(77)(78) and is one of the most common causes of pneumonia during the first few months of life (79)(80)(81)(82)(83)(84)(85). Infants with chlamydia pneumonia are at increased risk for abnormal pulmonary function tests later in childhood (86)(87)(88).\n\n# Clinical Spectrum of Chlamydial Infection Among Men\nAlthough urethritis is the most common illness resulting from chlamydia, chlamydial infections among men rarely result in sequelae. However, asymptomatic infected men may unknowingly infect their sex partner(s) before seeking treatment.\nChlamydial infections among heterosexual men are usually urethral. Symptoms are similar to gonorrhea (e.g., urethral discharge or dysuria). In contrast to gonorrheal urethritis, chlamydia symptoms are often absent or mild (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)89 ). Therefore, the number of heterosexual men with asymptomatic chlamydial infections is larger than the number of such men with gonorrhea.\nChlamydial infections of the lower genitourinary tract account for 30%-40% of the 4-6 million physician visits for nongonococcal urethritis (NGU), and 50% of the 158,000 outpatient visits and 7,000 hospitalizations for epididymitis among adolescent and young adult males (2,3,90,91 ). Chlamydial infections among men readily respond to treatment with antibiotics. Most of the morbidity and economic costs of chlamydial infections among heterosexual men result from infection of female sex partners who develop sequelae (3 ).\nThe rectum is a common site of initial chlamydial infection for men who engage in receptive anal intercourse. Rectal infections are generally asymptomatic, but may cause symptoms characteristic of proctitis (e.g., rectal discharge, pain during defecation) or proctocolitis (92)(93)(94)(95)(96).\n\n# Other Chlamydial Illnesses\nAmong adolescents and young adults of both sexes, chlamydial infection is an important part of the differential diagnosis for other, less common, illnesses. Chlamydia salpingitis may progress to perihepatitis-the Fitz-Hugh-Curtis syndrome (97 ). Although chlamydia is an uncommon cause of cystitis symptoms among female patients, chlamydia has been an important cause of such symptoms in some groups of young women who have pyuria, but sterile urine cultures (acute dysuria-pyuria syndrome or urethral syndrome) (5,38,98 ).\nAnother important, but uncommon complication of urogenital chlamydial infection is Reiter's syndrome (reactive arthritis, conjunctivitis, and urethritis), which occurs primarily among men. Chlamydia is receiving greater emphasis in the differential diagnosis of arthritis in young women because of the availability of diagnostic tests for chlamydia. Chlamydial infection is more likely to be missed among women than among men who have arthritis because of the less obvious role of urethritis.\nChlamydia is also part of the differential diagnosis of chronic conjunctivitis among adolescents and young adults (99)(100)(101)(102). Ocular or ophthalmic infections may result from exposure to infectious genital secretions during oral-genital sexual contact, or by autoinoculation. Although chlamydia can be detected in the pharynx after inoculation from oral-genital exposure (103-111 ), chlamydia has not been established as a cause of pharyngitis (103,104,(110)(111)(112)(113)(114).\n\n# PREVENTION STRATEGIES\nThe principal goal of chlamydia prevention strategies is to prevent both overt and silent chlamydia salpingitis and its sequelae. Other goals include the prevention of perinatal and postpartum infection and other adverse consequences of chlamydial infection.\n\n# General Approach\nThe prevention of chlamydia salpingitis, pregnancy-related complications, and other chlamydial illnesses requires that chlamydia prevention programs include both primary and secondary prevention strategies.\n\n# Primary Prevention Strategies\nPrimary prevention strategies are efforts to prevent chlamydial infection. Primary prevention of chlamydia can be accomplished in two general ways.\n- Behavioral changes that reduce the risk of acquiring or transmitting infection should be promoted (e.g., delaying age at first intercourse, decreasing the number of sex partners, partner selection, and the use of barrier contraception ). Efforts to effect behavioral changes are not specific to chlamydia prevention but are also critical components in preventing sexual transmission of the human immunodeficiency virus (HIV) and other sexually transmitted diseases (STDs) (45,(115)(116)(117).\n- Identify and treat persons with genital chlamydial infection before they infect their sex partners, and for pregnant women before they infect their babies. Efforts to detect chlamydial infection are essential to chlamydia prevention. Identifying and treating chlamydial infections require active screening and referral of sex partners of infected persons, since infections among women and men are usually asymptomatic.\n\n# Secondary Prevention Strategies\nSecondary prevention strategies are efforts to prevent complications among persons infected with chlamydia. The most important complication to be prevented is salpingitis and its potential sequelae (i.e., ectopic pregnancy, tubal infertility, and chronic pelvic pain). Secondary prevention of chlamydia salpingitis can be accomplished by a) screening women to identify and treat asymptomatic chlamydial infection; b) treating the female partners of men with infection; c) recognizing clinical conditions such as mucopurulent cervicitis (MPC) and the urethral syndrome, and then applying or using appropriate chlamydia diagnostic tests and treatment, as appropriate.\n\n# Target Population\nChlamydial infection is especially prevalent among adolescents. Furthermore, PID occurs more commonly after chlamydial infection among adolescent females than among older women (42 ). Therefore, chlamydia prevention efforts should be directed toward young women.\nAll sexually active adolescents and young adults are at high risk for chlamydia; the infection is broadly distributed geographically and socioeconomically. Therefore, chlamydia prevention programs should target all sexually active adolescents and young adults. All private and public health-care providers should be involved in these prevention efforts.\n\n# Specific Strategies\nSpecific strategies for the prevention of chlamydia are grouped into two categories. Those categories are: a) community-based strategies, and b) health-care provider strategies.\n\n# Community-Based Strategies\nSince the prevalence of chlamydia is consistently high among adolescents and young adults regardless of socioeconomic status, race, or geographic location, prevention efforts should be implemented communitywide.\nPublic Awareness. Community-based strategies should increase public awareness of chlamydia, its consequences, and the availability and importance of diagnosis and treatment. Groups at high risk for chlamydial infection and the persons who educate and care for them (e.g., parents, teachers, and health-care providers) must be informed about the high rate of genital chlamydial infection and its sequelae among sexually active adolescents and young adults.\nHIV/STD Risk Reduction Programs. Programs designed to reduce the risk of sexual transmission of HIV and other STDs by means of behavioral changes should emphasize the especially high risk of chlamydial infection. In addition, chlamydial infection may be a sentinel for unsafe sexual practices. Concern about chlamydia may provide additional motivation for persons to delay initiation of sexual activity, limit the number of sex partners, avoid sex partners at increased risk for STDs, and use condoms.\nSchools. Because of their access to adolescents, educators have an important role to play in chlamydia prevention programs. Chlamydia-specific material should be integrated into educational curricula that address HIV and other STDs. In addition, school programs should assist students in developing the social and behavioral skills needed to avoid chlamydial infection, HIV, and other STDs.\nAlthough most school health education curricula address HIV, fewer discuss other STDs (including chlamydia). Information that should be provided through school health education programs are listed below:\n- Rates of chlamydial infection among adolescents - Adverse consequences of chlamydia (e.g., PID and infertility)\n- Symptoms and signs of chlamydial infection (and other STDs)\n- Asymptomatic infection - Treatment for sex partners\n- Where and how to obtain health care (including locations, telephone numbers , costs, and issues of confidentiality) Some schools may offer more than classroom instruction (e.g., access to health care for infected persons and screening programs to identify asymptomatic chlamydial infection). Personnel in school-based clinics that perform pelvic examinations should use the opportunity to test for chlamydial infection. However, tests also are needed to identify asymptomatic males (e.g., by screening urine collected during sports physical examinations or other health-screening programs). The leukocyte esterase test (LET) of urine is one possible method for testing males, but the accuracy of the test requires additional evaluation (118 ). Such approaches to identifying and treating young men with asymptomatic chlamydial infection may prove important since these persons may account for most of the transmission of chlamydia to young women (see Laboratory Testing and Patient Care: An Expanded Role for the Use of Chlamydia Tests).\nOut-of-school Adolescents. The prevalence of chlamydia may be even greater among adolescents who have dropped out of school. Therefore, organizations serving these adolescents (e.g., Job Corps, vocational training centers, detention centers, community-based recreational programs) should offer health care that addresses chlamydial infection as part of STD/HIV risk reduction programs.\n\n# Health-Care Provider Strategies\nReducing the high prevalence of chlamydial infection requires that health-care providers be aware of the high prevalence of chlamydia and recognize chlamydial illness, screen asymptomatic patients, arrange for the treatment of sex partners, and counsel all sexually active patients about the risks of STD infections. Medical providers should be trained to recognize and manage the following conditions that may be caused by chlamydia: MPC, PID, urethral syndrome (women), and urethritis and epididymitis (men).\nScreening. The screening of women for chlamydial infection is a critical component in a chlamydia prevention program since many women are asymptomatic, and the infection may persist for extended periods of time. Many women of reproductive age undergo pelvic examination during visits for routine health care or because of illness. During these examinations, specimens can be obtained for chlamydia screening tests.\nFemale patients of adolescent-care providers, women undergoing induced abortion, women attending STD clinics, and women in detention facilities should be screened for chlamydial infection. Screening of these women is important because a) many are adolescents or young adults, b) they are at high risk for salpingitis, and c) they or their partners are likely to transmit infection.\nChlamydia screening at family planning and prenatal care clinics is particularly cost-effective because of the large number of sexually active young women who undergo pelvic examinations.\nProviders such as family physicians, internists, obstetricians-gynecologists, and pediatricians who provide care for sexually active young women also should implement chlamydia screening programs-although a lower volume of such patients may increase the cost of testing. The following criteria can help identify women who should be tested for chlamydia:\n- Women with MPC - Sexually active women 24 years of age who meet both criteria-inconsistent use of barrier contraception, or new or more than one sex partner during the last 3 months.\nPatient selection criteria should be evaluated periodically. Although the incidence of chlamydial infection among all women previously tested for chlamydia is unknown, the incidence of chlamydial infection among previously infected adolescent females has been as high as 39% (118 ). Because of the high incidence of chlamydial infection among sexually active adolescent females, recommendations for the frequency of testing are listed below:\n- Women <20 years of age should be tested when undergoing a pelvic examination, unless sexual activity since the last test for chlamydia has been limited to a single, mutually monogamous partner.\n- All other women who meet the suggested screening criteria (listed above) should be tested for chlamydia annually.\nAlthough young men infrequently seek routine health care, medical providers should use such opportunities to evaluate them for asymptomatic chlamydial infection, possibly by means of the LET (119 ) (see Laboratory Testing and Patient Care: An Expanded Role for the Use of Chlamydia Tests).\nTreatment of Sex Partners. Treatment of sex partners of infected persons is an important strategy for reaching large numbers of men and women with asymptomatic chlamydial infection. Also, if partners are not treated, reinfection may occur. In addition, treating the male partners of infected women is critical since this is the principal way to eliminate asymptomatic infection among males. If chlamydia screening is widely implemented, the number of infected women identified may exceed the capacity of some public health systems to notify, evaluate, and treat partners. Therefore, health department personnel should assist health-care providers in developing cooperative approaches to refer partners for treatment. Where possible, health-care providers who treat female patients for chlamydia should offer examination and treatment services for the patients' male sex partner(s), or should arrange the appropriate referral of such partners.\n\n# Risk Reduction\nCounseling. In addition to screening, treatment, and referral of sex partners(s) of persons with chlamydial infection, health-care providers should:\n- Educate sexually active patients regarding HIV and other STDs,\n- Assess the patients' risk factors for infection,\n- Offer at-risk patients advice about behavior changes to reduce the risk of infection,\n- Encourage the use of condoms.\nPreventing Chlamydial Infection During Pregnancy. To prevent maternal postnatal complications and chlamydial infection among infants, pregnant women should be screened for chlamydia during the third trimester, so that treatment, if needed, will be completed before delivery (see Primary Prevention Strategies). The screening criteria already discussed can identify those at higher risk for infection. Screening during the first trimester prevents transmission of the infection and adverse effects of chlamydia during the pregnancy. However, the evidence for adverse effects during pregnancy is minimal. If screening is performed only during the first trimester, a longer period exists for infection before delivery.\nInfants with chlamydial infections respond readily to treatment; morbidity can be limited by the early diagnosis and systemtic treatment of infants who have conjunctivitis and pneumonia caused by chlamydial infection (secondary prevention strategies). Further, the mothers of infants diagnosed with chlamydial infection and the sex partner(s) of those mothers should be evaluated and treated.\n\n# LABORATORY TESTING\nDiagnostic test manufacturers have introduced a variety of nonculture tests for chlamydia, including enzyme immunoassays (EIAs) to detect chlamydia antigens, fluorescein-conjugated monoclonal antibodies for the direct visualization of chlamydia elementary bodies on smears, nucleic acid hybridization tests, and rapid (stat) tests. Because nonculture tests do not require strict handling of specimens, they are easier to perform and less expensive than culture tests; consequently the numbers of laboratories and health-care providers offering chlamydia testing have increased. The expanded use of nonculture tests is a cornerstone of chlamydia prevention strategies.\nAlthough nonculture tests have advantages that make them more suitable than cell culture tests for widespread screening programs, nonculture tests also have limitations. In particular, nonculture tests are less specific than culture tests and may produce false-positive results. All positive nonculture results should be interpreted as presumptive infection until verified by culture or other nonculture test. The decision to treat and perform additional tests should be based on the specific clinical situation.\nThe test methodologies discussed in these recommendations are for the detection of Chlamydia trachomatis -not other chlamydia species (e.g., C. psittaci and C. pneumoniae ). A number of commercial products for the detection of C. trachomatis are available; however, most information relating to the performance of most of these products is the manufacturers' data. When possible, health-care providers and laboratory staff should compare a potential nonculture test's performance with that of an appropriate standard in their own laboratory.\n\n# Specimens for Screening\nThe proper collection and handling of specimens are important in all the methods used to identify chlamydia. Even diagnostic tests with the highest performance ratings cannot produce accurate results when specimens submitted to the laboratory are improperly collected. Clinicians require training and periodic assessment to maintain proper technique.\nBecause chlamydia are obligate intracellular organisms that infect the columnar epithelium, the objective of specimen collection procedures is to obtain columnar epithelial cells from the endocervix or the urethra. The following recommendations for specimen collection apply to all screening tests.\n\n# Preferred Anatomic Sites\nThe endocervix is the preferred anatomic site to collect screening specimens from women. When culture isolation is to be used, processing an additional specimen from the urethra may increase sensitivity by 23% (120 ). Placing the two specimens in the same transport container is acceptable. For nonculture tests, the usefulness of a second specimen from the urethra has not been determined.\nThe urethra is the preferred site for collecting screening specimens from men.\n\n# Collecting Specimens\nThe following guidelines are recommended for obtaining endocervical specimens:\n- Obtain specimens for chlamydia tests after obtaining specimens for gramstained smear, Neisseria gonorrhoeae culture, or Papanicolaou smear.\n- Before obtaining a specimen for a chlamydia test, use a sponge or large swab to remove all secretions and discharge from the cervical os.\n- For nonculture chlamydia tests, use the swab supplied or specified by the manufacturer of the test.\n- Insert the appropriate swab or endocervical brush 1-2 cm into the endocervical canal (i.e., past the squamocolumnar junction). Rotate the swab against the wall of the endocervical canal several times for 10-30 seconds. Withdraw the swab without touching any vaginal surfaces and place it in the appropriate transport medium (culture, EIA, or deoxyribonucleic acid probe testing) or prepare a slide (direct fluorescent antibody testing).\nThe following guidelines are recommended for obtaining urethral specimens:\n- Delay obtaining specimens until 2 hours after the patient has voided.\n- Obtain specimens for chlamydia tests after obtaining specimens for gram-stain smear or N. gonorrhoeae culture.\n- For nonculture chlamydia tests, use the swab supplied or specified by the manufacturer.\n- Gently insert the urogenital swab into the urethra (females: 1-2 cm, males: 2-4 cm). Rotate the swab in one direction for at least one revolution for 5 seconds. Withdraw the swab and place it in the appropriate transport medium (culture, EIA, or DNA probe testing) or use the swab to prepare a slide for DFA testing.\n\n# Quality Assurance of Specimen Collection\nWithout specimen quality assurance, ≥10% of specimens are likely to be unsatisfactory because they contain secretions or exudate, but lack urethral or endocervical columnar cells (6,(121)(122). Periodic cytologic evaluation of specimen quality is recommended when using non-DFA tests to ensure continued proper specimen collection.\n\n# Cell Culture\nCompared with other diagnostic tests for C. trachomatis, a major advantage of cell culture isolation is a specificity that approaches 100%. In cell culture, organisms from each of the three chlamydia species (C. trachomatis, C. pneumoniae, C. psittaci ) grow and produce intracytoplasmic inclusions. The direct visualization of these inclusions contributes to the specificity of cell culture in identifying chlamydia. The preferred method for identifying inclusions is to stain the infected cells with a species-specific, monoclonal fluorescein-labeled antibody (FA) for C. trachomatis. Alternative antibodies used to stain chlamydia inclusions that bind to chlamydia lipopolysaccharide (LPS) are NOT specific for C. trachomatis and also will stain C. psittaci and C. pneumoniae inclusions. In these recommendations, the use of C. trachomatis-specific, anti-major outer membrane protein (MOMP) antibody is the presumed method used for the detection of C. trachomatis isolated in cell culture.\nCulture sensitivity is approximately 70%-90% in experienced laboratories (123 ). Since culture amplifies small numbers of organisms, it is preferred for specimens in which low numbers of organisms are anticipated (e.g., asymptomatic infection). Culture also allows the organism to be preserved for additional studies, including the determination of immunotype (serovar) and antimicrobial susceptibilities.\nCell culture isolation has several disadvantages. First, the method is technically difficult and requires 3-7 days to obtain a result. Second, since only viable organisms are detected, special transport media must be used, and transportation and storage temperature requirements are stringent. Finally, some specimens contain contaminating microorganisms or substances that are toxic to the cell monolayers used for isolating chlamydia.\n\n# Indications for the Use of Cell Culture\nA high-quality culture system for chlamydia is the diagnostic method of choice and is essential for the diagnosis of chlamydia in all medical/legal situations.\nCulture serves as the standard for the quality assurance of nonculture tests and for the evaluation of new diagnostic methods. Culture is recommended for detection of chlamydia in specimens for which nonculture methods have not been developed, have not been adequately evaluated, or perform poorly. Culture is recommended for specimens from the following sites:\n- Urethral specimens (women and asymptomatic men).\n- Nasopharyngeal specimens (infants).\n- Rectal specimens (all patients, regardless of age).\n- Vaginal specimens (prepubertal girls).\n\n# Collecting Specimens for Cell Culture\nSwabs with plastic or wire shafts can be used to obtain cell cultures. Swab tips can be made of cotton, rayon, dacron, or calcium alginate. Swabs with wooden shafts should not be used because the wood may contain substances that are toxic to chlamydia. As part of routine quality control, samples of each lot of swabs that are used to collect specimens for chlamydia isolation should be screened for possible toxicity to chlamydia.\nThe substitution of an endocervical brush for a swab may increase the sensitivity of culture for endocervical specimens from nonpregnant women (124 ). However, the use of the endocervical brush may induce bleeding. Although such bleeding does not interfere with the isolation of C. trachomatis, patients should be advised about possible spotting.\n\n# Transporting Cell Culture Specimens\nThe viability of chlamydia organisms must be maintained during transport to the laboratory. Consult with the laboratory regarding the selection of appropriate transport medium and procedures (125,126 ). Specific recommendations for transporting specimens are listed below:\n- Specimens for culture should be stored at 4 C and inoculated in cell culture as quickly as possible after collection. The elapsed time until inoculation should not exceed 24 hours. If specimens cannot be inoculated within 24 hours, the specimens should be maintained at -70 C or colder.\n- Specimens for culture should never be stored at -20 C or in \"frost-free\" freezers.\nThese conditions cause a decrease in chlamydia viability. - Only cell lines that have been checked for their ability to support chlamydial growth should be used.\n\n# Analyzing Cell Culture Specimens\n- The identification of C. trachomatis should be based on visualizing characteristic chlamydia inclusions using species-specific FA staining.\n- Laboratories should determine periodically whether multiple passages will increase sensitivity.\n\n# NOTE:\nThe specificity of culture is based on the identification of inclusions. The identification of chlamydia after culture by EIA, or any other method that does not identify characteristic intracytoplasmic inclusions, is NOT recommended.\n\n# Interpreting Cell Culture Results\nA positive cell culture and visualization of characteristic inclusions by species-specific monoclonal FA staining is required to diagnose a chlamydial infection. With proper technique, the specificity of cell culture isolation of C. trachomatis is nearly 100%.\nA negative chlamydia culture does not rule out the presence of a chlamydial infection. The sensitivity of culture is approximately 70%-90% when recommended laboratory and specimen collection techniques are performed.\n\n# Quality Assurance of Cell Culture Specimen Collection\nThe isolation and detection of chlamydia in cell culture are technically demanding.\nThe training of clinicians and laboratorians, along with quality assurance of laboratory performance and specimen collection, is critical to performing cell culture adequately. Specific recommendations to follow for cell culture specimens are listed below:\n- To monitor the sensitivity and specificity of the cell culture system, laboratories should include known samples to analyze appropriate positive and negative controls when clinical specimens are cultured.\n- Periodically (i.e., monthly or bimonthly), positive controls should be submitted from patient settings to verify the effectiveness of transport systems.\n- Reference laboratories should provide a quality assurance system for monitoring culture performance and specimen adequacy. These laboratories also should provide assistance in the evaluation of unexpected or discrepant results.\n\n# Nonculture Chlamydia Tests\nMore aggressive prevention strategies are now possible with the availability of nonculture test methods for the detection of chlamydia. Published evaluations of the performance of nonculture chlamydia tests are based primarily on the MicroTrak ® DFA (Syva) test and the Chlamydiazyme ® EIA (Abbott) test. Additional tests have been approved by the FDA for the detection of chlamydial infection. Published information on these other tests is increasing rapidly, but is still limited. The recommended uses of nonculture chlamydia tests for presumptive diagnosis, with and without additional testing, to verify a positive result are summarized in these recommendations (Table 1).\n\n# Description of Nonculture Tests\nNonculture chlamydia tests include several categories that differ in format and execution.\nDirect Fluorescent Antibody (DFA) tests. Depending on the commercial product used, the antigen that is detected by the antibody in the DFA procedure is either the MOMP or LPS. Specimen material is obtained with a swab or endocervical brush which is then rolled over the specimen \"well\" of a slide. After the slide has dried and the fixative has been applied, the slide can be stored or shipped at ambient temperature. The slide should be processed by the laboratory within 7 days after the specimen has been obtained. Staining consists of covering the smear with fluorescent monoclonal antibody that binds to chlamydia elementary bodies. Stained elementary bodies are then identified by fluorescence microscopy. Total processing time is 30-40 minutes. Only C. trachomatis organisms will stain with the anti-MOMP antibodies used in commercial kits. Cross-reactions can occur between the anti-LPS antibodies used in commercial kits and other bacterial species, as well as with C. pneumoniae and C. psittaci.\nEnzyme Immunoassay (EIA) Tests. EIA tests detect chlamydia LPS with a monoclonal or polyclonal antibody that has been labeled with an enzyme. The enzyme converts a colorless substrate into a colored product. The intensity of the color is measured with a spectrophotometer, which provides a numerical readout. The specimens for EIA are collected by using specimen collection kits supplied by the manufacturer. These kits include swabs, transport tubes, and instructions (to obtain optimum performance of the test kit, manufacturer's instructions should be followed). Specimens can be stored and transported at ambient temperature and should be processed within the time indicated by the manufacturer. Total processing time is 3-4 hours.\nOne disadvantage of the EIA methods that detect LPS is that cross-reaction of the antibody with other microorganisms leads to false-positive results (125,(127)(128)(129). In addition, the LPS-based EIA tests detect all three chlamydia species and, therefore, are not specific for C. trachomatis. Some manufacturers have developed blocking assays that are used to verify positive EIA test results. The test is repeated on initially positive specimens with the addition of a monoclonal antibody specific for chlamydia LPS. The monoclonal antibody competitively inhibits chlamydia-specific binding by the enzyme-labeled antibody; a negative result with the blocking antibody is interpreted as verification of the initial positive test result.\nNucleic Acid Hybridization Tests (DNA Probe). Nucleic acid hybridization methods can be used for the diagnosis of chlamydial infections. In the hybridization assay, a chemiluminescent DNA probe that is complimentary to a specific sequence of C. trachomatis ribosomal RNA (rRNA) is allowed to hybridize to any chlamydia rRNA that is present in the specimen. The resulting DNA:rRNA hybrids are adsorbed to magnetic particles and are then detected by using a luminometer that provides a numerical readout. The test kit includes a specimen collection swab and transport medium. Specimens should be maintained at temperatures of 2-25 C during transport and storage. The manufacturer suggests that assays be performed within 7 days after collection; otherwise the specimens should be stored at -20 C or colder. Total processing time is 2-3 hours.\nThe technical requirements and the necessary expertise to perform nucleic acid hybridization tests are similar to those of the EIA methods. The probe assay is specific for C. trachomatis; cross-reactions with organisms other than C. trachomatis, including C. pneumoniae and C. psittaci, have not been reported. A competitive probe assay has been developed to provide a means of assuring high specificity. The usefulness of the competitive assay is being evaluated in clinical trials and has not been approved for in vitro use by the Food and Drug Administration (FDA).\nRapid Chlamydia Tests. Chlamydia tests have been developed that can be performed within 30 minutes, do not require expensive or sophisticated equipment, and are packaged as single units. The results are read qualitatively. These rapid or stat tests can offer advantages in physicians' offices, small clinics and hospitals, and settings in which results are needed immediately (e.g., when making decisions about additional testing or treatment while the patient is still present). Like EIAs, these tests use antibodies against LPS that detect all three chlamydia species, but are subject to the same potential for false-positive results due to cross-reactions with other microorganisms. The performance characteristics of these tests have not been extensively evaluated. In addition, since rapid chlamydia tests are designed to be performed by nonlaboratory personnel, quality assurance is essential. Personnel requirements, quality assurance, and quality control requirements relating to the use of these and other tests are published in the Clinical Laboratory Improvement Amendments (CLIA) (130 ) and are governed by the test categorization compilation.\n\n# Leukocyte Esterase Test (LET).\nThe LET is a dipstick test that is applied to urine specimens to screen for urinary tract infection. The LET detects enzymes that are produced by polymorphonuclear leukocytes. These enzymes hydrolyze an indoxylcarbonic acid ester on the dipstick to indoxyl, which reacts with an indicator in the strip to produce a purple color. The procedure requires <2 minutes to perform after the specimen is collected.\n\n# Accuracy of Nonculture Tests and Recommendations for Use\nFor small-volume testing, DFA may be preferred because the quality of the specimen can be assessed. Automated tests are probably preferable for high-volume testing, but a quality control system is essential for monitoring the adequacy of specimens.\nPublished evaluations of the performance of nonculture chlamydia tests are based primarily on the MicroTrak ® DFA (Syva) test and the Chlamydiazyme ® EIA (Abbott) test. Additional tests have been approved by the FDA for the detection of chlamydial infection. Published information on these other tests is increasing, but is still limited.\n\n# Cervical Specimens from Women (Sensitivity).\nThe performance characteristics of Mi-croTrak ® DFA and Chlamydiazyme ® nonculture chlamydia tests have been reported in published evaluations of women in high-prevalence (≥5%) patient populations. Sensitivities, using culture as a standard, have varied greatly but generally exceed 70% (CDC, unpublished review ). This variability in reported sensitivity is a result of differences in specimen collection technique, performance of the culture system used as a standard, and patient characteristics (e.g., age, MPC, and other factors such as prevalence of chlamydial infection, duration of infection, and previous exposure to chlamydia) (121,122,128,(131)(132)(133)(134)(135)(136). A sensitivity of at least 70% is adequate for screening, but not sufficient to exclude chlamydial infection (see Patient Care: An Expanded Role for the Use of Chlamydia Tests).\nEvaluations have been presented or published for the use of a number of tests for cervical specimens from women. Such tests include IDEIA ® (Dako Diagnostics), Pace 2 ® (Gen-Probe), MicroTrak ® EIA (Syva), and Clearview ® (Unipath) tests. Sensitivities reported for these tests are comparable to sensitivities reported for Chlamydiazyme ® and MicroTrak ® DFA. However, chlamydia diagnostics experts recommend additional evaluation of these tests. First, the true sensitivity of these tests may be less than that indicated in published reports. The number of evaluations published for any given test is small and the number of patients with chlamydial infections studied in most evaluations is also small. Therefore, sensitivities may prove to be lower (or higher) as more evaluations are reported. More evaluations need to be conducted by laboratories that have quality assurance programs for culture including, for example, exchange of specimens with other laboratories (proficiency testing). Evaluations that compare new tests directly with established tests would aid in determining the performance of new tests. Second, none of these tests have been adequately evaluated in low-prevalence patient populations. Diagnostics experts are concerned that differences in factors such as previous exposure to chlamydia and duration of infection may result in lower test sensitivities in low-prevalence populations (128 ). Third, although the reported performance of the Clearview ® rapid (stat) test approaches that of Chlamydiazyme ® and MicroTrak ® DFA, additional evaluations are needed to determine its performance when the test is used in an outpatient setting during the patient's visit. Too few evaluations have been reported for other chlamydia tests to assess their sensitivities (≤3 patient care-laboratory settings or 240 patients with chlamydia isolated by cell culture).\n\n# Specificity and Predictive Value\nPositive. The specificity of nonculture tests for cervical specimens has been high (97%-99%). However, clinicians should be aware that even with these high specificities, false positive results account for an important proportion of all positive test results among groups of patients with a low prevalence of chlamydial infection. The effect of false-positive tests in a population can be quantified by the predictive value positive (PVP). The PVP is the proportion of all persons who have a positive test result for a condition who actually have that condition. In chlamydia screening applications, the PVP is influenced primarily by the specificity of the test and the prevalence of chlamydia. For example, when a nonculture test with a specificity of 98% and a sensitivity of 80% is used to screen 1,000 patients from a high-risk patient population with a chlamydia prevalence of 15% (150 patients have an infection), the test produces 137 positive results: 120 patients are actually infected and 17 are not infected (false-positives). The PVP is 120/137=0.88. When this same test is used to screen 1,000 patients from a low-risk patient population with a chlamydia prevalence of only 2% (20 patients have an infection), 36 positive results are obtained: 16 patients are infected and 20 are not. The PVP is 16/36=0.44. In the low-risk patient population, fewer than half the patients with positive tests actually have chlamydial infection; the remainder are at risk of being incorrectly identified as having an STD unless the clinician takes other measures, such as arranging for verification when screening results are positive.\nSpecificities of the nonculture tests have been <99% in most published evaluations even when a third test was used to detect false-negative cultures. Contamination of cervical specimens with vaginal secretions is responsible for some false-positive tests when using Chlamydiazyme. The polyclonal anti-LPS antibody used in Chlamydiazyme crossreacts with LPS on other bacteria found in the vagina and urinary tract of these patients (121,122,125,127,128,137 ). The source of nonspecific fluorescence with MicroTrak ® DFA and of nonspecific signals with tests using monoclonal antibodies or genetic probes has not been determined. NOTE: Hereafter, a prevalence of <5% is considered to be \"low prevalence.\" At a 5% prevalence (specificity 99% and sensitivity 80%), the PVP would be 80%. Although defining low prevalence as <5% is arbitrary, the potential for 20% of positive test results to be falsely positive (in the absence of a second test for verification) supports the utility of this cutoff.\nVerifying Positive Screening Test Results. Clinicians should verify positive screening test results with a supplemental test if a false-positive test result is likely to have adverse medical, social, or psychological consequences (Table 1). Verification should probably be routine in low-prevalence patient populations, but might be selective in high-prevalence populations. Methods that are suitable for verifying positive nonculture tests for cervical specimens are recommended below:\n- Verify positive tests by culture, using fluorescein-conjugated C. trachomatisspecific antibody. Culture is the most sensitive and specific method for verification. However, verification with culture requires a second specimen that is collected either at the time the first specimen is collected or during a return visit. Because of the limited availability of culture testing and the requirement for a second specimen, culture should be used for verification only if very high specificity is required (e.g., medical/legal situations).\n- Perform a second nonculture test that identifies a C. trachomatis antigen or a nucleic acid sequence that is different from that identified by the screening test.\nTheoretically, detecting a second, highly specific antigen or nucleic acid sequence should provide adequate specificity for verification. However, this approach has had limited evaluation in field trials. A positive screening test may be verified by a second test using a second specimen that is collected either at the time the first specimen is collected or during a return visit. To avoid taking a second specimen, some EIA test manufacturers suggest using the excess specimen in the EIA transport medium for verification of positive EIA tests with a DFA test.\n- Use an unlabeled \"blocking\" antibody or \"competitive\" probe that verifies a positive test result by preventing attachment of the labeled antibody or probe that is used in the standard assay. These methods are theoretically less desirable because they identify the same molecules as those identified by the initial nonculture tests. However, the Chlamydiazyme ® blocking antibody test appears to produce adequate results (127,(138)(139)(140)(141)(142). These methods do not require collecting a second specimen.\nWith the exception of the Chlamydiazyme ® blocking antibody test, nonculture methods of verifying initial positive chlamydia test results have received insufficient evaluation. Since the sensitivity of tests used for verification of positive chlamydia tests is uncertain but <90%, failure to verify the initial positive test does not rule out chlamydial infection. Evaluation studies are needed to determine which of the above approaches is preferable in relation to sensitivity, specificity, and cost (see Clinician-Laboratory Protocols for Verifying Positive Tests).\nUrethral Specimens from Men. The use of the Chlamydiazyme ® EIA test and the Mi-croTrak ® DFA test for urethral specimens from males with symptomatic urethritis has been evaluated in published studies. Reported sensitivities of the Chlamydiazyme ® EIA and MicroTrak ® DFA tests among men with chlamydial urethritis have been highly variable but usually exceed 70%. These sensitivities are sufficiently high to recommend using these tests to detect chlamydial infections among men with symptomatic urethritis. In such men, detection of chlamydial infection may be useful in promoting examination and treatment of sex partners and managing the patient's infection. Neither nonculture tests nor tissue culture isolation are sufficiently sensitive to rule out chlamydial infection based solely on a negative test result.\nPositive Chlamydiazyme ® and MicroTrak ® DFA tests have been highly predictive of chlamydial infection among adolescent and young adult men with symptomatic urethritis. The reported specificities of the Chlamydiazyme ® EIA and MicroTrak ® DFA tests for urethral specimens from men with symptomatic urethritis have been sufficiently high (97%-≥99%). Because Chlamydiazyme ® may yield false-positive results from the urine of men with bladder infections, a positive nonculture test result may be less predictive of chlamydial infection among older men who have a higher incidence of nonchlamydial urinary tract infection (143 ).\nBecause information on the performance of the nonculture tests among asymptomatic men is limited and tests for identifying asymptomatic urethral infection among men may be insensitive, none of the nonculture tests are recommended for this group of patients.\n\n# Other Nonculture Test Specimens\nUrine. The LET can be used to screen sexually active teenage males for urethritis, which is often caused by chlamydia or gonorrhea. Patients with positive results indicating the presence of urethritis require specific tests for C. trachomatis and N. gonorrhoeae. Reported sensitivities of the LET in screening for chlamydia and gonorrhea range from 46% to 100% and specificities range from 83% to 100% (19,20,144,145 ). Data are insufficient to recommend its use for older males or for women.\nRectum. Culture is the preferred method for detecting chlamydia in rectal specimens. Some DFA reagents have been approved by the FDA to evaluate rectal specimens; however, the specificity of the test for rectal specimens may be less than that for specimens from the cervix or the urethra. If DFA is used, slides should be read only by highly experienced microscopists.\nConjunctiva. Although data are limited, the performance of nonculture tests with conjunctival specimens has been at least as effective as with genital specimens. Nasopharynx (Infants). Nonculture tests have not been adequately evaluated for the detection of C. trachomatis in nasopharyngeal specimens. Many of these tests cannot distinguish between C. trachomatis, C. pneumoniae, or C. psittaci.\n\n# Serum.\nChlamydia serology has little value in the routine clinical care of genital tract infections. Commercial serologic tests are not useful in routine diagnosis because previous chlamydial infections elicit long-lasting antibodies that cannot be easily distinguished from the antibodies produced in a current infection.\nImmunoglobulin M microimmunofluorescence (MIF) is the test used frequently for the diagnosis of chlamydial pneumonia among infants. Chlamydia serology is also useful for persons with symptoms consistent with lymphogranuloma venereum (LGV). For such persons, a fourfold rise in MIF titer to LGV antigens or a complement fixation titer of ≥1:32 supports a presumptive diagnosis of LGV. The difficulties in preparing antigens and in performing these tests restrict their use to a limited number of reference and research laboratories.\nPost-Treatment Tests. If a post-treatment test is performed using a nonculture test, the test should be scheduled a minimum of 3 weeks after completion of antimicrobial therapy. Tests performed earlier may be false-negative because of small numbers of chlamydia organisms; the presence of dead organisms also causes false-positive nonculture test results (see Follow-up of Patients Treated for Chlamydial Infection).\n\n# Quality Assurance of Nonculture Tests\nAs more laboratories begin to provide diagnostic services for chlamydial infections, the development of an infrastructure for laboratory quality assurance is increasingly important. Sites in which laboratory testing is performed must adhere to the CLIA regulations for staffing, professional training, patient test management, quality assurance, and quality control (130 ). Federal and state regulatory agencies that monitor quality assurance and quality control may have additional requirements and should be consulted for specific information.\nEach laboratory should verify the accuracy of nonculture test methods by periodically comparing its results with those obtained by using a high-quality culture system. In addition, CLIA recommends that laboratories enroll in proficiency testing programs, such as those provided by the College of American Pathologists and the American Proficiency Institute. These quality assurance measures are especially important when a laboratory implements a new test method.\nTraining is recommended for the performance of all laboratory tests for chlamydia. Sources of training include product manufacturers, the National Laboratory Training Network (a source of instructional material that also may assist in locating or cosponsoring training workshops), and individual state public health laboratories.\nAll clinicians, particularly new providers of chlamydia testing services, should be trained in order to obtain adequate specimens. This training should include a) instruction in obtaining sufficient numbers of cells from any particular site, and b) instruction in obtaining endocervical cells rather than ectocervical cells or vaginal material from the cervix.\n\n# Laboratory Testing for Sexual Assault and Abuse Victims\nDetailed information concerning the evaluation and treatment of suspected victims of sexual assault or abuse may be obtained from the 1993 Sexually Transmitted Diseases Treatment Guidelines (146 ) and the Sexually Transmitted Diseases Clinical Practice Guidelines 1991 (147 ).\nSpecimens that are taken for chlamydia testing immediately after sexual assault may yield false-negative results because of small numbers of organisms present early in infection. Also, tests may be positive because of prior -not assault-acquiredinfection. Specimens for chlamydia cultures should be obtained from adults and adolescents during the initial evaluation and at a follow-up visit 2 weeks later. Specimens should be obtained from all sites of exposure. Among children, specimens should be routinely collected from the pharynx and the rectum in addition to the vagina (girls). In the absence of signs of urethral infection, obtaining a urethral specimen from boys may not be justified because of a relatively low yield of positive test results and the discomfort associated with obtaining the specimen. The decision to obtain specimens at a follow-up examination must be determined according to each case. Obtaining such follow-up specimens may not be justified if the exposure occurred several days or more before the initial examination, or if the examination would be psychologically traumatic.\nOnly cell culture isolation using standard methods employing C. trachomatisspecific antibodies should be used to detect C. trachomatis infection in the investigation of possible sexual abuse (129 ). Nonculture tests are not sufficiently sensitive or specific to be used in the investigation of sexual abuse (129,138,(148)(149)(150)(151). All specimens and isolates from both suspected victims and alleged assailants should be stored at -70 C or colder in case additional testing by a qualified reference laboratory is needed.\n\n# Future Directions for Laboratory Testing\nThe availability of sensitive and noninvasive C. trachomatis-specific screening tests for men and women (e.g., urine tests) will greatly expand the population that can be screened. For women, such tests are not now available. For men, sensitivities for EIA methods for detecting chlamydia in first-voided urine range from 30% in a group of asymptomatic men (152 ) to approximately 88% in men with symptoms (153 ). Although specificity is ≥97%, increased rates of false-positive results have been reported with specimens from men with urinary tract infections caused by Escherichia coli and Klebsiella pneumoniae (143 ). Further studies are needed before noninvasive C. trachomatis screening tests for asymptomatic men can be recommended.\nRecent evidence suggests that the numerical results of nonculture tests, together with the cutoff point for a positive result, might aid laboratories and clinicians in determining when to perform a second test to verify the initial results (139,154 ). Positive results that substantially exceed the cutoff point may be more likely to be true positives than those near the cutoff point. Similarly, negative results that are close to the cutoff point may be less likely to be true negatives than those with lower values. By establishing a zone just above and just below the cutoff, specimens giving low-positive or high-negative results would be evaluated by a second test. The desired effect would be to increase both the sensitivity and specificity of tests. Although studies are in progress, data are insufficient for a formal recommendation on the use of numerical results.\nTechnologies will continue to be refined, thereby improving both the sensitivity and the specificity of available tests for sexually transmitted chlamydial infections. Because of their ability to amplify chlamydia DNA in the specimen, new technologies such as polymerase chain reaction (CPCR) and ligase chain reaction (LCR) promise specificities equal to, and sensitivities higher than, those of culture.\n\n# PATIENT CARE: AN EXPANDED ROLE FOR THE USE OF CHLAMYDIA TESTS\nThe Chlamydia trachomatis infections policy guidelines published in 1985 (1 ) emphasized the need to include treatment for chlamydia in regimens for patients whose diagnoses were strongly associated with chlamydial infection. The increasing availability of accurate and economical chlamydia tests permits widespread screening of asymptomatic persons, but also suggests that chlamydia treatment for symptomatic patients and the referral of sex partners in the absence of testing, a key strategy in past guidelines, should be discouraged. These tests should be used to diagnose chlamydia for patients with symptoms or signs suggestive of chlamydial infection even if therapy is administered and partners are referred before test results are available. A specific chlamydia diagnosis should facilitate sex partner referral since a positive chlamydia test result indicates that the patient's infection is sexually transmitted. A specific diagnosis may also facilitate medical care for patients who do not respond as expected to initial chlamydia therapy. Some providers do not have resources to screen asymptomatic patients for chlamydia and to also test patients whose conditions warrant presumptive treatment and partner referral. If presumptive treatment of patients with symptoms or signs of chlamydia without testing is elected, efforts must be made to ensure the treatment of partners.\nAlthough the benefits of chlamydia tests for screening and diagnosis justify their use, the potential for adverse consequences must also be recognized and steps taken to minimize them. The adverse consequences for infected patients and their sex partners, including disease complications and transmission of chlamydial infection, may occur if chlamydia treatment is delayed while waiting for test results or if treatment is withheld because of a false-negative test result. Adverse consequences also may occur if uninfected patients and their sex partners are treated unnecessarily because the chlamydia test result is unavailable or false-positive. The adverse consequences of treating uninfected persons are more likely to be psychosocial, resulting from the misdiagnosis of a sexually transmitted infection; adverse effects of the antibiotic used to treat chlamydia are relatively uncommon and mild.\nThese adverse consequences can be avoided by a) treating patients who are symptomatic or have a substantially increased risk of chlamydial infection and treating their sex partners for chlamydia without waiting for chlamydia test results, and b) arranging for a second test to verify an initial positive screening test result for patients and their sex partners who are susceptible to the adverse psychosocial consequences of having a false diagnosis of an STD.\n\n# Presumptive Diagnosis of Chlamydial Infection\nSeveral conditions-NGU, PID, epididymitis, and gonococcal infection-are consistently associated with an increased prevalence of chlamydial infection among patients and their sex partners (Table 2). Patients with these illnesses require immediate treatment to relieve symptoms and/or to prevent complications. Treatment for these conditions should include an antibiotic regimen for chlamydia. Sex partners of infected patients should be evaluated and treated for chlamydia without waiting for the patient's test results.\nImmediate chlamydia treatment of MPC is warranted by an increased prevalence of chlamydia among women with this condition in most patient care settings. However, immediate chlamydia treatment of MPC or urethral syndrome among females or proctitis among homosexual males-and the referral of sex partners of patients with any of these conditions before obtaining a microbiologic diagnosis-may not always be warranted (Table 3). Chlamydia risk factors (e.g., age <25 years, having new or multiple sex partners) and the likelihood of compliance with follow-up visits should be considered when deciding whether to defer chlamydia treatment and referral of sex partners until chlamydia test results are available. Whenever possible, these decisions should be based on local estimates of chlamydia prevalence.\n\n# Chlamydia Tests for Patients Who Are Treated Presumptively\nEven if a patient with a presumptive diagnosis of chlamydial infection will be treated and counseled to refer partners before test results are known, chlamydia tests should be performed:\n- Ensuring appropriate medical care, particularly if symptoms persist,\n- Facilitating counseling of the patient,\n- Providing firm grounds for partner notification,\n- Improving compliance.\nLimited resources may require health-care providers to decide between performing chlamydia tests for patients who would be treated for chlamydia because of symptoms or signs and patients who are asymptomatic and would not otherwise receive chlamydia treatment. If the health-care provider elects to provide presumptive treatment for patients with symptoms or signs-but without chlamydia testing-efforts must be made to ensure treating the sex partners of patients.\n\n# Screening Women for Chlamydial Infection\nScreening of women for chlamydial infection is a principal element of a chlamydia prevention program (see Health-Care Provider Strategies). The decision to provide treatment for patients whose screening results are positive and to evaluate and treat their sex partners depends upon the patient's risk for a sexually transmitted infection and the potential for adverse psychosocial consequences. A positive second chlamydia test strongly supports the validity of a positive screening test; a negative second test following a positive second test does not rule out chlamydial infection.\nVerification of the initial positive chlamydia test result should be obtained for persons who have a positive nonculture chlamydia test and who are at low risk for infection (e.g., involved in a monogamous relationship, have no history of sexually transmitted infection, member of low-prevalence patient populations) or for whom a misdiagnosis of chlamydial infection could lead to social/psychological distress. If verification of the initial positive chlamydia test result is indicated, these patients and their sex partners should be treated while waiting for the results of the supplementary test. The health-care provider should postpone treatment and partner referral only if the likelihood and adverse consequences of a false-positive test outweigh the risks of transmission and disease progression. Risk factors for chlamydial infection and the probability that the patient will return for follow-up visits should also be considered. (see Nonculture Chlamydia Tests and Clinician-Laboratory Protocols for Verifying Positive Tests).\n\n# Screening Men for Chlamydial Infection\nScreening tests for chlamydia would be more acceptable if urine rather than intraurethral swab specimens could be used. Chlamydia-specific nonculture tests (i.e., EIA, DFA, and nucleic acid probe tests) have not been adequately evaluated for use with urine. However, the LET detects inflammatory cells in urine. Persons whose LET test results are positive require further evaluation of the cause of inflammation, which generally will be urethritis due to chlamydia, N. gonorrhoeae or other sexually transmitted agents, or occasionally a urinary tract infection unrelated to a sexually transmitted agent. The utility of the LET in detecting urethritis has been evaluated primarily among adolescent males for whom urinary tract infections other than urethritis are rare. In this group, the sensitivity of the LET in detecting asymptomatic chlamydial infection has varied from 46% to 100% (19,20,144,145 ). Compared with the use of chlamydia-specific tests, the LET is inexpensive, easy-to-use, and provides immediate results. Although the test cannot exclude infection among asymptomatic males, continued evaluation of the LET is recommended to better define its usefulness in detecting asymptomatic chlamydial (and gonococcal) infections.\n\n# Physical Examination of Sex Partners\nFemale partners of males with chlamydial infection should be referred for examination, chlamydia testing, and treatment. The examination and testing of female partners is recommended because a) sensitive tests are available, and a positive test result may lead to additional partners who are likely to be infected; b) women can be asymptomatic but, when examined, have signs of PID, which requires more intensive therapy; and c) women may be asymptomatically infected with other STDs. However, information is needed on the rates of PID and other STDs among female partners of infected men.\nMale sex partners of females with chlamydial infections should be evaluated for symptoms of chlamydia and other sexually transmitted infections and for allergy to the treatment drug. A physical examination of male sex partners should be encouraged, but an examination is less important than treatment.\nThe examination and testing of asymptomatic male partners are recommended because a) a positive test result may lead to the treatment of additional partners who are likely to be infected, b) men can be asymptomatically infected with other STDs, and c) male partners may be allergic to the treatment drug. However, chlamydia tests for asymptomatic males are insensitive. Further, low rates of other STDs among asymptomatic male partners of women with chlamydial infection have been demonstrated in limited studies. Also, many males do not have readily identifiable sources of medical care for STDs and so may be unlikely to be evaluated by a clinician even if asked to do so by a sex partner. For some male partners of women with chlamydial infection, therefore, it may be reasonable for the woman's clinician to evaluate the male partner even if, in the case of providers who do not offer health-care services for men, this means evaluation without a physical examination. Although approaches to evaluating male partners without a physical examination have not been adequately studied, evaluation of the male partner could be performed at the clinician's office or possibly by telephone. Before prescribing treatment without an examination, the clinician should determine that the male partner does not have symptoms suggestive of another STD and is not allergic to the treatment drug.\n\n# Exposure Periods\nFor women with chlamydial infections and for asymptomatically infected men, health-care providers should treat all sex partners with whom patients have ongoing sexual relations and all other partners with whom patients have had sexual exposures within 60 days before the date of the patient's examination/test.\nFor males with symptomatic chlamydial infection, the 30-day period is sufficient to detect person(s) who probably transmitted the infection to the index patient, as well as recent sex partners who may have been exposed to the infection by the patient.\nFor males and females with asymptomatic infections, a longer exposure period helps to identify additional infected partners. These extended periods, however, have received insufficient evaluation to support specific recommendations. If no sexual exposure has occurred within the specified exposure periods, the most recent sex partner is presumed to be at increased risk for chlamydial infection and should be evaluated.\n\n# Responsibility for Referral of Sex Partners\nHealth-care providers should inform infected patients that they must have their sex partners evaluated and treated. Health-care providers or health departments should ensure the notification, evaluation, and treatment of the sex partners of patients with chlamydial infection. Partner referral can be performed by patients (patient referral) or by providers (provider referral). Patients who do comply with partner referral notify their sex partners of their exposure and encourage them to be examined and treated. Provider referrals require that third parties (e.g., health department personnel) assume responsibility for notifying sex partners of their exposure and providing evaluation and treatment.\nProvider referral of partners-including field follow-up by health department staff-is cost effective (155 ). However, because of the high prevalence of chlamydial infection among some populations and the limited number of health department outreach workers, patient referrals remain the only method of referral available to most clinicians.\nThe responsibility for evaluating the sex partners of persons with chlamydial infection is often unclear and is a major reason partners remain untreated. This is a particular problem for male partners of females with chlamydial infection; male partners (who are often asymptomatic) may be reluctant to visit an STD clinic. Health-care providers who treat women with chlamydial infection should assist in making arrangements for the evaluation and treatment of male partner(s). Health departments can assist health-care providers in developing effective referral systems.\n\n# Clinician-Laboratory Protocols for Verifying Positive Tests\nClinician-laboratory protocols for chlamydia testing are necessary to maximize the benefits of testing for chlamydia while minimizing adverse consequences and cost. These protocols should address which initial and supplementary tests the laboratory will perform, how clinicians should request these tests, and what specimens the clinicians should collect and submit to the laboratory during the patient's initial and follow-up visits. State and local health departments should facilitate the collaboration between health-care providers and laboratories that is necessary to develop suitable testing protocols (See Nonculture Chlamydia Tests).\nWhen developing clinician-laboratory protocols for chlamydia testing, the prevalence of chlamydial infection in the patient population should be considered. In settings with a high prevalence of infection (e.g., false-positive test results account for a small proportion of total positive test results), initial positive test results might only be verified if requested by the clinician on the basis of an assessment of a patient's risk for infection and the potential adverse effects of a false-positive result. In settings with a low prevalence of infection (e.g., false-positive test results account for a substantial proportion of total positive test results), an additional test for verification should be performed on all patients whose screening test results are positive.\nThree alternative testing protocols are suitable for supplementary testing. With the first protocol, a test system is chosen that permits performing the supplementary test on the residual material from the initial specimen. With the second protocol, a test system is chosen in which the supplementary test is performed on a second specimen. The clinician routinely obtains the second specimen at the same time as the initial specimen and submits both specimens to the laboratory; the supplementary test is performed on the second specimen if the initial test is positive and verification is required. With the third protocol, the laboratory reports a positive result from the initial test to the clinician who arranges the patient's return visit for treatment and then obtains a second specimen for a supplemental test. In most settings, one of the first two protocols is preferable since they do not require a return visit to collect an additional specimen. The choice of supplementary test systems and related protocols is difficult because insufficient information is available regarding their comparative performance and cost.\n\n# ANTIMICROBIAL REGIMENS\nRecommendations for the treatment of genital chlamydial infections have been published (146,156 ). Two new antimicrobials approved by the FDA for the treatment of chlamydia-ofloxacin and azithromycin-offer the clinician additional therapeutic choices. A substantial advantage of azithromycin, in comparison with all other therapies, is that a single dose is effective; this antimicrobial may prove most useful in situations in which compliance with a 7-day regimen of another antimicrobial cannot be ensured. In view of the high efficacy of tetracycline and doxycycline, cost also should be considered when selecting a treatment regimen.\nThe recommended treatment regimens for uncomplicated urethral, endocervical, or rectal chlamydial infections among adults are listed below:\n- Doxycycline 100 mg orally 2 times a day for 7 days or - Azithromycin 1 gm orally in a single dose NOTE: Doxycycline and azithromycin are not recommended for use during pregnancy.\n\n# Alternative Treatment Regimens\nAlternative treatment regimens for uncomplicated urethral, endocervical, or rectal chlamydial infections among adults are listed below:\n- Ofloxacin 300 mg orally 2 times a day for 7 days or - Erythromycin base 500 mg orally 4 times a day for 7 days or - Erythromycin ethylsuccinate 800 mg orally 4 times a day for 7 days or - Sulfisoxazole 500 mg orally 4 times a day for 10 days NOTE: Ofloxacin is not recommended for treating adolescents ≤17 years of age nor for pregnant women. The efficacy of sulfisoxazole is inferior to other regimens.\nThe recommended treatment regimen for chlamydial infection during pregnancy is stated below:\n- Erythromycin base 500 mg orally times a day for 7 days If this regimen cannot be tolerated, the following regimens are recommended:\n- Erythromycin base 250 mg orally 4 times a day for 14 days or - Erythromycin ethylsuccinate 800 mg orally 4 times a day for 7 days or - Erythromycin ethylsuccinate 400 mg orally 4 times a day for 14 days If the patient cannot tolerate erythromycin, the following regimen is recommended:\n- Amoxicillin 500 mg orally 3 times a day for 7-10 days NOTE: Erythromycin estolate is contraindicated during pregnancy, since drug-related hepatotoxicity can result.\nFor the treatment of complicated chlamydial infection, chlamydia-associated conditions, and chlamydial infection among infants or children, see the 1993 Sexually Transmitted Diseases Treatment Guidelines (146 ) for the treatment of adults, and the American Academy of Pediatrics Report of the Committee on Infectious Diseases (157 ) for the treatment of infants and children.\n\n# Follow-up of Patients Treated for Chlamydial Infection\nTreatment failure, indicated by positive cultures 7-14 days after therapy, is uncommon after successful completion of a ≥7 day regimen of tetracycline or doxycycline; failure rates of 0%-3% have been reported for males and 0%-8% for females (156,158 ). However, in one study of adolescents followed up to 24 months after therapy for chlamydial infection, rates of infection were 39% (118 ). Whether these infections are reinfections or cases of latent, unsuccessfully treated chlamydial infection is unknown. Further, some studies suggest that women with chlamydial infections are at increased risk for subsequent infection.\nAlthough routine test-of-cure visits during the immediate post-treatment period are not recommended, health-care providers should consider retesting females infected with chlamydia weeks to months after initial therapy (see Nonculture Chlamydia Tests).\n\n# Establishing a Surveillance System\nTo measure chlamydia trends accurately, identify populations with an increased frequency of chlamydial infection and to estimate the burden of chlamydia disease, health departments should develop active chlamydia surveillance systems. These systems should incorporate the following recommendations:\n- Encourage participation by private and public health-care providers and laboratories to ensure that results are representative of the whole population.\n- Include measures of incidence as well as prevalence of chlamydial infections.\n- Use screening results as an index of the prevalence of asymptomatic chlamydial infection.\n\n# Monitoring Incidence\nHealth departments should monitor chlamydia incidence by collecting information regarding men who seek care because of symptoms of urethritis. If tests are performed, the results of chlamydia and gonorrhea laboratory tests should be included with reported cases of urethritis. If chlamydia testing is not performed, the reported incidence of NGU should be used as an index of chlamydia incidence.\n\n# Monitoring Prevalence (Screening)\nThe number of chlamydia cases identified by community screening programs should be monitored as an index of chlamydia prevalence. Information on the following factors that affect the number of chlamydia cases detected should also be collected:\n- Number of chlamydia tests being performed\n- Reason for chlamydia testing (e.g., asymptomatic screening or diagnostic testing performed because of symptoms)\n- Characteristics of the population undergoing chlamydia testing In some states, the volume of chlamydia cases precludes collecting sufficient information on each case of chlamydia. These states should develop community-based sentinel surveillance to monitor trends in the distribution of chlamydial infections and disease burden by demographic, behavioral, and clinical factors.\nWith a sentinel system, a group of health-care providers serving patients who are representative of select populations in the community are recruited to monitor chlamydial infection rates. Examples of potential sentinel sites include STD clinics, family planning clinics, prenatal-care providers, community health centers, school health providers, jails and detention centers, and group practices or health maintenance organizations.\nA sentinel site monitoring the prevalence of chlamydia should test all patients (or a given number of consecutive patients or a random or systematic sample of patients) for chlamydial infection regardless of the patient's chief complaint or symptom status. Demographic, behavioral, and clinical information should be recorded for all patients tested. A sentinel site that monitors the incidence of NGU should collect information on all male patients with symptoms of urethritis and negative test results for gonorrhea. When possible, sentinel sites should monitor the prevalence of gonococcal infections and the incidence of gonococcal urethritis for all patients and the key sequelae of chlamydial and gonococcal infections (e.g., PID, infertility, ectopic pregnancy).\n\n# Laboratory Surveillance\nBecause the surveillance definition of chlamydial infection requires laboratory testing, local laboratories are an important component of a chlamydia surveillance system. Health departments should establish an inventory of laboratories conducting chlamydia testing and poll them regularly for the number of chlamydia tests performed and the number of positive test results.\n\n# Monitoring Interventions\nChlamydia prevention programs should monitor intervention activities. Health departments should monitor the extent and quality of the interventions (process evaluation). Data should be analyzed to determine whether chlamydia trends (measured by surveillance systems) can be linked to interventions (outcome evaluation). Screening and partner notification are interventions of particular interest. The following guidelines are recommended:\n- To permit health departments to monitor screening programs, participating health-care providers should provide screening test results (see Monitoring Prevalence).\n- Where substantial resources are allocated to partner notification or other interventions, health departments should monitor these activities to ensure optimal distribution of those resources.\n\n# ORGANIZING STRATEGIC PARTNERSHIPS\nThe primary goal of a chlamydia prevention strategy should be to secure the resources to provide adolescents and young adults with access to information regarding chlamydial infection, screening and treatment services, and partner notification. Meeting this goal will require the cooperation of all agencies and programs that serve the health-care needs of adolescents and young adults. Every community has an opportunity to provide appropriate educational material regarding STDs and sexual behaviors, and to make screening and treatment for STDs more readily available to those at high risk for chlamydial infection. For example, some family planning programs provide chlamydia testing and treatment for their clients and their male sex partners, and a similar service is provided in some STD clinics. However, these efforts reach only a portion of the population that is infected with chlamydia. Such programs should be expanded to include other primary care providers who deliver medical services to sexually active adolescents and young adults-community health centers, migrant health centers, Native-American health centers, school-based clinics, Job Corps, detention centers, active-duty military facilities, hospital emergency rooms, and providers in the private sector. Schools, community-based recreational and after-school programs such as YMCAs, and other agencies can offer information about STDs (including HIV infection).\nA successful chlamydia prevention program should effectively coordinate all resources in a community. State STD/HIV prevention programs can provide solutions since their staff have experience in organizing clinical, educational, and laboratory resources within states, and they have developed partnerships with providers (e.g., family planning, prenatal, and migrant health clinics) who are part of any prevention program. The challenge is to focus on the common problem-high rates of chlamydial infection throughout the country-and to develop the interagency relationships and coalitions that are needed to deliver appropriate chlamydia services in both public and private settings.\n\n# SURVEILLANCE AND PROGRAM EVALUATION\nInformation should be collected at the national, state, and local levels to provide quantitative estimates of disease occurrence, monitor trends, and monitor interventions and evaluate their impact. The epidemiologic analysis of surveillance and intervention data should be the basis for decision-making in chlamydia prevention programs, including allocation of intervention resources and evaluation of prevention efforts. In addition, these data can be used to develop hypotheses for etiologic and intervention research.\nSurveillance of chlamydial infections is difficult for four reasons. First, the prevalence rate is high and the potential burden of reporting cases correspondingly large. Second, many infected patients are asymptomatic and, therefore, are difficult to identify except through screening programs. Third, because the duration of infection cannot be determined for many patients, prevalence and incidence are difficult to distinguish. Finally, maintaining a surveillance system requires substantial resources for laboratory testing and information systems.\n\n# Reporting Laws\nAll states should have laws or regulations requiring that information on cases of chlamydial infection be reported to the appropriate public health departments.\n- Reporting laws or regulations should acknowledge chlamydia as a public health problem and should provide the legal basis for establishing chlamydia surveillance systems.\n- Reporting laws or regulations should allow states to collect information regarding cases of chlamydial infection from health-care providers and laboratories. Specific categories of data should include demographics (age, race/ethnicity, sex, geographic location, source of report), clinical characteristics (anatomic site, symptoms/signs, treatment), and behaviors (risk factors).\n\n# NOTE:\nIn many areas, reporting laws or regulations are also important because they are linked to the laws and regulations that authorize health departments to initiate and support prevention activities such as screening and partner notification.\n\n# Reportable Conditions\nThe recommended surveillance definition is a case of chlamydial infection diagnosed by a positive laboratory test result. If tests are performed to verify a positive chlamydia test result, reporting should be contingent on verification of the initial positive test result. Reports of chlamydial complications or of conditions serving as surrogates for chlamydial infection-when chlamydia tests are not available-should be analyzed separately.\nNGU, PID, ophthalmia neonatorum, and epididymitis are the principal conditions that might be reported as complications of, or surrogates for, chlamydial infection. The performance of chlamydia tests and their results should be included with reports of these conditions. All material in the MMWR Series is in the public domain and may be used and reprinted without special permission; citation as to source, however, is appreciated.\n\n# MMWR"},"raw_text":{"kind":"string","value":"CDC convened a workshop in Atlanta on March 26-28, 1991, to discuss chlamydia prevention. The following persons participated in the workshop and provided expert technical and scientific review:# INTRODUCTION\nChlamydia trachomatis infections are common in sexually active adolescents and young adults in the United States (CDC, unpublished review ). More than 4 million chlamydial infections occur annually (2,3 ). Infection by this organism is insidioussymptoms are absent or minor among most infected women and many men. This large group of asymptomatic and infectious persons sustains transmission within a community. In addition, these persons are at risk for acute illness and serious longterm sequelae. The direct and indirect costs of chlamydial illness exceed $2.4 billion annually (2-4 )*.\nUntil recently, chlamydia prevention and patient care were impeded by the lack of suitable laboratory tests for screening and diagnosis. Such tests are now available. Through education, screening, partner referral, and proper patient care, public health workers and health-care practitioners can combine efforts to decrease the morbidity and costs resulting from this infection.\n# Prevalence of Chlamydial Infection\nAdolescents and young adults are at substantial risk of becoming infected with chlamydia. Unrecognized infection is highly prevalent in this group (CDC, unpublished review ).\nIn the United States, published studies of sexually active females screened during visits to health-care providers indicate that age is the sociodemographic factor most strongly associated with chlamydial infection. Prevalence has been highest (>10%) among sexually active, adolescent females (CDC, unpublished review ). The prevalence of chlamydial infection also has been higher among those patients who live in inner cities, have a lower socioeconomic status, or are black (5)(6)(7)(8)(9)(10)(11). Although prevalences have been higher in these subgroups, with few exceptions prevalences are ≥5% regardless of region of the country, urban/rural location of provider, or race/ethnicity (CDC, unpublished review ).\nFewer screening studies have been reported for men, but prevalences have been >5% among young men seeking health care for reasons other than genitourinary tract problems. Published reports of these studies from North America and Europe have included male high school students (12 ), military personnel (13,14 ), semen donors (15,16 ), adolescents in detention centers (17)(18)(19)(20), and teens attending adolescent clinics (17,20 ), adolescents attending university health centers (20,21 ), and chemical dependency units (22 ).\n# Clinical Spectrum of Chlamydial Infection Among Nonpregnant Women\nPelvic inflammatory disease (PID) accounts for most of the serious acute illness, morbidity, and economic cost resulting from chlamydial infection. Treating women with acute, symptomatic PID is not a sufficient prevention strategy because treatment does not always prevent sequelae and because many women with tubal infection have symptoms too mild or too nonspecific for them to seek treatment.\nA woman's exposure to chlamydia is usually a result of sexual intercourse. The site of initial infection is most often the cervix; the urethra and the rectum may also be infected (23)(24)(25)(26)(27)(28). Chlamydia causes symptoms in a minority of infected women (9,(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). When symptoms occur, they include vaginal discharge and dysuria (9,23,(25)(26)(27)(29)(30)(31)(32)(33)(35)(36)(37)(38). The ascension of lower, genitourinary tract infection to the endometrium and fallopian tubes may cause lower abdominal pain and menstrual abnormalities. Untreated infections among women often persist for months (7,34,(39)(40)(41). During this period, complications may develop, and many of these women transmit their infection to others.\nThe proportion of women with chlamydial infection who develop infection of the upper reproductive tract (endometritis, salpingitis, and pelvic peritonitis) is uncertain; however, an estimated 8% of women with chlamydia also had overt salpingitis (42). A second study of women with dual gonococcal and chlamydial infections, but who were treated only for gonorrhea, revealed that 30% developed salpingitis during follow-up (43 ). Chlamydia, alone or with other microorganisms, has been isolated from 5% to 50% of women seeking care for symptoms of PID (CDC, unpublished review). Symptomatic PID prompts 2.5 million outpatient visits to physicians annually (44,45 ). More than 275,000 women are hospitalized and more than 100,000 surgical procedures are performed yearly because of PID (45 ). Both the diagnosis and the treatment of PID are unsatisfactory: approximately 17% of women treated for PID will be infertile; an equal proportion will experience chronic pelvic pain as a result of infection (46,47 ); and 10% who do conceive will have an ectopic pregnancy (48 ).\nThe importance of undetected, untreated fallopian tube infections as a cause of infertility and ectopic pregnancy is clear. In two studies of chlamydia and PID in infertile women, PID was the cause of the infertility in half of the women, and anti-chlamydial antibody was strongly associated with a tubal etiology for infertility (49,50 ). Of concern in these studies was the small proportion of women with tubalfactor infertility who reported a past history of salpingitis. Other studies indicate that many of these women may have had salpingitis, but were not treated because symptoms were absent or nonspecific (49,(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). Unrecognized PID also may be a contributor to the occurrence of ectopic pregnancies (60,61 ). Because chlamydial infections are not usually associated with overt symptoms, prevention of infection is the most effective means of preventing sequelae.\nPregnant women with chlamydial infection are at risk for postpartum PID. Postpartum and perinatal disease are preventable by treating infected pregnant women and their sex partners. Endometritis, and possibly salpingitis, developed among 10%-28% of pregnant women with untreated chlamydial infection who underwent induced abortions (27,(62)(63)(64). Similarly, endometritis may develop during the late postpartum period among 19%-34% of infected pregnant women who deliver vaginally and atterm (65,66 ).\n# Clinical Spectrum of Chlamydial Infection Among Infants\nNearly two-thirds of the infants born vaginally to mothers with chlamydial infection become infected during delivery (67,68 ). Even after ophthalmia prophylaxis with silver nitrate or antibiotic ointment, 15%-25% of infants exposed to chlamydia developed chlamydia conjunctivitis, and 3%-16% developed chlamydia pneumonia (41,(68)(69)(70)(71)(72)(73). C. trachomatis is the most common cause of neonatal conjunctivitis (72,(74)(75)(76)(77)(78) and is one of the most common causes of pneumonia during the first few months of life (79)(80)(81)(82)(83)(84)(85). Infants with chlamydia pneumonia are at increased risk for abnormal pulmonary function tests later in childhood (86)(87)(88).\n# Clinical Spectrum of Chlamydial Infection Among Men\nAlthough urethritis is the most common illness resulting from chlamydia, chlamydial infections among men rarely result in sequelae. However, asymptomatic infected men may unknowingly infect their sex partner(s) before seeking treatment.\nChlamydial infections among heterosexual men are usually urethral. Symptoms are similar to gonorrhea (e.g., urethral discharge or dysuria). In contrast to gonorrheal urethritis, chlamydia symptoms are often absent or mild (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)89 ). Therefore, the number of heterosexual men with asymptomatic chlamydial infections is larger than the number of such men with gonorrhea.\nChlamydial infections of the lower genitourinary tract account for 30%-40% of the 4-6 million physician visits for nongonococcal urethritis (NGU), and 50% of the 158,000 outpatient visits and 7,000 hospitalizations for epididymitis among adolescent and young adult males (2,3,90,91 ). Chlamydial infections among men readily respond to treatment with antibiotics. Most of the morbidity and economic costs of chlamydial infections among heterosexual men result from infection of female sex partners who develop sequelae (3 ).\nThe rectum is a common site of initial chlamydial infection for men who engage in receptive anal intercourse. Rectal infections are generally asymptomatic, but may cause symptoms characteristic of proctitis (e.g., rectal discharge, pain during defecation) or proctocolitis (92)(93)(94)(95)(96).\n# Other Chlamydial Illnesses\nAmong adolescents and young adults of both sexes, chlamydial infection is an important part of the differential diagnosis for other, less common, illnesses. Chlamydia salpingitis may progress to perihepatitis-the Fitz-Hugh-Curtis syndrome (97 ). Although chlamydia is an uncommon cause of cystitis symptoms among female patients, chlamydia has been an important cause of such symptoms in some groups of young women who have pyuria, but sterile urine cultures (acute dysuria-pyuria syndrome or urethral syndrome) (5,38,98 ).\nAnother important, but uncommon complication of urogenital chlamydial infection is Reiter's syndrome (reactive arthritis, conjunctivitis, and urethritis), which occurs primarily among men. Chlamydia is receiving greater emphasis in the differential diagnosis of arthritis in young women because of the availability of diagnostic tests for chlamydia. Chlamydial infection is more likely to be missed among women than among men who have arthritis because of the less obvious role of urethritis.\nChlamydia is also part of the differential diagnosis of chronic conjunctivitis among adolescents and young adults (99)(100)(101)(102). Ocular or ophthalmic infections may result from exposure to infectious genital secretions during oral-genital sexual contact, or by autoinoculation. Although chlamydia can be detected in the pharynx after inoculation from oral-genital exposure (103-111 ), chlamydia has not been established as a cause of pharyngitis (103,104,(110)(111)(112)(113)(114).\n# PREVENTION STRATEGIES\nThe principal goal of chlamydia prevention strategies is to prevent both overt and silent chlamydia salpingitis and its sequelae. Other goals include the prevention of perinatal and postpartum infection and other adverse consequences of chlamydial infection.\n# General Approach\nThe prevention of chlamydia salpingitis, pregnancy-related complications, and other chlamydial illnesses requires that chlamydia prevention programs include both primary and secondary prevention strategies.\n# Primary Prevention Strategies\nPrimary prevention strategies are efforts to prevent chlamydial infection. Primary prevention of chlamydia can be accomplished in two general ways.\n• Behavioral changes that reduce the risk of acquiring or transmitting infection should be promoted (e.g., delaying age at first intercourse, decreasing the number of sex partners, partner selection, and the use of barrier contraception [condoms]). Efforts to effect behavioral changes are not specific to chlamydia prevention but are also critical components in preventing sexual transmission of the human immunodeficiency virus (HIV) and other sexually transmitted diseases (STDs) (45,(115)(116)(117).\n• Identify and treat persons with genital chlamydial infection before they infect their sex partners, and for pregnant women before they infect their babies. Efforts to detect chlamydial infection are essential to chlamydia prevention. Identifying and treating chlamydial infections require active screening and referral of sex partners of infected persons, since infections among women and men are usually asymptomatic.\n# Secondary Prevention Strategies\nSecondary prevention strategies are efforts to prevent complications among persons infected with chlamydia. The most important complication to be prevented is salpingitis and its potential sequelae (i.e., ectopic pregnancy, tubal infertility, and chronic pelvic pain). Secondary prevention of chlamydia salpingitis can be accomplished by a) screening women to identify and treat asymptomatic chlamydial infection; b) treating the female partners of men with infection; c) recognizing clinical conditions such as mucopurulent cervicitis (MPC) and the urethral syndrome, and then applying or using appropriate chlamydia diagnostic tests and treatment, as appropriate.\n# Target Population\nChlamydial infection is especially prevalent among adolescents. Furthermore, PID occurs more commonly after chlamydial infection among adolescent females than among older women (42 ). Therefore, chlamydia prevention efforts should be directed toward young women.\nAll sexually active adolescents and young adults are at high risk for chlamydia; the infection is broadly distributed geographically and socioeconomically. Therefore, chlamydia prevention programs should target all sexually active adolescents and young adults. All private and public health-care providers should be involved in these prevention efforts.\n# Specific Strategies\nSpecific strategies for the prevention of chlamydia are grouped into two categories. Those categories are: a) community-based strategies, and b) health-care provider strategies.\n# Community-Based Strategies\nSince the prevalence of chlamydia is consistently high among adolescents and young adults regardless of socioeconomic status, race, or geographic location, prevention efforts should be implemented communitywide.\nPublic Awareness. Community-based strategies should increase public awareness of chlamydia, its consequences, and the availability and importance of diagnosis and treatment. Groups at high risk for chlamydial infection and the persons who educate and care for them (e.g., parents, teachers, and health-care providers) must be informed about the high rate of genital chlamydial infection and its sequelae among sexually active adolescents and young adults.\nHIV/STD Risk Reduction Programs. Programs designed to reduce the risk of sexual transmission of HIV and other STDs by means of behavioral changes should emphasize the especially high risk of chlamydial infection. In addition, chlamydial infection may be a sentinel for unsafe sexual practices. Concern about chlamydia may provide additional motivation for persons to delay initiation of sexual activity, limit the number of sex partners, avoid sex partners at increased risk for STDs, and use condoms.\nSchools. Because of their access to adolescents, educators have an important role to play in chlamydia prevention programs. Chlamydia-specific material should be integrated into educational curricula that address HIV and other STDs. In addition, school programs should assist students in developing the social and behavioral skills needed to avoid chlamydial infection, HIV, and other STDs.\nAlthough most school health education curricula address HIV, fewer discuss other STDs (including chlamydia). Information that should be provided through school health education programs are listed below:\n• Rates of chlamydial infection among adolescents • Adverse consequences of chlamydia (e.g., PID and infertility)\n• Symptoms and signs of chlamydial infection (and other STDs)\n• Asymptomatic infection • Treatment for sex partners\n• Where and how to obtain health care (including locations, telephone numbers [e.g., STD hot-line number], costs, and issues of confidentiality) Some schools may offer more than classroom instruction (e.g., access to health care for infected persons and screening programs to identify asymptomatic chlamydial infection). Personnel in school-based clinics that perform pelvic examinations should use the opportunity to test for chlamydial infection. However, tests also are needed to identify asymptomatic males (e.g., by screening urine collected during sports physical examinations or other health-screening programs). The leukocyte esterase test (LET) of urine is one possible method for testing males, but the accuracy of the test requires additional evaluation (118 ). Such approaches to identifying and treating young men with asymptomatic chlamydial infection may prove important since these persons may account for most of the transmission of chlamydia to young women (see Laboratory Testing and Patient Care: An Expanded Role for the Use of Chlamydia Tests).\nOut-of-school Adolescents. The prevalence of chlamydia may be even greater among adolescents who have dropped out of school. Therefore, organizations serving these adolescents (e.g., Job Corps, vocational training centers, detention centers, community-based recreational programs) should offer health care that addresses chlamydial infection as part of STD/HIV risk reduction programs.\n# Health-Care Provider Strategies\nReducing the high prevalence of chlamydial infection requires that health-care providers be aware of the high prevalence of chlamydia and recognize chlamydial illness, screen asymptomatic patients, arrange for the treatment of sex partners, and counsel all sexually active patients about the risks of STD infections. Medical providers should be trained to recognize and manage the following conditions that may be caused by chlamydia: MPC, PID, urethral syndrome (women), and urethritis and epididymitis (men).\nScreening. The screening of women for chlamydial infection is a critical component in a chlamydia prevention program since many women are asymptomatic, and the infection may persist for extended periods of time. Many women of reproductive age undergo pelvic examination during visits for routine health care or because of illness. During these examinations, specimens can be obtained for chlamydia screening tests.\nFemale patients of adolescent-care providers, women undergoing induced abortion, women attending STD clinics, and women in detention facilities should be screened for chlamydial infection. Screening of these women is important because a) many are adolescents or young adults, b) they are at high risk for salpingitis, and c) they or their partners are likely to transmit infection.\nChlamydia screening at family planning and prenatal care clinics is particularly cost-effective because of the large number of sexually active young women who undergo pelvic examinations.\nProviders such as family physicians, internists, obstetricians-gynecologists, and pediatricians who provide care for sexually active young women also should implement chlamydia screening programs-although a lower volume of such patients may increase the cost of testing. The following criteria can help identify women who should be tested for chlamydia:\n• Women with MPC • Sexually active women <20 years of age • Women 20-24 years of age who meet either of the following criteria, or women >24 years of age who meet both criteria-inconsistent use of barrier contraception, or new or more than one sex partner during the last 3 months.\nPatient selection criteria should be evaluated periodically. Although the incidence of chlamydial infection among all women previously tested for chlamydia is unknown, the incidence of chlamydial infection among previously infected adolescent females has been as high as 39% (118 ). Because of the high incidence of chlamydial infection among sexually active adolescent females, recommendations for the frequency of testing are listed below:\n• Women <20 years of age should be tested when undergoing a pelvic examination, unless sexual activity since the last test for chlamydia has been limited to a single, mutually monogamous partner.\n• All other women who meet the suggested screening criteria (listed above) should be tested for chlamydia annually.\nAlthough young men infrequently seek routine health care, medical providers should use such opportunities to evaluate them for asymptomatic chlamydial infection, possibly by means of the LET (119 ) (see Laboratory Testing and Patient Care: An Expanded Role for the Use of Chlamydia Tests).\nTreatment of Sex Partners. Treatment of sex partners of infected persons is an important strategy for reaching large numbers of men and women with asymptomatic chlamydial infection. Also, if partners are not treated, reinfection may occur. In addition, treating the male partners of infected women is critical since this is the principal way to eliminate asymptomatic infection among males. If chlamydia screening is widely implemented, the number of infected women identified may exceed the capacity of some public health systems to notify, evaluate, and treat partners. Therefore, health department personnel should assist health-care providers in developing cooperative approaches to refer partners for treatment. Where possible, health-care providers who treat female patients for chlamydia should offer examination and treatment services for the patients' male sex partner(s), or should arrange the appropriate referral of such partners.\n# Risk Reduction\nCounseling. In addition to screening, treatment, and referral of sex partners(s) of persons with chlamydial infection, health-care providers should:\n• Educate sexually active patients regarding HIV and other STDs,\n• Assess the patients' risk factors for infection,\n• Offer at-risk patients advice about behavior changes to reduce the risk of infection,\n• Encourage the use of condoms.\nPreventing Chlamydial Infection During Pregnancy. To prevent maternal postnatal complications and chlamydial infection among infants, pregnant women should be screened for chlamydia during the third trimester, so that treatment, if needed, will be completed before delivery (see Primary Prevention Strategies). The screening criteria already discussed can identify those at higher risk for infection. Screening during the first trimester prevents transmission of the infection and adverse effects of chlamydia during the pregnancy. However, the evidence for adverse effects during pregnancy is minimal. If screening is performed only during the first trimester, a longer period exists for infection before delivery.\nInfants with chlamydial infections respond readily to treatment; morbidity can be limited by the early diagnosis and systemtic treatment of infants who have conjunctivitis and pneumonia caused by chlamydial infection (secondary prevention strategies). Further, the mothers of infants diagnosed with chlamydial infection and the sex partner(s) of those mothers should be evaluated and treated.\n# LABORATORY TESTING\nDiagnostic test manufacturers have introduced a variety of nonculture tests for chlamydia, including enzyme immunoassays (EIAs) to detect chlamydia antigens, fluorescein-conjugated monoclonal antibodies for the direct visualization of chlamydia elementary bodies on smears, nucleic acid hybridization tests, and rapid (stat) tests. Because nonculture tests do not require strict handling of specimens, they are easier to perform and less expensive than culture tests; consequently the numbers of laboratories and health-care providers offering chlamydia testing have increased. The expanded use of nonculture tests is a cornerstone of chlamydia prevention strategies.\nAlthough nonculture tests have advantages that make them more suitable than cell culture tests for widespread screening programs, nonculture tests also have limitations. In particular, nonculture tests are less specific than culture tests and may produce false-positive results. All positive nonculture results should be interpreted as presumptive infection until verified by culture or other nonculture test. The decision to treat and perform additional tests should be based on the specific clinical situation.\nThe test methodologies discussed in these recommendations are for the detection of Chlamydia trachomatis -not other chlamydia species (e.g., C. psittaci and C. pneumoniae ). A number of commercial products for the detection of C. trachomatis are available; however, most information relating to the performance of most of these products is the manufacturers' data. When possible, health-care providers and laboratory staff should compare a potential nonculture test's performance with that of an appropriate standard in their own laboratory.\n# Specimens for Screening\nThe proper collection and handling of specimens are important in all the methods used to identify chlamydia. Even diagnostic tests with the highest performance ratings cannot produce accurate results when specimens submitted to the laboratory are improperly collected. Clinicians require training and periodic assessment to maintain proper technique.\nBecause chlamydia are obligate intracellular organisms that infect the columnar epithelium, the objective of specimen collection procedures is to obtain columnar epithelial cells from the endocervix or the urethra. The following recommendations for specimen collection apply to all screening tests.\n# Preferred Anatomic Sites\nThe endocervix is the preferred anatomic site to collect screening specimens from women. When culture isolation is to be used, processing an additional specimen from the urethra may increase sensitivity by 23% (120 ). Placing the two specimens in the same transport container is acceptable. For nonculture tests, the usefulness of a second specimen from the urethra has not been determined.\nThe urethra is the preferred site for collecting screening specimens from men.\n# Collecting Specimens\nThe following guidelines are recommended for obtaining endocervical specimens:\n• Obtain specimens for chlamydia tests after obtaining specimens for gramstained smear, Neisseria gonorrhoeae culture, or Papanicolaou smear.\n• Before obtaining a specimen for a chlamydia test, use a sponge or large swab to remove all secretions and discharge from the cervical os.\n• For nonculture chlamydia tests, use the swab supplied or specified by the manufacturer of the test.\n• Insert the appropriate swab or endocervical brush 1-2 cm into the endocervical canal (i.e., past the squamocolumnar junction). Rotate the swab against the wall of the endocervical canal several times for 10-30 seconds. Withdraw the swab without touching any vaginal surfaces and place it in the appropriate transport medium (culture, EIA, or deoxyribonucleic acid [DNA] probe testing) or prepare a slide (direct fluorescent antibody [DFA] testing).\nThe following guidelines are recommended for obtaining urethral specimens:\n• Delay obtaining specimens until 2 hours after the patient has voided.\n• Obtain specimens for chlamydia tests after obtaining specimens for gram-stain smear or N. gonorrhoeae culture.\n• For nonculture chlamydia tests, use the swab supplied or specified by the manufacturer.\n• Gently insert the urogenital swab into the urethra (females: 1-2 cm, males: 2-4 cm). Rotate the swab in one direction for at least one revolution for 5 seconds. Withdraw the swab and place it in the appropriate transport medium (culture, EIA, or DNA probe testing) or use the swab to prepare a slide for DFA testing.\n# Quality Assurance of Specimen Collection\nWithout specimen quality assurance, ≥10% of specimens are likely to be unsatisfactory because they contain secretions or exudate, but lack urethral or endocervical columnar cells (6,(121)(122). Periodic cytologic evaluation of specimen quality is recommended when using non-DFA tests to ensure continued proper specimen collection.\n# Cell Culture\nCompared with other diagnostic tests for C. trachomatis, a major advantage of cell culture isolation is a specificity that approaches 100%. In cell culture, organisms from each of the three chlamydia species (C. trachomatis, C. pneumoniae, C. psittaci ) grow and produce intracytoplasmic inclusions. The direct visualization of these inclusions contributes to the specificity of cell culture in identifying chlamydia. The preferred method for identifying inclusions is to stain the infected cells with a species-specific, monoclonal fluorescein-labeled antibody (FA) for C. trachomatis. Alternative antibodies used to stain chlamydia inclusions that bind to chlamydia lipopolysaccharide (LPS) are NOT specific for C. trachomatis and also will stain C. psittaci and C. pneumoniae inclusions. In these recommendations, the use of C. trachomatis-specific, anti-major outer membrane protein (MOMP) antibody is the presumed method used for the detection of C. trachomatis isolated in cell culture.\nCulture sensitivity is approximately 70%-90% in experienced laboratories (123 ). Since culture amplifies small numbers of organisms, it is preferred for specimens in which low numbers of organisms are anticipated (e.g., asymptomatic infection). Culture also allows the organism to be preserved for additional studies, including the determination of immunotype (serovar) and antimicrobial susceptibilities.\nCell culture isolation has several disadvantages. First, the method is technically difficult and requires 3-7 days to obtain a result. Second, since only viable organisms are detected, special transport media must be used, and transportation and storage temperature requirements are stringent. Finally, some specimens contain contaminating microorganisms or substances that are toxic to the cell monolayers used for isolating chlamydia.\n# Indications for the Use of Cell Culture\nA high-quality culture system for chlamydia is the diagnostic method of choice and is essential for the diagnosis of chlamydia in all medical/legal situations.\nCulture serves as the standard for the quality assurance of nonculture tests and for the evaluation of new diagnostic methods. Culture is recommended for detection of chlamydia in specimens for which nonculture methods have not been developed, have not been adequately evaluated, or perform poorly. Culture is recommended for specimens from the following sites:\n• Urethral specimens (women and asymptomatic men).\n• Nasopharyngeal specimens (infants).\n• Rectal specimens (all patients, regardless of age).\n• Vaginal specimens (prepubertal girls).\n# Collecting Specimens for Cell Culture\nSwabs with plastic or wire shafts can be used to obtain cell cultures. Swab tips can be made of cotton, rayon, dacron, or calcium alginate. Swabs with wooden shafts should not be used because the wood may contain substances that are toxic to chlamydia. As part of routine quality control, samples of each lot of swabs that are used to collect specimens for chlamydia isolation should be screened for possible toxicity to chlamydia.\nThe substitution of an endocervical brush for a swab may increase the sensitivity of culture for endocervical specimens from nonpregnant women (124 ). However, the use of the endocervical brush may induce bleeding. Although such bleeding does not interfere with the isolation of C. trachomatis, patients should be advised about possible spotting.\n# Transporting Cell Culture Specimens\nThe viability of chlamydia organisms must be maintained during transport to the laboratory. Consult with the laboratory regarding the selection of appropriate transport medium and procedures (125,126 ). Specific recommendations for transporting specimens are listed below:\n• Specimens for culture should be stored at 4 C and inoculated in cell culture as quickly as possible after collection. The elapsed time until inoculation should not exceed 24 hours. If specimens cannot be inoculated within 24 hours, the specimens should be maintained at -70 C or colder.\n• Specimens for culture should never be stored at -20 C or in \"frost-free\" freezers.\nThese conditions cause a decrease in chlamydia viability. • Only cell lines that have been checked for their ability to support chlamydial growth should be used.\n# Analyzing Cell Culture Specimens\n• The identification of C. trachomatis should be based on visualizing characteristic chlamydia inclusions using species-specific FA staining.\n• Laboratories should determine periodically whether multiple passages will increase sensitivity.\n# NOTE:\nThe specificity of culture is based on the identification of inclusions. The identification of chlamydia after culture by EIA, or any other method that does not identify characteristic intracytoplasmic inclusions, is NOT recommended.\n# Interpreting Cell Culture Results\nA positive cell culture and visualization of characteristic inclusions by species-specific monoclonal FA staining is required to diagnose a chlamydial infection. With proper technique, the specificity of cell culture isolation of C. trachomatis is nearly 100%.\nA negative chlamydia culture does not rule out the presence of a chlamydial infection. The sensitivity of culture is approximately 70%-90% when recommended laboratory and specimen collection techniques are performed.\n# Quality Assurance of Cell Culture Specimen Collection\nThe isolation and detection of chlamydia in cell culture are technically demanding.\nThe training of clinicians and laboratorians, along with quality assurance of laboratory performance and specimen collection, is critical to performing cell culture adequately. Specific recommendations to follow for cell culture specimens are listed below:\n• To monitor the sensitivity and specificity of the cell culture system, laboratories should include known samples to analyze appropriate positive and negative controls when clinical specimens are cultured.\n• Periodically (i.e., monthly or bimonthly), positive controls should be submitted from patient settings to verify the effectiveness of transport systems.\n• Reference laboratories should provide a quality assurance system for monitoring culture performance and specimen adequacy. These laboratories also should provide assistance in the evaluation of unexpected or discrepant results. \n# Nonculture Chlamydia Tests\nMore aggressive prevention strategies are now possible with the availability of nonculture test methods for the detection of chlamydia. Published evaluations of the performance of nonculture chlamydia tests are based primarily on the MicroTrak ® DFA (Syva) test and the Chlamydiazyme ® EIA (Abbott) test. Additional tests have been approved by the FDA for the detection of chlamydial infection. Published information on these other tests is increasing rapidly, but is still limited. The recommended uses of nonculture chlamydia tests for presumptive diagnosis, with and without additional testing, to verify a positive result are summarized in these recommendations (Table 1).\n# Description of Nonculture Tests\nNonculture chlamydia tests include several categories that differ in format and execution.\nDirect Fluorescent Antibody (DFA) tests. Depending on the commercial product used, the antigen that is detected by the antibody in the DFA procedure is either the MOMP or LPS. Specimen material is obtained with a swab or endocervical brush which is then rolled over the specimen \"well\" of a slide. After the slide has dried and the fixative has been applied, the slide can be stored or shipped at ambient temperature. The slide should be processed by the laboratory within 7 days after the specimen has been obtained. Staining consists of covering the smear with fluorescent monoclonal antibody that binds to chlamydia elementary bodies. Stained elementary bodies are then identified by fluorescence microscopy. Total processing time is 30-40 minutes. Only C. trachomatis organisms will stain with the anti-MOMP antibodies used in commercial kits. Cross-reactions can occur between the anti-LPS antibodies used in commercial kits and other bacterial species, as well as with C. pneumoniae and C. psittaci.\nEnzyme Immunoassay (EIA) Tests. EIA tests detect chlamydia LPS with a monoclonal or polyclonal antibody that has been labeled with an enzyme. The enzyme converts a colorless substrate into a colored product. The intensity of the color is measured with a spectrophotometer, which provides a numerical readout. The specimens for EIA are collected by using specimen collection kits supplied by the manufacturer. These kits include swabs, transport tubes, and instructions (to obtain optimum performance of the test kit, manufacturer's instructions should be followed). Specimens can be stored and transported at ambient temperature and should be processed within the time indicated by the manufacturer. Total processing time is 3-4 hours.\nOne disadvantage of the EIA methods that detect LPS is that cross-reaction of the antibody with other microorganisms leads to false-positive results (125,(127)(128)(129). In addition, the LPS-based EIA tests detect all three chlamydia species and, therefore, are not specific for C. trachomatis. Some manufacturers have developed blocking assays that are used to verify positive EIA test results. The test is repeated on initially positive specimens with the addition of a monoclonal antibody specific for chlamydia LPS. The monoclonal antibody competitively inhibits chlamydia-specific binding by the enzyme-labeled antibody; a negative result with the blocking antibody is interpreted as verification of the initial positive test result.\nNucleic Acid Hybridization Tests (DNA Probe). Nucleic acid hybridization methods can be used for the diagnosis of chlamydial infections. In the hybridization assay, a chemiluminescent DNA probe that is complimentary to a specific sequence of C. trachomatis ribosomal RNA (rRNA) is allowed to hybridize to any chlamydia rRNA that is present in the specimen. The resulting DNA:rRNA hybrids are adsorbed to magnetic particles and are then detected by using a luminometer that provides a numerical readout. The test kit includes a specimen collection swab and transport medium. Specimens should be maintained at temperatures of 2-25 C during transport and storage. The manufacturer suggests that assays be performed within 7 days after collection; otherwise the specimens should be stored at -20 C or colder. Total processing time is 2-3 hours.\nThe technical requirements and the necessary expertise to perform nucleic acid hybridization tests are similar to those of the EIA methods. The probe assay is specific for C. trachomatis; cross-reactions with organisms other than C. trachomatis, including C. pneumoniae and C. psittaci, have not been reported. A competitive probe assay has been developed to provide a means of assuring high specificity. The usefulness of the competitive assay is being evaluated in clinical trials and has not been approved for in vitro use by the Food and Drug Administration (FDA).\nRapid Chlamydia Tests. Chlamydia tests have been developed that can be performed within 30 minutes, do not require expensive or sophisticated equipment, and are packaged as single units. The results are read qualitatively. These rapid or stat tests can offer advantages in physicians' offices, small clinics and hospitals, and settings in which results are needed immediately (e.g., when making decisions about additional testing or treatment while the patient is still present). Like EIAs, these tests use antibodies against LPS that detect all three chlamydia species, but are subject to the same potential for false-positive results due to cross-reactions with other microorganisms. The performance characteristics of these tests have not been extensively evaluated. In addition, since rapid chlamydia tests are designed to be performed by nonlaboratory personnel, quality assurance is essential. Personnel requirements, quality assurance, and quality control requirements relating to the use of these and other tests are published in the Clinical Laboratory Improvement Amendments (CLIA) (130 ) and are governed by the test categorization compilation.\n# Leukocyte Esterase Test (LET).\nThe LET is a dipstick test that is applied to urine specimens to screen for urinary tract infection. The LET detects enzymes that are produced by polymorphonuclear leukocytes. These enzymes hydrolyze an indoxylcarbonic acid ester on the dipstick to indoxyl, which reacts with an indicator in the strip to produce a purple color. The procedure requires <2 minutes to perform after the specimen is collected.\n# Accuracy of Nonculture Tests and Recommendations for Use\nFor small-volume testing, DFA may be preferred because the quality of the specimen can be assessed. Automated tests are probably preferable for high-volume testing, but a quality control system is essential for monitoring the adequacy of specimens.\nPublished evaluations of the performance of nonculture chlamydia tests are based primarily on the MicroTrak ® DFA (Syva) test and the Chlamydiazyme ® EIA (Abbott) test. Additional tests have been approved by the FDA for the detection of chlamydial infection. Published information on these other tests is increasing, but is still limited.\n# Cervical Specimens from Women (Sensitivity).\nThe performance characteristics of Mi-croTrak ® DFA and Chlamydiazyme ® nonculture chlamydia tests have been reported in published evaluations of women in high-prevalence (≥5%) patient populations. Sensitivities, using culture as a standard, have varied greatly but generally exceed 70% (CDC, unpublished review ). This variability in reported sensitivity is a result of differences in specimen collection technique, performance of the culture system used as a standard, and patient characteristics (e.g., age, MPC, and other factors such as prevalence of chlamydial infection, duration of infection, and previous exposure to chlamydia) (121,122,128,(131)(132)(133)(134)(135)(136). A sensitivity of at least 70% is adequate for screening, but not sufficient to exclude chlamydial infection (see Patient Care: An Expanded Role for the Use of Chlamydia Tests).\nEvaluations have been presented or published for the use of a number of tests for cervical specimens from women. Such tests include IDEIA ® (Dako Diagnostics), Pace 2 ® (Gen-Probe), MicroTrak ® EIA (Syva), and Clearview ® (Unipath) tests. Sensitivities reported for these tests are comparable to sensitivities reported for Chlamydiazyme ® and MicroTrak ® DFA. However, chlamydia diagnostics experts recommend additional evaluation of these tests. First, the true sensitivity of these tests may be less than that indicated in published reports. The number of evaluations published for any given test is small and the number of patients with chlamydial infections studied in most evaluations is also small. Therefore, sensitivities may prove to be lower (or higher) as more evaluations are reported. More evaluations need to be conducted by laboratories that have quality assurance programs for culture including, for example, exchange of specimens with other laboratories (proficiency testing). Evaluations that compare new tests directly with established tests would aid in determining the performance of new tests. Second, none of these tests have been adequately evaluated in low-prevalence patient populations. Diagnostics experts are concerned that differences in factors such as previous exposure to chlamydia and duration of infection may result in lower test sensitivities in low-prevalence populations (128 ). Third, although the reported performance of the Clearview ® rapid (stat) test approaches that of Chlamydiazyme ® and MicroTrak ® DFA, additional evaluations are needed to determine its performance when the test is used in an outpatient setting during the patient's visit. Too few evaluations have been reported for other chlamydia tests to assess their sensitivities (≤3 patient care-laboratory settings or 240 patients with chlamydia isolated by cell culture).\n# Specificity and Predictive Value\nPositive. The specificity of nonculture tests for cervical specimens has been high (97%-99%). However, clinicians should be aware that even with these high specificities, false positive results account for an important proportion of all positive test results among groups of patients with a low prevalence of chlamydial infection. The effect of false-positive tests in a population can be quantified by the predictive value positive (PVP). The PVP is the proportion of all persons who have a positive test result for a condition who actually have that condition. In chlamydia screening applications, the PVP is influenced primarily by the specificity of the test and the prevalence of chlamydia. For example, when a nonculture test with a specificity of 98% and a sensitivity of 80% is used to screen 1,000 patients from a high-risk patient population with a chlamydia prevalence of 15% (150 patients have an infection), the test produces 137 positive results: 120 patients are actually infected and 17 are not infected (false-positives). The PVP is 120/137=0.88. When this same test is used to screen 1,000 patients from a low-risk patient population with a chlamydia prevalence of only 2% (20 patients have an infection), 36 positive results are obtained: 16 patients are infected and 20 are not. The PVP is 16/36=0.44. In the low-risk patient population, fewer than half the patients with positive tests actually have chlamydial infection; the remainder are at risk of being incorrectly identified as having an STD unless the clinician takes other measures, such as arranging for verification when screening results are positive.\nSpecificities of the nonculture tests have been <99% in most published evaluations even when a third test was used to detect false-negative cultures. Contamination of cervical specimens with vaginal secretions is responsible for some false-positive tests when using Chlamydiazyme. The polyclonal anti-LPS antibody used in Chlamydiazyme crossreacts with LPS on other bacteria found in the vagina and urinary tract of these patients (121,122,125,127,128,137 ). The source of nonspecific fluorescence with MicroTrak ® DFA and of nonspecific signals with tests using monoclonal antibodies or genetic probes has not been determined. NOTE: Hereafter, a prevalence of <5% is considered to be \"low prevalence.\" At a 5% prevalence (specificity 99% and sensitivity 80%), the PVP would be 80%. Although defining low prevalence as <5% is arbitrary, the potential for 20% of positive test results to be falsely positive (in the absence of a second test for verification) supports the utility of this cutoff.\nVerifying Positive Screening Test Results. Clinicians should verify positive screening test results with a supplemental test if a false-positive test result is likely to have adverse medical, social, or psychological consequences (Table 1). Verification should probably be routine in low-prevalence patient populations, but might be selective in high-prevalence populations. Methods that are suitable for verifying positive nonculture tests for cervical specimens are recommended below:\n• Verify positive tests by culture, using fluorescein-conjugated C. trachomatisspecific antibody. Culture is the most sensitive and specific method for verification. However, verification with culture requires a second specimen that is collected either at the time the first specimen is collected or during a return visit. Because of the limited availability of culture testing and the requirement for a second specimen, culture should be used for verification only if very high specificity is required (e.g., medical/legal situations).\n• Perform a second nonculture test that identifies a C. trachomatis antigen or a nucleic acid sequence that is different from that identified by the screening test.\nTheoretically, detecting a second, highly specific antigen or nucleic acid sequence should provide adequate specificity for verification. However, this approach has had limited evaluation in field trials. A positive screening test may be verified by a second test using a second specimen that is collected either at the time the first specimen is collected or during a return visit. To avoid taking a second specimen, some EIA test manufacturers suggest using the excess specimen in the EIA transport medium for verification of positive EIA tests with a DFA test.\n• Use an unlabeled \"blocking\" antibody or \"competitive\" probe that verifies a positive test result by preventing attachment of the labeled antibody or probe that is used in the standard assay. These methods are theoretically less desirable because they identify the same molecules as those identified by the initial nonculture tests. However, the Chlamydiazyme ® blocking antibody test appears to produce adequate results (127,(138)(139)(140)(141)(142). These methods do not require collecting a second specimen.\nWith the exception of the Chlamydiazyme ® blocking antibody test, nonculture methods of verifying initial positive chlamydia test results have received insufficient evaluation. Since the sensitivity of tests used for verification of positive chlamydia tests is uncertain but <90%, failure to verify the initial positive test does not rule out chlamydial infection. Evaluation studies are needed to determine which of the above approaches is preferable in relation to sensitivity, specificity, and cost (see Clinician-Laboratory Protocols for Verifying Positive Tests).\nUrethral Specimens from Men. The use of the Chlamydiazyme ® EIA test and the Mi-croTrak ® DFA test for urethral specimens from males with symptomatic urethritis has been evaluated in published studies. Reported sensitivities of the Chlamydiazyme ® EIA and MicroTrak ® DFA tests among men with chlamydial urethritis have been highly variable but usually exceed 70%. These sensitivities are sufficiently high to recommend using these tests to detect chlamydial infections among men with symptomatic urethritis. In such men, detection of chlamydial infection may be useful in promoting examination and treatment of sex partners and managing the patient's infection. Neither nonculture tests nor tissue culture isolation are sufficiently sensitive to rule out chlamydial infection based solely on a negative test result.\nPositive Chlamydiazyme ® and MicroTrak ® DFA tests have been highly predictive of chlamydial infection among adolescent and young adult men with symptomatic urethritis. The reported specificities of the Chlamydiazyme ® EIA and MicroTrak ® DFA tests for urethral specimens from men with symptomatic urethritis have been sufficiently high (97%-≥99%). Because Chlamydiazyme ® may yield false-positive results from the urine of men with bladder infections, a positive nonculture test result may be less predictive of chlamydial infection among older men who have a higher incidence of nonchlamydial urinary tract infection (143 ).\nBecause information on the performance of the nonculture tests among asymptomatic men is limited and tests for identifying asymptomatic urethral infection among men may be insensitive, none of the nonculture tests are recommended for this group of patients.\n# Other Nonculture Test Specimens\nUrine. The LET can be used to screen sexually active teenage males for urethritis, which is often caused by chlamydia or gonorrhea. Patients with positive results indicating the presence of urethritis require specific tests for C. trachomatis and N. gonorrhoeae. Reported sensitivities of the LET in screening for chlamydia and gonorrhea range from 46% to 100% and specificities range from 83% to 100% (19,20,144,145 ). Data are insufficient to recommend its use for older males or for women.\nRectum. Culture is the preferred method for detecting chlamydia in rectal specimens. Some DFA reagents have been approved by the FDA to evaluate rectal specimens; however, the specificity of the test for rectal specimens may be less than that for specimens from the cervix or the urethra. If DFA is used, slides should be read only by highly experienced microscopists.\nConjunctiva. Although data are limited, the performance of nonculture tests with conjunctival specimens has been at least as effective as with genital specimens. Nasopharynx (Infants). Nonculture tests have not been adequately evaluated for the detection of C. trachomatis in nasopharyngeal specimens. Many of these tests cannot distinguish between C. trachomatis, C. pneumoniae, or C. psittaci.\n# Serum.\nChlamydia serology has little value in the routine clinical care of genital tract infections. Commercial serologic tests are not useful in routine diagnosis because previous chlamydial infections elicit long-lasting antibodies that cannot be easily distinguished from the antibodies produced in a current infection.\nImmunoglobulin M microimmunofluorescence (MIF) is the test used frequently for the diagnosis of chlamydial pneumonia among infants. Chlamydia serology is also useful for persons with symptoms consistent with lymphogranuloma venereum (LGV). For such persons, a fourfold rise in MIF titer to LGV antigens or a complement fixation titer of ≥1:32 supports a presumptive diagnosis of LGV. The difficulties in preparing antigens and in performing these tests restrict their use to a limited number of reference and research laboratories.\nPost-Treatment Tests. If a post-treatment test is performed using a nonculture test, the test should be scheduled a minimum of 3 weeks after completion of antimicrobial therapy. Tests performed earlier may be false-negative because of small numbers of chlamydia organisms; the presence of dead organisms also causes false-positive nonculture test results (see Follow-up of Patients Treated for Chlamydial Infection).\n# Quality Assurance of Nonculture Tests\nAs more laboratories begin to provide diagnostic services for chlamydial infections, the development of an infrastructure for laboratory quality assurance is increasingly important. Sites in which laboratory testing is performed must adhere to the CLIA regulations for staffing, professional training, patient test management, quality assurance, and quality control (130 ). Federal and state regulatory agencies that monitor quality assurance and quality control may have additional requirements and should be consulted for specific information.\nEach laboratory should verify the accuracy of nonculture test methods by periodically comparing its results with those obtained by using a high-quality culture system. In addition, CLIA recommends that laboratories enroll in proficiency testing programs, such as those provided by the College of American Pathologists and the American Proficiency Institute. These quality assurance measures are especially important when a laboratory implements a new test method.\nTraining is recommended for the performance of all laboratory tests for chlamydia. Sources of training include product manufacturers, the National Laboratory Training Network (a source of instructional material that also may assist in locating or cosponsoring training workshops), and individual state public health laboratories.\nAll clinicians, particularly new providers of chlamydia testing services, should be trained in order to obtain adequate specimens. This training should include a) instruction in obtaining sufficient numbers of cells from any particular site, and b) instruction in obtaining endocervical cells rather than ectocervical cells or vaginal material from the cervix.\n# Laboratory Testing for Sexual Assault and Abuse Victims\nDetailed information concerning the evaluation and treatment of suspected victims of sexual assault or abuse may be obtained from the 1993 Sexually Transmitted Diseases Treatment Guidelines (146 ) and the Sexually Transmitted Diseases Clinical Practice Guidelines 1991 (147 ).\nSpecimens that are taken for chlamydia testing immediately after sexual assault may yield false-negative results because of small numbers of organisms present early in infection. Also, tests may be positive because of prior -not assault-acquiredinfection. Specimens for chlamydia cultures should be obtained from adults and adolescents during the initial evaluation and at a follow-up visit 2 weeks later. Specimens should be obtained from all sites of exposure. Among children, specimens should be routinely collected from the pharynx and the rectum in addition to the vagina (girls). In the absence of signs of urethral infection, obtaining a urethral specimen from boys may not be justified because of a relatively low yield of positive test results and the discomfort associated with obtaining the specimen. The decision to obtain specimens at a follow-up examination must be determined according to each case. Obtaining such follow-up specimens may not be justified if the exposure occurred several days or more before the initial examination, or if the examination would be psychologically traumatic.\nOnly cell culture isolation using standard methods employing C. trachomatisspecific antibodies should be used to detect C. trachomatis infection in the investigation of possible sexual abuse (129 ). Nonculture tests are not sufficiently sensitive or specific to be used in the investigation of sexual abuse (129,138,(148)(149)(150)(151). All specimens and isolates from both suspected victims and alleged assailants should be stored at -70 C or colder in case additional testing by a qualified reference laboratory is needed.\n# Future Directions for Laboratory Testing\nThe availability of sensitive and noninvasive C. trachomatis-specific screening tests for men and women (e.g., urine tests) will greatly expand the population that can be screened. For women, such tests are not now available. For men, sensitivities for EIA methods for detecting chlamydia in first-voided urine range from 30% in a group of asymptomatic men (152 ) to approximately 88% in men with symptoms (153 ). Although specificity is ≥97%, increased rates of false-positive results have been reported with specimens from men with urinary tract infections caused by Escherichia coli and Klebsiella pneumoniae (143 ). Further studies are needed before noninvasive C. trachomatis screening tests for asymptomatic men can be recommended.\nRecent evidence suggests that the numerical results of nonculture tests, together with the cutoff point for a positive result, might aid laboratories and clinicians in determining when to perform a second test to verify the initial results (139,154 ). Positive results that substantially exceed the cutoff point may be more likely to be true positives than those near the cutoff point. Similarly, negative results that are close to the cutoff point may be less likely to be true negatives than those with lower values. By establishing a zone just above and just below the cutoff, specimens giving low-positive or high-negative results would be evaluated by a second test. The desired effect would be to increase both the sensitivity and specificity of tests. Although studies are in progress, data are insufficient for a formal recommendation on the use of numerical results.\nTechnologies will continue to be refined, thereby improving both the sensitivity and the specificity of available tests for sexually transmitted chlamydial infections. Because of their ability to amplify chlamydia DNA in the specimen, new technologies such as polymerase chain reaction (CPCR) and ligase chain reaction (LCR) promise specificities equal to, and sensitivities higher than, those of culture.\n# PATIENT CARE: AN EXPANDED ROLE FOR THE USE OF CHLAMYDIA TESTS\nThe Chlamydia trachomatis infections policy guidelines published in 1985 (1 ) emphasized the need to include treatment for chlamydia in regimens for patients whose diagnoses were strongly associated with chlamydial infection. The increasing availability of accurate and economical chlamydia tests permits widespread screening of asymptomatic persons, but also suggests that chlamydia treatment for symptomatic patients and the referral of sex partners in the absence of testing, a key strategy in past guidelines, should be discouraged. These tests should be used to diagnose chlamydia for patients with symptoms or signs suggestive of chlamydial infection even if therapy is administered and partners are referred before test results are available. A specific chlamydia diagnosis should facilitate sex partner referral since a positive chlamydia test result indicates that the patient's infection is sexually transmitted. A specific diagnosis may also facilitate medical care for patients who do not respond as expected to initial chlamydia therapy. Some providers do not have resources to screen asymptomatic patients for chlamydia and to also test patients whose conditions warrant presumptive treatment and partner referral. If presumptive treatment of patients with symptoms or signs of chlamydia without testing is elected, efforts must be made to ensure the treatment of partners.\nAlthough the benefits of chlamydia tests for screening and diagnosis justify their use, the potential for adverse consequences must also be recognized and steps taken to minimize them. The adverse consequences for infected patients and their sex partners, including disease complications and transmission of chlamydial infection, may occur if chlamydia treatment is delayed while waiting for test results or if treatment is withheld because of a false-negative test result. Adverse consequences also may occur if uninfected patients and their sex partners are treated unnecessarily because the chlamydia test result is unavailable or false-positive. The adverse consequences of treating uninfected persons are more likely to be psychosocial, resulting from the misdiagnosis of a sexually transmitted infection; adverse effects of the antibiotic used to treat chlamydia are relatively uncommon and mild.\nThese adverse consequences can be avoided by a) treating patients who are symptomatic or have a substantially increased risk of chlamydial infection and treating their sex partners for chlamydia without waiting for chlamydia test results, and b) arranging for a second test to verify an initial positive screening test result for patients and their sex partners who are susceptible to the adverse psychosocial consequences of having a false diagnosis of an STD.\n# Presumptive Diagnosis of Chlamydial Infection\nSeveral conditions-NGU, PID, epididymitis, and gonococcal infection-are consistently associated with an increased prevalence of chlamydial infection among patients and their sex partners (Table 2). Patients with these illnesses require immediate treatment to relieve symptoms and/or to prevent complications. Treatment for these conditions should include an antibiotic regimen for chlamydia. Sex partners of infected patients should be evaluated and treated for chlamydia without waiting for the patient's test results.\nImmediate chlamydia treatment of MPC is warranted by an increased prevalence of chlamydia among women with this condition in most patient care settings. However, immediate chlamydia treatment of MPC or urethral syndrome among females or proctitis among homosexual males-and the referral of sex partners of patients with any of these conditions before obtaining a microbiologic diagnosis-may not always be warranted (Table 3). Chlamydia risk factors (e.g., age <25 years, having new or multiple sex partners) and the likelihood of compliance with follow-up visits should be considered when deciding whether to defer chlamydia treatment and referral of sex partners until chlamydia test results are available. Whenever possible, these decisions should be based on local estimates of chlamydia prevalence.\n# Chlamydia Tests for Patients Who Are Treated Presumptively\nEven if a patient with a presumptive diagnosis of chlamydial infection will be treated and counseled to refer partners before test results are known, chlamydia tests should be performed:\n• Ensuring appropriate medical care, particularly if symptoms persist,\n• Facilitating counseling of the patient,\n• Providing firm grounds for partner notification,\n• Improving compliance.\nLimited resources may require health-care providers to decide between performing chlamydia tests for patients who would be treated for chlamydia because of symptoms or signs and patients who are asymptomatic and would not otherwise receive chlamydia treatment. If the health-care provider elects to provide presumptive treatment for patients with symptoms or signs-but without chlamydia testing-efforts must be made to ensure treating the sex partners of patients. \n# Screening Women for Chlamydial Infection\nScreening of women for chlamydial infection is a principal element of a chlamydia prevention program (see Health-Care Provider Strategies). The decision to provide treatment for patients whose screening results are positive and to evaluate and treat their sex partners depends upon the patient's risk for a sexually transmitted infection and the potential for adverse psychosocial consequences. A positive second chlamydia test strongly supports the validity of a positive screening test; a negative second test following a positive second test does not rule out chlamydial infection.\nVerification of the initial positive chlamydia test result should be obtained for persons who have a positive nonculture chlamydia test and who are at low risk for infection (e.g., involved in a monogamous relationship, have no history of sexually transmitted infection, member of low-prevalence [<5%] patient populations) or for whom a misdiagnosis of chlamydial infection could lead to social/psychological distress. If verification of the initial positive chlamydia test result is indicated, these patients and their sex partners should be treated while waiting for the results of the supplementary test. The health-care provider should postpone treatment and partner referral only if the likelihood and adverse consequences of a false-positive test outweigh the risks of transmission and disease progression. Risk factors for chlamydial infection and the probability that the patient will return for follow-up visits should also be considered. (see Nonculture Chlamydia Tests and Clinician-Laboratory Protocols for Verifying Positive Tests).\n# Screening Men for Chlamydial Infection\nScreening tests for chlamydia would be more acceptable if urine rather than intraurethral swab specimens could be used. Chlamydia-specific nonculture tests (i.e., EIA, DFA, and nucleic acid probe tests) have not been adequately evaluated for use with urine. However, the LET detects inflammatory cells in urine. Persons whose LET test results are positive require further evaluation of the cause of inflammation, which generally will be urethritis due to chlamydia, N. gonorrhoeae or other sexually transmitted agents, or occasionally a urinary tract infection unrelated to a sexually transmitted agent. The utility of the LET in detecting urethritis has been evaluated primarily among adolescent males for whom urinary tract infections other than urethritis are rare. In this group, the sensitivity of the LET in detecting asymptomatic chlamydial infection has varied from 46% to 100% (19,20,144,145 ). Compared with the use of chlamydia-specific tests, the LET is inexpensive, easy-to-use, and provides immediate results. Although the test cannot exclude infection among asymptomatic males, continued evaluation of the LET is recommended to better define its usefulness in detecting asymptomatic chlamydial (and gonococcal) infections.\n# Physical Examination of Sex Partners\nFemale partners of males with chlamydial infection should be referred for examination, chlamydia testing, and treatment. The examination and testing of female partners is recommended because a) sensitive tests are available, and a positive test result may lead to additional partners who are likely to be infected; b) women can be asymptomatic but, when examined, have signs of PID, which requires more intensive therapy; and c) women may be asymptomatically infected with other STDs. However, information is needed on the rates of PID and other STDs among female partners of infected men.\nMale sex partners of females with chlamydial infections should be evaluated for symptoms of chlamydia and other sexually transmitted infections and for allergy to the treatment drug. A physical examination of male sex partners should be encouraged, but an examination is less important than treatment.\nThe examination and testing of asymptomatic male partners are recommended because a) a positive test result may lead to the treatment of additional partners who are likely to be infected, b) men can be asymptomatically infected with other STDs, and c) male partners may be allergic to the treatment drug. However, chlamydia tests for asymptomatic males are insensitive. Further, low rates of other STDs among asymptomatic male partners of women with chlamydial infection have been demonstrated in limited studies. Also, many males do not have readily identifiable sources of medical care for STDs and so may be unlikely to be evaluated by a clinician even if asked to do so by a sex partner. For some male partners of women with chlamydial infection, therefore, it may be reasonable for the woman's clinician to evaluate the male partner even if, in the case of providers who do not offer health-care services for men, this means evaluation without a physical examination. Although approaches to evaluating male partners without a physical examination have not been adequately studied, evaluation of the male partner could be performed at the clinician's office or possibly by telephone. Before prescribing treatment without an examination, the clinician should determine that the male partner does not have symptoms suggestive of another STD and is not allergic to the treatment drug.\n# Exposure Periods\nFor women with chlamydial infections and for asymptomatically infected men, health-care providers should treat all sex partners with whom patients have ongoing sexual relations and all other partners with whom patients have had sexual exposures within 60 days before the date of the patient's examination/test.\nFor males with symptomatic chlamydial infection, the 30-day period is sufficient to detect person(s) who probably transmitted the infection to the index patient, as well as recent sex partners who may have been exposed to the infection by the patient.\nFor males and females with asymptomatic infections, a longer exposure period helps to identify additional infected partners. These extended periods, however, have received insufficient evaluation to support specific recommendations. If no sexual exposure has occurred within the specified exposure periods, the most recent sex partner is presumed to be at increased risk for chlamydial infection and should be evaluated.\n# Responsibility for Referral of Sex Partners\nHealth-care providers should inform infected patients that they must have their sex partners evaluated and treated. Health-care providers or health departments should ensure the notification, evaluation, and treatment of the sex partners of patients with chlamydial infection. Partner referral can be performed by patients (patient referral) or by providers (provider referral). Patients who do comply with partner referral notify their sex partners of their exposure and encourage them to be examined and treated. Provider referrals require that third parties (e.g., health department personnel) assume responsibility for notifying sex partners of their exposure and providing evaluation and treatment.\nProvider referral of partners-including field follow-up by health department staff-is cost effective (155 ). However, because of the high prevalence of chlamydial infection among some populations and the limited number of health department outreach workers, patient referrals remain the only method of referral available to most clinicians.\nThe responsibility for evaluating the sex partners of persons with chlamydial infection is often unclear and is a major reason partners remain untreated. This is a particular problem for male partners of females with chlamydial infection; male partners (who are often asymptomatic) may be reluctant to visit an STD clinic. Health-care providers who treat women with chlamydial infection should assist in making arrangements for the evaluation and treatment of male partner(s). Health departments can assist health-care providers in developing effective referral systems.\n# Clinician-Laboratory Protocols for Verifying Positive Tests\nClinician-laboratory protocols for chlamydia testing are necessary to maximize the benefits of testing for chlamydia while minimizing adverse consequences and cost. These protocols should address which initial and supplementary tests the laboratory will perform, how clinicians should request these tests, and what specimens the clinicians should collect and submit to the laboratory during the patient's initial and follow-up visits. State and local health departments should facilitate the collaboration between health-care providers and laboratories that is necessary to develop suitable testing protocols (See Nonculture Chlamydia Tests).\nWhen developing clinician-laboratory protocols for chlamydia testing, the prevalence of chlamydial infection in the patient population should be considered. In settings with a high prevalence of infection (e.g., false-positive test results account for a small proportion of total positive test results), initial positive test results might only be verified if requested by the clinician on the basis of an assessment of a patient's risk for infection and the potential adverse effects of a false-positive result. In settings with a low prevalence of infection (e.g., false-positive test results account for a substantial proportion of total positive test results), an additional test for verification should be performed on all patients whose screening test results are positive.\nThree alternative testing protocols are suitable for supplementary testing. With the first protocol, a test system is chosen that permits performing the supplementary test on the residual material from the initial specimen. With the second protocol, a test system is chosen in which the supplementary test is performed on a second specimen. The clinician routinely obtains the second specimen at the same time as the initial specimen and submits both specimens to the laboratory; the supplementary test is performed on the second specimen if the initial test is positive and verification is required. With the third protocol, the laboratory reports a positive result from the initial test to the clinician who arranges the patient's return visit for treatment and then obtains a second specimen for a supplemental test. In most settings, one of the first two protocols is preferable since they do not require a return visit to collect an additional specimen. The choice of supplementary test systems and related protocols is difficult because insufficient information is available regarding their comparative performance and cost.\n# ANTIMICROBIAL REGIMENS\nRecommendations for the treatment of genital chlamydial infections have been published (146,156 ). Two new antimicrobials approved by the FDA for the treatment of chlamydia-ofloxacin and azithromycin-offer the clinician additional therapeutic choices. A substantial advantage of azithromycin, in comparison with all other therapies, is that a single dose is effective; this antimicrobial may prove most useful in situations in which compliance with a 7-day regimen of another antimicrobial cannot be ensured. In view of the high efficacy of tetracycline and doxycycline, cost also should be considered when selecting a treatment regimen.\nThe recommended treatment regimens for uncomplicated urethral, endocervical, or rectal chlamydial infections among adults are listed below:\n• Doxycycline 100 mg orally 2 times a day for 7 days or • Azithromycin 1 gm orally in a single dose NOTE: Doxycycline and azithromycin are not recommended for use during pregnancy.\n# Alternative Treatment Regimens\nAlternative treatment regimens for uncomplicated urethral, endocervical, or rectal chlamydial infections among adults are listed below:\n• Ofloxacin 300 mg orally 2 times a day for 7 days or • Erythromycin base 500 mg orally 4 times a day for 7 days or • Erythromycin ethylsuccinate 800 mg orally 4 times a day for 7 days or • Sulfisoxazole 500 mg orally 4 times a day for 10 days NOTE: Ofloxacin is not recommended for treating adolescents ≤17 years of age nor for pregnant women. The efficacy of sulfisoxazole is inferior to other regimens.\nThe recommended treatment regimen for chlamydial infection during pregnancy is stated below:\n• Erythromycin base 500 mg orally times a day for 7 days If this regimen cannot be tolerated, the following regimens are recommended:\n• Erythromycin base 250 mg orally 4 times a day for 14 days or • Erythromycin ethylsuccinate 800 mg orally 4 times a day for 7 days or • Erythromycin ethylsuccinate 400 mg orally 4 times a day for 14 days If the patient cannot tolerate erythromycin, the following regimen is recommended:\n• Amoxicillin 500 mg orally 3 times a day for 7-10 days NOTE: Erythromycin estolate is contraindicated during pregnancy, since drug-related hepatotoxicity can result.\nFor the treatment of complicated chlamydial infection, chlamydia-associated conditions, and chlamydial infection among infants or children, see the 1993 Sexually Transmitted Diseases Treatment Guidelines (146 ) for the treatment of adults, and the American Academy of Pediatrics Report of the Committee on Infectious Diseases (157 ) for the treatment of infants and children.\n# Follow-up of Patients Treated for Chlamydial Infection\nTreatment failure, indicated by positive cultures 7-14 days after therapy, is uncommon after successful completion of a ≥7 day regimen of tetracycline or doxycycline; failure rates of 0%-3% have been reported for males and 0%-8% for females (156,158 ). However, in one study of adolescents followed up to 24 months after therapy for chlamydial infection, rates of infection were 39% (118 ). Whether these infections are reinfections or cases of latent, unsuccessfully treated chlamydial infection is unknown. Further, some studies suggest that women with chlamydial infections are at increased risk for subsequent infection.\nAlthough routine test-of-cure visits during the immediate post-treatment period are not recommended, health-care providers should consider retesting females infected with chlamydia weeks to months after initial therapy (see Nonculture Chlamydia Tests).\n# Establishing a Surveillance System\nTo measure chlamydia trends accurately, identify populations with an increased frequency of chlamydial infection and to estimate the burden of chlamydia disease, health departments should develop active chlamydia surveillance systems. These systems should incorporate the following recommendations:\n• Encourage participation by private and public health-care providers and laboratories to ensure that results are representative of the whole population.\n• Include measures of incidence as well as prevalence of chlamydial infections.\n• Use screening results as an index of the prevalence of asymptomatic chlamydial infection.\n# Monitoring Incidence\nHealth departments should monitor chlamydia incidence by collecting information regarding men who seek care because of symptoms of urethritis. If tests are performed, the results of chlamydia and gonorrhea laboratory tests should be included with reported cases of urethritis. If chlamydia testing is not performed, the reported incidence of NGU should be used as an index of chlamydia incidence.\n# Monitoring Prevalence (Screening)\nThe number of chlamydia cases identified by community screening programs should be monitored as an index of chlamydia prevalence. Information on the following factors that affect the number of chlamydia cases detected should also be collected:\n• Number of chlamydia tests being performed\n• Reason for chlamydia testing (e.g., asymptomatic screening or diagnostic testing performed because of symptoms)\n• Characteristics of the population undergoing chlamydia testing In some states, the volume of chlamydia cases precludes collecting sufficient information on each case of chlamydia. These states should develop community-based sentinel surveillance to monitor trends in the distribution of chlamydial infections and disease burden by demographic, behavioral, and clinical factors.\nWith a sentinel system, a group of health-care providers serving patients who are representative of select populations in the community are recruited to monitor chlamydial infection rates. Examples of potential sentinel sites include STD clinics, family planning clinics, prenatal-care providers, community health centers, school health providers, jails and detention centers, and group practices or health maintenance organizations.\nA sentinel site monitoring the prevalence of chlamydia should test all patients (or a given number of consecutive patients or a random or systematic sample of patients) for chlamydial infection regardless of the patient's chief complaint or symptom status. Demographic, behavioral, and clinical information should be recorded for all patients tested. A sentinel site that monitors the incidence of NGU should collect information on all male patients with symptoms of urethritis and negative test results for gonorrhea. When possible, sentinel sites should monitor the prevalence of gonococcal infections and the incidence of gonococcal urethritis for all patients and the key sequelae of chlamydial and gonococcal infections (e.g., PID, infertility, ectopic pregnancy).\n# Laboratory Surveillance\nBecause the surveillance definition of chlamydial infection requires laboratory testing, local laboratories are an important component of a chlamydia surveillance system. Health departments should establish an inventory of laboratories conducting chlamydia testing and poll them regularly for the number of chlamydia tests performed and the number of positive test results.\n# Monitoring Interventions\nChlamydia prevention programs should monitor intervention activities. Health departments should monitor the extent and quality of the interventions (process evaluation). Data should be analyzed to determine whether chlamydia trends (measured by surveillance systems) can be linked to interventions (outcome evaluation). Screening and partner notification are interventions of particular interest. The following guidelines are recommended:\n• To permit health departments to monitor screening programs, participating health-care providers should provide screening test results (see Monitoring Prevalence).\n• Where substantial resources are allocated to partner notification or other interventions, health departments should monitor these activities to ensure optimal distribution of those resources.\n# ORGANIZING STRATEGIC PARTNERSHIPS\nThe primary goal of a chlamydia prevention strategy should be to secure the resources to provide adolescents and young adults with access to information regarding chlamydial infection, screening and treatment services, and partner notification. Meeting this goal will require the cooperation of all agencies and programs that serve the health-care needs of adolescents and young adults. Every community has an opportunity to provide appropriate educational material regarding STDs and sexual behaviors, and to make screening and treatment for STDs more readily available to those at high risk for chlamydial infection. For example, some family planning programs provide chlamydia testing and treatment for their clients and their male sex partners, and a similar service is provided in some STD clinics. However, these efforts reach only a portion of the population that is infected with chlamydia. Such programs should be expanded to include other primary care providers who deliver medical services to sexually active adolescents and young adults-community health centers, migrant health centers, Native-American health centers, school-based clinics, Job Corps, detention centers, active-duty military facilities, hospital emergency rooms, and providers in the private sector. Schools, community-based recreational and after-school programs such as YMCAs, and other agencies can offer information about STDs (including HIV infection).\nA successful chlamydia prevention program should effectively coordinate all resources in a community. State STD/HIV prevention programs can provide solutions since their staff have experience in organizing clinical, educational, and laboratory resources within states, and they have developed partnerships with providers (e.g., family planning, prenatal, and migrant health clinics) who are part of any prevention program. The challenge is to focus on the common problem-high rates of chlamydial infection throughout the country-and to develop the interagency relationships and coalitions that are needed to deliver appropriate chlamydia services in both public and private settings.\n# SURVEILLANCE AND PROGRAM EVALUATION\nInformation should be collected at the national, state, and local levels to provide quantitative estimates of disease occurrence, monitor trends, and monitor interventions and evaluate their impact. The epidemiologic analysis of surveillance and intervention data should be the basis for decision-making in chlamydia prevention programs, including allocation of intervention resources and evaluation of prevention efforts. In addition, these data can be used to develop hypotheses for etiologic and intervention research.\nSurveillance of chlamydial infections is difficult for four reasons. First, the prevalence rate is high and the potential burden of reporting cases correspondingly large. Second, many infected patients are asymptomatic and, therefore, are difficult to identify except through screening programs. Third, because the duration of infection cannot be determined for many patients, prevalence and incidence are difficult to distinguish. Finally, maintaining a surveillance system requires substantial resources for laboratory testing and information systems.\n# Reporting Laws\nAll states should have laws or regulations requiring that information on cases of chlamydial infection be reported to the appropriate public health departments.\n• Reporting laws or regulations should acknowledge chlamydia as a public health problem and should provide the legal basis for establishing chlamydia surveillance systems.\n• Reporting laws or regulations should allow states to collect information regarding cases of chlamydial infection from health-care providers and laboratories. Specific categories of data should include demographics (age, race/ethnicity, sex, geographic location, source of report), clinical characteristics (anatomic site, symptoms/signs, treatment), and behaviors (risk factors).\n# NOTE:\nIn many areas, reporting laws or regulations are also important because they are linked to the laws and regulations that authorize health departments to initiate and support prevention activities such as screening and partner notification.\n# Reportable Conditions\nThe recommended surveillance definition is a case of chlamydial infection diagnosed by a positive laboratory test result. If tests are performed to verify a positive chlamydia test result, reporting should be contingent on verification of the initial positive test result. Reports of chlamydial complications or of conditions serving as surrogates for chlamydial infection-when chlamydia tests are not available-should be analyzed separately.\nNGU, PID, ophthalmia neonatorum, and epididymitis are the principal conditions that might be reported as complications of, or surrogates for, chlamydial infection. The performance of chlamydia tests and their results should be included with reports of these conditions. All material in the MMWR Series is in the public domain and may be used and reprinted without special permission; citation as to source, however, is appreciated.\n# MMWR\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":275,"cells":{"id":{"kind":"string","value":"5039a8f36fe9a99ac0e87559a7caba25962db046"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Laboratory data, including CD4 and viral load test results, are an essential component of the national HIV surveillance system. CD4 and viral load data can be used to identify cases, classify stage of disease at diagnosis, and monitor disease progression. These data can also be used to evaluate HIV testing and prevention efforts, determine entry into care and retention in care, measure viral load suppression, and assess unmet health care needs. Analyses at the national level to monitor progress against HIV can only occur if all HIV-related CD4 and viral load test results are reported by all jurisdictions. States with laws, regulations, or policies that support the reporting of all CD4 and viral load test results to HIV surveillance programs have increased reporting and improved completeness and timeliness of HIV surveillance data. Although all states have reporting laws, regulations, or policies, the level at which results must be reported varies. A state, for example, may require only data for CD4 counts above 500 or detectable viral load results be reported. CDC recommends the reporting of all HIV-related CD4 results (counts and percentages) and all viral load results (undetectable and specific values). Where laws, regulations, or policies are not aligned with these recommendations, states might consider strategies to best implement these recommendations within current parameters or consider steps to resolve conflicts with these recommendations. In addition, reporting of HIV-1 nucleotide sequences from genotypic resistance testing might also be considered to monitor prevalence of antiretroviral drug resistance, and HIV genetic diversity subtypes and transmission patterns.#\nmethods that meet Federal Information Processing Standards (FIPS) Publication 197, ADVANCED ENCRYPTION STANDARD (AES) (See .) and sent securely to the state/local health department along with results from all other reportable conditions. If reported to a central location within the health department, the data would then be parsed by the health department and HIV-related results shared with the HIV program.\nThe Epidemiology and Laboratory Capacity for Infectious Disease Cooperative Agreement (ELC) is a CDC cooperative agreement that includes support for implementing electronic laboratory reporting (ELR) solutions. The ELC has assisted many jurisdictions with developing an infrastructure for ELR. All jurisdictions receive ELC funds in some capacity, and most have taken advantage of these funds by implementing tools for receiving laboratory reports electronically. HIV programs are encouraged to leverage existing ELC-funded resources when implementing ELR.\nEnhancements in electronic death reporting systems can also improve quality and timeliness of death ascertainment for persons with HIV and can be achieved through implementation of electronic death registration. Mortality surveillance is a core public health function and critical to HIV surveillance to ensure accurate estimates of prevalence and other related measures used to monitor the NHAS. HIV surveillance programs are encouraged to work with their Vital Records offices to support adoption of electronic death registration where possible.\nCDC is committed to providing the technical assistance necessary to improve laboratory reporting so that it enhances, rather than disrupts, ongoing HIV surveillance."},"raw_text":{"kind":"string","value":"Laboratory data, including CD4 and viral load test results, are an essential component of the national HIV surveillance system. CD4 and viral load data can be used to identify cases, classify stage of disease at diagnosis, and monitor disease progression. These data can also be used to evaluate HIV testing and prevention efforts, determine entry into care and retention in care, measure viral load suppression, and assess unmet health care needs. Analyses at the national level to monitor progress against HIV can only occur if all HIV-related CD4 and viral load test results are reported by all jurisdictions. States with laws, regulations, or policies that support the reporting of all CD4 and viral load test results to HIV surveillance programs have increased reporting and improved completeness and timeliness of HIV surveillance data. Although all states have reporting laws, regulations, or policies, the level at which results must be reported varies. A state, for example, may require only data for CD4 counts above 500 or detectable viral load results be reported. CDC recommends the reporting of all HIV-related CD4 results (counts and percentages) and all viral load results (undetectable and specific values). Where laws, regulations, or policies are not aligned with these recommendations, states might consider strategies to best implement these recommendations within current parameters or consider steps to resolve conflicts with these recommendations. In addition, reporting of HIV-1 nucleotide sequences from genotypic resistance testing might also be considered to monitor prevalence of antiretroviral drug resistance, and HIV genetic diversity subtypes and transmission patterns.# \nmethods that meet Federal Information Processing Standards (FIPS) Publication 197, ADVANCED ENCRYPTION STANDARD (AES) (See http://csrc.nist.gov/publications/fips/fips197/fips-197.pdf.) and sent securely to the state/local health department along with results from all other reportable conditions. If reported to a central location within the health department, the data would then be parsed by the health department and HIV-related results shared with the HIV program.\nThe Epidemiology and Laboratory Capacity for Infectious Disease Cooperative Agreement (ELC) is a CDC cooperative agreement that includes support for implementing electronic laboratory reporting (ELR) solutions. The ELC has assisted many jurisdictions with developing an infrastructure for ELR. All jurisdictions receive ELC funds in some capacity, and most have taken advantage of these funds by implementing tools for receiving laboratory reports electronically. HIV programs are encouraged to leverage existing ELC-funded resources when implementing ELR.\nEnhancements in electronic death reporting systems can also improve quality and timeliness of death ascertainment for persons with HIV and can be achieved through implementation of electronic death registration. Mortality surveillance is a core public health function and critical to HIV surveillance to ensure accurate estimates of prevalence and other related measures used to monitor the NHAS. HIV surveillance programs are encouraged to work with their Vital Records offices to support adoption of electronic death registration where possible.\nCDC is committed to providing the technical assistance necessary to improve laboratory reporting so that it enhances, rather than disrupts, ongoing HIV surveillance. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":276,"cells":{"id":{"kind":"string","value":"b807443b0086ba32386aac51b2328554d0479e1c"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Services (HHS), including the Administration for Children and Families (ACF), Food and Drug Administration (FDA), and National Institutes of Health (NIH). CDC acknowledges Mr. Pete Hunt (HHS/CDC) for his role as lead author of these guidelines. CDC also acknowledges Dr.# Introduction\n\n# Overview\nFood allergies are a growing food safety and public health concern that affect an estimated 4%-6% of children in the United States. 1,2 Children with food allergies are two to four times more likely to have asthma or other allergic conditions than those without food allergies. 1 The prevalence of food allergies among children increased 18% during 1997-2007, and allergic reactions to foods have become the most common cause of anaphylaxis in community health settings. 1,3 In 2006, about 88% of schools had one or more students with a food allergy. 4 Staff who work in schools and early care and education (ECE) programs should develop plans for how they will respond effectively to children with food allergies.\nAlthough the number of children with food allergies in any one school or ECE program may seem small, allergic reactions can be life-threatening and have far-reaching effects on children and their families, as well as on the schools or ECE programs they attend. Any child with a food allergy deserves attention and the school or ECE program should create a plan for preventing an allergic reaction and responding to a food allergy emergency.\nStudies show that 16%-18% of children with food allergies have had a reaction from accidentally eating food allergens while at school. 5,6 In addition, 25% of the severe and potentially life-threatening reactions (anaphylaxis) reported at schools happened in children with no previous diagnosis of food allergy. 5,7 School and ECE program staff should be ready to address the needs of children with known food allergies. They also should be prepared to respond effectively to the emergency needs of children who are not known to have food allergies but who exhibit allergic signs and symptoms.\nUntil now, no national guidelines had been developed to help schools and ECE programs address the needs of the growing numbers of children with food allergies. However, 14 states and many school districts have formal policies or guidelines to improve the management of food allergies in schools. 8,9 Many schools and ECE programs have implemented some of the steps needed to manage food allergies effectively. 4 Yet systematic planning for managing the risk of food allergies and responding to food allergy emergencies in schools and ECE programs remain incomplete and inconsistent. 10,11\n\n# FDA Food Safety Modernization Act\nThese guidelines, Voluntary Guidelines for Managing Food Allergies in Schools and Early Care and Education Programs (hereafter called the Voluntary Guidelines for Managing Food Allergies), were developed in response to Section 112 of the FDA Food Safety Modernization Act, which was enacted in 2011. 12 This act is designed to improve food safety in the United States by shifting the focus from response to prevention. Section 112(b) calls for the Secretary of Health and Human Services, in consultation with the Secretary of Education, to \"develop guidelines to be used on a voluntary basis to develop plans for individuals to manage the risk of food allergy and anaphylaxis in schools a and early childhood education programs b \" and \"make such guidelines available to local educational agencies, schools, early childhood education programs, and other interested entities and individuals to be implemented on a voluntary basis only. \" 12 Each plan, described in the act to manage the risk of food allergy and anaphylaxis in schools and early childhood education programs, that is developed for an individual shall be considered an education record for the purpose of Section 444 of the General Education Provisions Act (commonly referred to as the Family Educational Rights and Privacy Act). The act specifies that nothing in the guidelines developed under its auspices should be construed to preempt state law. (A link to FDA Food Safety Modernization Act, including Section 112 statutory language is provided in Section 6, Resources.) Specifically, the content of these guidelines should address the following:\n- Parental obligation to provide the school or early childhood education program, prior to the start of every school year, with documentation from their child's physician or nurse supporting a diagnosis of food allergy, and any risk of anaphylaxis, if applicable; identifying any food to which the child is allergic; describing, if appropriate, any prior history of anaphylaxis; listing any medication prescribed for the child for the treatment of anaphylaxis; detailing emergency treatment procedures in the event of a reaction; listing the signs and symptoms of a reaction; assessing the child's readiness for self-administration of prescription medication; and a list of substitute meals that may be offered to the child by school or early childhood education program food service personnel.\n- The creation and maintenance of an individual plan for food allergy management, in consultation with the parent, tailored to the needs of each child with a documented risk for anaphylaxis, including any procedures for the self-administration of medication by such children in instances where the children are capable of self-administering medication; and such administration is not prohibited by state law.\n- Communication strategies between individual schools or early childhood education programs and providers of emergency medical services, including appropriate instructions for emergency medical response.\n- Strategies to reduce the risk of exposure to anaphylactic causative agents in classrooms and common school or early childhood education program areas such as cafeterias.\na. The term school is defined in the FDA Food Safety Modernization Act (FDA FSMA) to include public kindergartens, elementary schools, and secondary schools. 12 b. The term early childhood education program is defined in the FDA Food Safety Modernization Act to include a Head Start program or an Early Head Start program carried out under the Head Start Act (42 U.S.C. 9831 et seq.), a statelicensed or state-regulated child care program or school, or a state prekindergarten program that serves children from birth through kindergarten. 12 Some of these early childhood education programs may provide early intervention and preschool services under the Individuals with Disabilities Education Act (IDEA). Some programs that provide these IDEA early intervention and preschool services may not fall under the FDA FSMA, but may still wish to consider these voluntary guidelines when developing procedures for children with food allergies.\n- The dissemination of general information on life threatening food allergies to school or early childhood education program staff, parents, and children.\n- Food allergy management training of school or early childhood education program personnel who regularly come into contact with children with life-threatening food allergies.\n- The authorization and training of school or early childhood education program personnel to administer epinephrine when the nurse is not immediately available.\n- The timely accessibility of epinephrine by school or early childhood education program personnel when the nurse is not immediately available.\n- The creation of a plan contained in each individual plan for food allergy management that addresses the appropriate response to an incident of anaphylaxis of a child while such child is engaged in extracurricular programs of a school or early childhood education program, such as non-academic outings and field trips, before-and afterschool programs or before-and after-early childhood education programs, and schoolsponsored or early childhood education program-sponsored programs held on weekends.\n- Maintenance of information for each administration of epinephrine to a child at risk for anaphylaxis and prompt notification to parents.\n- Other elements determined necessary for the management of food allergies and anaphylaxis in schools and early childhood education programs. 12 Section 1 of the Voluntary Guidelines for Managing Food Allergies addresses these content requirements. Section 2 provides a list of recommended actions for school board members and administrators and staff at the district level. Section 3 provides a list of recommended actions for administrators and staff in schools, while Section 4 provides recommended actions for administrators and staff in ECE programs. Section 5 provides information about relevant federal laws that are enforced or administered by the U.S. Department of Education (ED), the U.S. Department of Justice (DOJ), and the U.S. Department of Agriculture (USDA). Section 6 provides a list of resources with more information and strategies.\n\n# Methods\nTo develop these guidelines, staff at the Centers for Disease Control and Prevention (CDC) created a systematic process to collect, review, and compile expert advice, scientific literature, state guidelines, best practice documents, and position statements from individuals, agencies, and organizations.\nIn January 2010, CDC sponsored a meeting of experts to gather their input into the critical processes and actions needed to protect students with food allergies and to respond to food allergy emergencies in schools. This meeting included representatives from the following groups (see Acknowledgements for details):\n- Federal agencies with expertise in food allergy management in the public health sector, including in schools (CDC, Food and Drug Administration, U.S. National Institute of Allergy and Infectious Diseases, U.S. Department of Education , U.S. Department of Agriculture ).\n- Organizations with expertise or experience in clinical food allergy management and food allergy advice to consumers (Food Allergy and Anaphylaxis Network, Food Allergy Initiative, Asthma and Allergy Foundation of America, American Academy of Pediatrics, and the American College of Asthma, Allergy, and Immunology).\n- Organizations representing professionals who work in schools (National School Boards Association, National Education Association, National Association of School Nurses, National Association of School Administrators, National Association of Elementary School Principals, National Association of Secondary School Principals, School Nutrition Association, American School Counseling Association, and the American School Health Association).\n- One state educational agency.\n- One local school district.\n- Two parents of children with food allergies.\nMeeting participants provided input on the organization and content for food allergy guidelines.\nIn terms of organization, they recommended that the guidelines should:\n- Use a management framework that is similar to the framework used to address other chronic conditions in schools and ECE programs. This framework should include creation of a building-wide team and essential elements of a plan to manage food allergies.\n- Make sure that management and support systems address the needs of children with food allergies and promote an allergen-safe c school or ECE program.\n- Promote partnerships among schools and ECE programs, children with food allergies and their families, and health care providers.\nc. The term allergen-safe refers to an environment that is made as safe as possible from food allergens. The phrase should not be interpreted to mean an allergen-free environment totally safe from food allergens. There is no failsafe way to prevent an allergen from inadvertently entering a school or ECE program facility. When guarding against exposures to food allergens, a school or ECE program should still properly plan for children with any life-threatening food allergies, to educate all school personnel accordingly, and ensure that school staff are trained and prepared to prevent and respond to a food allergy emergency.\n- Emphasize the value of an onsite, full-time registered nurse to manage food allergies in children, but provide guidance for schools and ECE programs that don't have a full-time or part-time registered nurse.\n- Convey scientific evidence and established clinical practice in terms that leaders and staff in schools and ECE programs understand. Make sure this information is consistent with regulatory and planning guidelines from other federal agencies.\n- Emphasize the need to follow state laws, including regulations (such as Nurse Practice Acts and state food safety regulations) and school or ECE program policies when deciding which procedures and actions are permissible or allowed.\nIn terms of content, meeting participants recommended that the guidelines should:\n- Recommend that children with food allergies be identified so an individual plan for managing their food allergies can be developed.\n- Include essential practices for protecting children from allergic reactions and responding to reactions that occur at schools or ECE programs, at sponsored events, or during transport to and from schools or ECE programs.\n- Develop strategies to reduce the risk of exposure to food allergens in classrooms, cafeterias, and other school or ECE program settings.\n- Develop steps for responding to food allergy emergencies, including the administration of epinephrine, that are consistent with a school's or ECE program's \"all-hazards\" plan.\n- Emphasize training for staff to improve their understanding of food allergies, their ability to help children prevent exposure to food allergens, and their ability to respond to food allergy emergencies (including administration of epinephrine). This training can help to create an environment of acceptance and support for children with food allergies.\n- Emphasize the need to teach children about food allergies as part of the school's or ECE program's health education curriculum.\n- Address the need to teach all parents about food allergies.\n- Address the physical safety and emotional needs of children with food allergies (i.e., stigma, bullying, harassment).\n- Include a list of actions for all staff working in schools and ECE programs that may have a role in managing risk of food allergy, including administrators, registered nurses, teachers, paraprofessional staff, counselors, food service staff, and custodial staff.\nMeeting participants provided an initial set of data and literature sources for analysis. CDC staff then reviewed published literature from peer-reviewed and nonpeer-reviewed sources, including descriptive studies, epidemiologic studies, expert statements, policy statements, and relevant Web-based content from federal agencies. CDC scientists conducted an extensive search for scientific reports, using four electronic citation databases: PubMed, Medline, Web of Science, and ERIC. To ensure a comprehensive review of food allergy sources, CDC used search terms that included a combination of terms, such as \"food allergy, \" \"school, \" \"anaphylaxis, \" \"epinephrine, \" \"peanut allergy, \" \"child, \" \"pediatric, \" \"food allergy and bullying, \" \"emergencies, \" \"life-threatening allergy, \" \"school nurse, \" and \"food allergy and child care. \" CDC staff reviewed all recommended documents and eliminated sources that were outdated (earlier than 2000), were superseded by more current data or recommendations, in conflict with current standards of clinical and school-based practice, reflected international recommendations not relevant to U.S. schools or ECE programs, or were limited to adult food allergies.\nCDC staff relied heavily on the content and references in the 2010 Guidelines for the Diagnosis and Management of Food Allergy in the United States. 13 These 2010 guidelines reflect the most up-to-date, extensive systematic review of the literature and assessment of the body of evidence on the science of food allergies. They met the standards of rigorous systematic search and review methods, and they provide clear recommendations that are based on consensus among researchers, scientists, clinical practitioners, and the public. While the 2010 guidelines did not address the management of patients with food allergies outside of clinical settings (and thus did not directly address the management of food allergies in schools), they were deemed an important source for informing the clinical practice recommendations for managing risks for children with food allergies in the Voluntary Guidelines for Managing Food Allergies.\nTo ensure that recommendations for managing the risk of food allergies were consistent with those recommended for other chronic conditions, CDC staff added search terms that included \"school\" and \"asthma, \"\"diabetes, \"\"epilepsy, \"\"chronic condition, \" and \"management. \" In particular, they used information from the following three documents: Students with Chronic Illness: Guidance for Families, Schools, and Students, 14 Managing Asthma: A Guide for Schools, 15 and Helping the Student with Diabetes Succeed: A Guide for School Personnel. 16 CDC staff analyzed best practice documents, state school food allergy guidelines (n = 14), and relevant health and education organizations' position statements for compatibility with the priorities outlined by experts, common themes, and the accuracy and clarity of recommendations or positions based on clinical standards and scientific evidence.\nTo ensure that these Voluntary Guidelines for Managing Food Allergies were compatible with existing federal laws, federal regulations, and current guidelines for schools and ECE programs, CDC solicited expertise and input from the following sources:\n- Office of the General Counsel; Office of Safe and Healthy Students, Office of Elementary and Secondary Education; Office for Civil Rights; and Office of Special Education and Rehabilitative Services, U.S. Department of Education (ED).\n- Civil Rights Division, U.S. Department of Justice (DOJ).\n- Office of the Deputy Assistant Secretary for Early Childhood, Administration for Children and Families, U.S. Department of Health and Human Services (HHS).\nIn addition to the input from the experts meeting, the analysis of research and practice documents, and the technical advice and assistance provided by regulatory federal agencies, CDC conducted three formal rounds of expert review and comment. During the first round, CDC staff worked with meeting participants and agency partners to get concurrence with recommendations. Second and third round reviews were used to refine the content. Reviewers included participants from the first meeting and additional reviewers added after each round to ensure input from at least one new person who had not previously reviewed the document. In addition to these formal reviews, CDC staff asked for multiple reviews from select experts in food allergy management, schools, and ECE programs to ensure the accuracy of the information and relevance of the recommendations to professional practice. During the review process, CDC staff reviewed and accepted additional references that supported changes made in draft recommendations.\nThe resulting Voluntary Guidelines for Managing Food Allergies include recommendations for practice in the following five priority areas that should be addressed in each school's or ECE program's Food Allergy Management Prevention Plan:\n1. Ensure the daily management of food allergies in individual children.\n2. Prepare for food allergy emergencies.\n3. Provide professional development on food allergies for staff members.\n4. Educate children and family members about food allergies.\n5. Create and maintain a healthy and safe educational environment.\n\n# Purpose\nThe Voluntary Guidelines for Managing Food Allergies are intended to support implementation of food allergy management and prevention plans and practices in schools and ECE programs. They provide practical information, planning steps, and strategies for reducing allergic reactions and responding to life-threatening reactions for parents, district administrators, school administrators and staff, and ECE program administrators and staff. They can guide improvements in existing food allergy management plans and practices. They can help schools and ECE programs develop a plan where none currently exists. Schools and ECE programs will not need to change their organization or structure or incorporate burdensome practices to respond effectively. They also should not have to incur significant financial costs where basic health and emergency services are already provided.\nAlthough the practices in these guidelines are voluntary, any actions taken for individual children must be implemented consistent with applicable federal and state laws and local policies. Many of the practices reinforce relevant federal laws and regulations administered or enforced by ED, HHS, DOJ, and USDA. How these laws apply case by case will depend upon the facts in each situation. These guidelines also do not address state and local laws or local school district policies because the requirements of these laws and policies vary from state to state and from school district to school district. References to state guidelines reflect support for and consistency with the recommendations in the Voluntary Food Allergy Guidelines, but do not suggest federal endorsement of state guidelines. While these guidelines provide information related to certain applicable laws, they should not be construed as giving legal advice. Schools and ECE programs should consult local legal professionals for such advice. Although schools and ECE programs have some common characteristics, they operate under different laws and regulations and serve children with different developmental and supervisory needs. Different practices are needed in each setting to manage the risk of food allergies. These guidelines include recommendations that apply to both settings, and they identify how the recommendations should be applied differently in each setting when appropriate. These guidelines do not provide specific guidance for unlicensed child care settings, although many recommendations can be used in these settings.\nIf a school or ECE program participates in the Child Nutrition Programs (CNPs), then USDA Food and Nutrition Service is the federal agency with oversight of the meals served. The CNPs include the National School Lunch and School Breakfast Programs, the Special Milk Program, the Fresh Fruit and Vegetable Program, the Child and Adult Care Food Program, and the Summer Food Service Program. Schools, institutions, and sites participating in the CNPs are required under relevant statutes to make accommodations to program meals for children that are determined to have a food allergy disability.\nA food related disability can be a food allergy if the allergy is acknowledged to be a disability by a licensed doctor. These guidelines can assist CNP program operators in providing safe meals and a safe environment for this population of children.\n\n# About Food Allergies\nA food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. 13 The immune response can be severe and life-threatening. Although the immune system normally protects people from germs, in people with food allergies, the immune system mistakenly responds to food as if it were harmful. One way that the immune system causes food allergies is by making a protein antibody called immunoglobulin E (IgE) to the food. The substance in foods that cause this reaction is called the food allergen. When exposed to the food allergen, the IgE antibodies alert cells to release powerful substances, such as histamine, that cause symptoms that can affect the respiratory system, gastrointestinal tract, skin, or cardiovascular system and lead to a lifethreatening reaction called anaphylaxis. 17 The Voluntary Guidelines for Managing Food Allergies focuses not on all food allergies but on food allergies associated with IgE because those are the food allergies that are associated with the risk of anaphylaxis.\nThere are other types of food-related conditions and diseases that range from the frequent problem of digesting lactose in milk, resulting in gas, bloating, and diarrhea, to reactions caused by cereal grains (celiac disease) that can result in severe malabsorption and a variety of other serious health problems. These conditions and diseases may be serious but are not immediately life-threatening and are not addressed in these guidelines. 13, More than 170 foods are known to cause IgE mediated food allergies. In the United States, the following eight foods or food groups account for 90% of serious allergic reactions: milk, eggs, fish, crustacean shellfish, wheat, soy, peanuts, and tree nuts. 13 Federal law requires food labels in the United States to clearly identify the food allergen source of all foods and ingredients that are (or contain any protein derived from) these common allergens. 20 Some nonfood products used in schools and ECE programssuch as clay, paste, or finger paints-can also contain allergens that may or may not be identified as ingredients on product labels. 21 The symptoms of allergic reactions to food vary both in type and severity among individuals and even in one individual over time. Symptoms associated with an allergic reaction to food include the following:\n- Mucous Membrane Symptoms: red watery eyes or swollen lips, tongue, or eyes.\n- Skin Symptoms: itchiness, flushing, rash, or hives.\n- Gastrointestinal Symptoms: nausea, pain, cramping, vomiting, diarrhea, or acid reflux.\n- Upper Respiratory Symptoms: nasal congestion, sneezing, hoarse voice, trouble swallowing, dry staccato cough, or numbness around mouth.\n- Lower Respiratory Symptoms: deep cough, wheezing, shortness of breath or difficulty breathing, or chest tightness.\n- Cardiovascular Symptoms: pale or blue skin color, weak pulse, dizziness or fainting, confusion or shock, hypotension (decrease in blood pressure), or loss of consciousness.\n- Mental or Emotional Symptoms: sense of \"impending doom, \" irritability, change in alertness, mood change, or confusion.\n\n# Food Allergy Symptoms in Children\nChildren with food allergies might communicate their symptoms in the following ways:\n- It feels like something is poking my tongue.\n- My tongue (or mouth) is tingling (or burning).\n- My tongue (or mouth) itches.\n- My tongue feels like there is hair on it.\n- My mouth feels funny.\n- There's a frog in my throat; there's something stuck in my throat.\n- My tongue feels full (or heavy).\n- My lips feel tight.\n- It feels like there are bugs in there (to describe itchy ears).\n- It (my throat) feels thick.\n- It feels like a bump is on the back of my tongue (throat).\nSource: The Food Allergy & Anaphylaxis Network. Food Allergy News. 2003;13 (2).\nChildren sometimes do not exhibit overt and visible symptoms after ingesting an allergen, making early diagnosis difficult. 13,22 Some children may not be able to communicate their symptoms clearly because of their age or developmental challenges. Complaints such as abdominal pain, itchiness, or other discomforts may be the first signs of an allergic reaction (see Food Allergy Symptoms in Children).\nSigns and symptoms can become evident within a few minutes or up to 1-2 hours after ingestion of the allergen, and rarely, several hours after ingestion. Symptoms of breathing difficulty, voice hoarseness, or faintness associated with change in mood or alertness or rapid progression of symptoms that involve a combination of the skin, gastrointestinal tract, or cardiovascular symptoms signal a more severe allergic reaction (anaphylaxis) and require immediate attention.\nThe severity of reactions to food allergens is difficult to predict and varies depending on the child's particular sensitivity to the food and on the type and amount of exposure to the food. Ingesting a food allergen triggers most severe reactions, while inhaling or having skin contact with food allergens generally causes mild reactions. 23,24,25 The severity of reaction from food ingestion also can be influenced by the child's age, how quickly the allergen is absorbed (e.g., absorption is faster if food is taken on an empty stomach or ingestion is associated with exercise), and by co-existing health conditions or factors. 17 For example, a person with asthma might be at greater risk of having a more severe anaphylactic reaction. Exercise and certain medications also can increase the harmful effects of certain food allergens. 13,26,27\n\n# Allergic Reactions and Anaphylaxis\nAnaphylaxis is best described as a severe allergic reaction that is rapid in onset and may cause death. 31 Not all allergic reactions will develop\n\n# Food Allergies and Asthma\nOne-third of children with food allergies also have asthma, which increases their risk of experiencing a severe or fatal reaction. 28 Data also suggest that children with asthma and food allergies have more visits to hospitals and emergency departments than children who don't have asthma. 2,29,30 Because asthma can pose serious risks to the health of children with food allergies, schools and ECE programs must consider these risks when they develop plans for managing food allergies.\ninto anaphylaxis. In fact, most are mild and resolve without problems. However, early signs of anaphylaxis can resemble a mild allergic reaction. Unless obvious symptoms-such as throat hoarseness or swelling, persistent wheezing, or fainting or low blood pressure-are present, it is not easy to predict whether these initial, mild symptoms will progress to become an anaphylactic reaction that can result in death. 13 Therefore, all children with known or suspected ingestion of a food allergen and the appearance of symptoms consistent with an allergic reaction must be closely monitored and possibly treated for early signs of anaphylaxis.\n\n# Characteristics and Risk Factors\nFood allergies account for 35%-50% of all cases of anaphylaxis in emergency care settings .32 Many different food allergens (e.g., milk, egg, fish, shellfish) can cause anaphylaxis.\nIn the United States, fatal or near fatal reactions are most often caused by peanuts (50%-62%) and tree nuts (15%-30%). 33 Results of studies of fatal allergic reactions to food found that a delay in administering epinephrine was one of the most significant risk factors associated with fatal outcomes. 13,26 Some population groups, including children with a history of anaphylaxis, are at higher risk of having a severe reaction to food (see Fatal Food Allergy Reactions).\n\n# Fatal Food Allergy Reactions\n\n# Risk Factors\n- Delayed administration of epinephrine.\n- Reliance on oral antihistamines alone to treat symptoms.\n- Consuming alcohol and the food allergen at the same time.\n\n# Groups at Higher Risk\n- Adolescents and young adults.\n- Children with a known food allergy.\n- Children with a prior history of anaphylaxis.\n- Children with asthma, particularly those with poorly controlled asthma.\n\n# Timing of Symptoms\nIn general, anaphylaxis caused by a food allergen occurs within minutes to several hours after food ingestion . 13 Death due to food-induced anaphylaxis may occur within 30 minutes to 2 hours of exposure, usually from cardiorespiratory compromise. 13 By the time symptoms of an allergic reaction are recognized, a child is likely to already be experiencing anaphylaxis. Symptoms of anaphylaxis can begin with mild skin symptoms (e.g., hives, flushing) that progress slowly, appear rapidly with more severe symptoms, or appear (in rare circumstances) with shock in the absence of other symptoms. In fact, many fatal anaphylaxis cases caused by food do not follow a predictable pattern that starts with mild skin symptoms.\nEven if initial symptoms are successfully treated or resolve completely, up to 20% of anaphylactic reactions recur within 4-8 hours (called biphasic reaction). In other cases, symptoms do not completely resolve and require additional emergency care. For these reasons, children with food-induced anaphylaxis must be monitored closely and evaluated as soon as possible in an emergency care setting.\n\n# Treatment of Anaphylaxis and Use of Epinephrine\nNo treatment exists to prevent reactions to food allergies or anaphylaxis. Strict avoidance of the food allergen\n\n# Allergens that May Result\nis the only way to prevent a reaction. However, avoidance in Anaphylaxis that Require Use is not always easy or possible, and staff in schools and ECE of Epinephrine programs must be prepared to deal with allergic reactions,\n- Foods such as peanuts, tree nuts, including anaphylaxis. Early and quick recognition and milk, eggs, fish, or shellfish. treatment of allergic reactions that may lead to anaphylaxis can prevent serious health problems or death.\n- Medications such as penicillin or aspirin. The recommended first line of treatment for anaphylaxis is the prompt use of epinephrine. Early use of epinephrine\n- Bee venom or insect stings, such to treat anaphylaxis improves a person's chance of survival as from yellow jackets, wasps, and quick recovery. 13,34 hornets, or fire ant).\nEpinephrine, also called adrenaline, is naturally produced - Latex, such as from gloves. by the body. When given by injection, it rapidly improves breathing, increases heart rate, and reduces swelling of the face, lips, and throat. Epinephrine is typically available in the form of an autoinjector, a spring loaded syringe used to deliver a measured dose of epinephrine, designed for self-administration by patients, or administration by persons untrained in other needle-based forms of epinephrine delivery. In a clinical setting, patients may receive epinephrine through other needle-based delivery methods.\nEpinephrine can quickly improve a person's symptoms, but the effects are not long lasting. If symptoms recur (biphasic reaction), additional doses of epinephrine are needed. Even when epinephrine is used, 911 or other emergency medical services (EMS) must be called so the person can be transported quickly in an emergency vehicle to the nearest hospital emergency department for further medical treatment and observation. 13 It is not possible to set one guideline for when to use epinephrine to treat allergic reactions caused by food. A person needs clinical experience and judgment to recognize the symptoms associated with anaphylaxis, and not all school or ECE program staff have this experience. Clinical guidelines for how to manage food-induced allergic reactions have mainly focused on the health care setting. They emphasize the need to watch patients closely and give the proper treatment, including epinephrine.\nTreatment decisions are based on the progression or increased severity of symptoms and whether the patient has a history of risk factors for anaphylaxis (see Fatal Food Allergy Reactions). 13 For example, the clinical guidelines favor quick and early use of epinephrine as soon as even mild symptoms appear for children who have had severe allergic reactions in the past. Some schools and ECE programs offer clinical services from a doctor or registered nurse. In these cases, the doctor or nurse can use the clinical guidelines to assess children and make decisions about treatment, including if or when to use epinephrine. However, many schools and most ECE programs do not have a doctor or nurse onsite to make such an assessment. In these cases, a staff person at the scene should call 911 or EMS immediately. If staff are trained to recognize symptoms of an allergic reaction or anaphylaxis and are delegated and trained to administer epinephrine, they also should administer epinephrine by auto-injector at the first signs of an allergic reaction, especially if the child's breathing changes. In addition, school or ECE program staff should make sure that the child is transported without delay in an emergency vehicle to the nearest hospital emergency department for further medical treatment and observation. 24,35 These actions may result in administering epinephrine and activating emergency response systems for a child whose allergic reaction does not progress to life-threatening anaphylaxis. However, the delay or failure to administer epinephrine and the lack of medical attention have contributed to many fatal anaphylaxis cases from food allergies. 25, The risk of death from untreated anaphylaxis outweighs the risk of adverse side effects from using epinephrine in these cases.\n\n# Emotional Impact on Children with Food Allergies and Their Parents d\nThe health of a child with a food allergy can be compromised at any time by an allergic reaction to food that is severe or life threatening. Many studies have shown that food allergies have a significant effect on the psychosocial well-being of children with food allergies and their families. Parents of a child with a food allergy may have constant fear about the possibility of a life-threatening reaction and stress from constant vigilance needed to prevent a reaction. They also have to trust their child to the care of others, make sure their child is safe outside the home, and help their child have a normal sense of identity.\nChildren with food allergies may also have constant fear and stress about the possibility of a lifethreatening reaction. The fear of ingesting a food allergen without knowing it can lead to coping strategies that limit social and other daily activities. Children can carry emotional burdens because they are not accepted by other people, they are socially isolated, or they believe they are a burden to others. They also may have anxiety and distress that is caused by teasing, taunting, harassment, or bullying by peers, teachers, or other adults. School and ECE program staff must consider these factors as they develop plans for managing the risk of food allergy for children with food allergies. d. For the purposes of this document, the word parent is used to refer to the adult primary caregiver(s) of a child's basic needs (e.g., feeding, safety). This includes biological parents; other biological relatives such as grandparents, aunts, uncles, or siblings; and non-biological parents such as adoptive, foster, or stepparents.\n\n# Section 1. Food Allergy Management in Schools and Early Care and Education Programs\n\n# Essential First Steps\nSchool and ECE program staff should develop a comprehensive strategy to manage the risk of food allergy reactions in children. This strategy should include (1) a coordinated approach, (2) strong leadership, and\n(3) a specific and comprehensive plan for managing food allergies.\n\n# Use a coordinated approach that is based on effective partnerships.\nThe management of any chronic health condition should be based on a partnership among school or ECE program staff, children and their families, and the family's allergist or other doctor. 11,42,46 School or ECE Program Staff\n\n# Child with Food Allergy and Parent\n\n# Effective Management of Food Allergies\n\n# Allergist or Other Doctor\nThe collective knowledge and experience of a licensed doctor, children with food allergies, and their families can guide the most effective management of food allergies in schools or ECE programs for each child. Close working relationships can help ease anxiety among parents, build trust, and improve the knowledge and skill of school or ECE program staff members. 10,14,42 In schools, all staff members play a part in protecting the health and safety of children with chronic conditions. These staff members include administrators, school nurses or school doctors, food service staff (including food service contract staff ), classroom and specialty teachers, athletic coaches, school counselors, bus drivers, custodial and maintenance staff, therapists, paraeducators, special education service providers, librarians and media specialists, security staff, substitute teachers, and volunteers, such as playground monitors and field trip chaperones. In ECE programs, staff members include the center director, health consultants, nutrition and food service staff, Head Start and child care providers, preschool teachers, teaching assistants, aides, volunteers, and transportation staff.\nA team structure allows for collective management of food allergies, with coordinated planning and communication to ensure that staff responsibilities are carried out in a clear and consistent manner. Instead of creating a new team to address the food allergy-related needs of a particular student with a food allergy, schools and ECE programs can use an existing team such as the student's Section 504 committee (which addresses Section 504 of the Rehabilitation Act of 1973), the student's Individualized Education Program (IEP) team , the school improvement team, child and learning support team, school health or wellness team, or Head Start Health Services Advisory Committee.\nInvolving the school doctor (if applicable), an allergist in the community, or the child's doctor can help the school or ECE program reduce the risk of accidental exposure to allergens. 47 A doctor's diagnosis of a food allergy is necessary to accurately inform plans for avoiding food allergens and managing allergic reactions. The doctor can also give advice on the best practices to control or manage food allergies. 24,25 An allergist is a licensed doctor with specialty training in the diagnosis and treatment of allergic diseases, asthma, and diseases of the immune system.\nChildren with food allergies and their parents have firsthand experience with allergic reactions and are most familiar with a child's unique signs and symptoms. Parents should give the school or ECE program documentation that supports a doctor's diagnosis of food allergy, as well as information about prior history and current risk of anaphylaxis. This information is critical to preventing risk of exposure to allergens and outlining the actions that must be taken if a food allergen exposure occurs. Parents should be continually involved in helping to build a learning environment that is responsive to their child's unique health condition. 47 By working together, parents and school or ECE program staff can communicate better and make sure they have the same expectations. This partnership also shows a shared commitment to the child's well-being and builds parental support and confidence in the ability of school or ECE program staff to manage food allergies.\nMany parents give their ECE program an Emergency Care Plan (ECP) developed by the child's allergist or other doctor. This plan may be the only information ECE program staff members have to manage the child's food allergy. When multiple children have food allergies, the result can be multiple approaches for addressing and managing food allergies and reactions. Instead, ECE programs should use a coordinated approach that is built on partnerships among ECE program staff, parents, and doctors. With a coordinated approach, staff can create one consistent plan of action for responding to any child with a food allergy and to any allergic reaction. 10,44,48\n\n# Provide clear leadership to guide planning and ensure implementation of food allergy management plans and practices.\nSuccessful coordination of food allergy planning requires strong school and ECE program leadership. The support of school principals and ECE program administrators is critical, but it may make more sense for the person who provides or coordinates health services for children to lead the food allergy planning process. 49,50 For example, most schools and some ECE programs have a school or district nurse, school doctor, or health consultant or manager. Nationwide, about 85% of schools have either a part-time or full-time nurse to provide health services to students (37% have a full-time nurse). 8 In Head Start programs, health services must be supervised by staff members or consultants with training in health-related fields. 50,51 School nurses, school doctors, and health consultants or managers should have the expertise to help schools and ECE programs develop plans to manage food allergies. Specifically, these staff members can:\n- Work with families and doctors to obtain or create an Emergency Care Plan (ECP) for children with food allergies.\n- Make sure that each child's plan for managing food allergies is consistent with federal laws and regulations, state laws, including regulations, local policies, and standards of professional practices.\n- Act as a liaison between school and district policy makers, ECE program administrators, health services staff members, food service staff members, community health service providers, and emergency responders.\n- Make sure that education records that include personally-identifiable information about a student's food allergy are generally not disclosed without the prior written consent of the parent (or eligible student) in compliance with the Family Educational Rights and Privacy Act of 1974 (FERPA), 20 U.S.C. 1232g and its implementing regulations in 34 CFR part 99, and any other applicable federal and state laws that protect the privacy or confidentiality of student information. (FERPA may not require parental consent in all circumstances.) FERPA also includes an emergency exception to the prior consent requirement if there is an articulable and significant threat to the health or safety of the student or others. (See Section 5 for more information about FERPA.)\n- Monitor the use of medication in the school or ECE program setting.\n- Obtain an epinephrine auto-injector and make sure it is rapidly available to designated and trained staff members to respond to a child's food allergy emergency.\n- Recognize and handle medical emergencies.\n- Learn about best practices for managing food allergies.\n- Help schools and ECE programs develop a comprehensive approach to managing food allergies. Coordinate a team to put the resulting plan into action.\n- Work with food service staff on parts of the plan that involve meal and snack preparation and services.\n- Identify internal resources and community partners that can support the planning process.\n- Share general information about food allergies with staff members, parents, and others who need it.\n- Make sure staff receive the training they need, including how to administer an epinephrine auto-injector. A doctor or registered nurse can provide this training.\n- Talk with staff members, doctors, children, and their families about food allergies and how they should be managed. Share concerns from parents and children with the food allergy management team.\n- Review the school or ECE program plan on a regular basis to look for ways to reduce exposure to food allergens and better manage allergic reactions. Recommend changes when needed to make the plans better. 49,50,52 The many responsibilities outlined in this section demonstrate the benefit of having a full-or parttime registered nurse (and a doctor part-time) and ECE programs having a medically trained and knowledgeable health consultant or manager. However, if a registered nurse, doctor, or health consultant or manager is not available, the school or ECE program administrator can develop a comprehensive plan that may include delegating some critical responsibilities to other trained professional staff. This plan should also include seeking advice from the child's primary doctor or allergist and training guidance and assistance from health services staff at the district level 47 (See Sections 2 and 3.)\n\n# Develop and implement a comprehensive plan for managing food allergies.\nTo effectively manage food allergies and the risks associated with these conditions, many people inside and outside the school or ECE program must come together to develop a comprehensive plan, called the Food Allergy Management and Prevention Plan (FAMPP). This plan should include all strategies and actions needed to manage food allergies in the school or ECE program. It also should be compatible with the approach used to address other chronic conditions in each individual setting. 14 The FAMPP should reinforce the efforts of each school or ECE program to create a safe learning environment for all children. It should address systemwide planning, implementation, and follow-up and include specific actions for each individual child with a food allergy. The FAMPP should:\n- Meet the requirements of federal laws and regulations, such as Section 504 of the Rehabilitation Act of 1973, the Americans with Disabilities Act (ADA) and the Richard B. Russell National School Lunch Act, if applicable. An explanation of how these federal laws could apply to students with food allergies is provided in Section 5. Among other things, these federal laws address individualized assessment of each child's needs and parental participation in the development of any plan or program designed to meet these dietary needs. An effective FAMPP also would need to meet the requirements of state and local laws and regulations and district policies.\n- Reflect clear goals, purposes, and expectations for food allergy management that are consistent with the school's or ECE program's mission and policies.\n- Be clear and easy to understand and implement.\n- Be responsive to the needs of any child with food allergies by taking into account the different and unique needs of each child.\n- Be adaptable and updated regularly on the basis of experiences, best practices, current research, and changes in district policy or state or county law.\nThe FAMPP should address the following five priorities:\n1. Ensure the daily management of food allergies for individual children.\n2. Prepare for food allergy emergencies.\n3. Provide professional development on food allergies for staff members.\n4. Educate children and family members about food allergies.\n5. Create and maintain a healthy and safe educational environment.\nThe remainder of this section provides more detail and specific recommendations for each priority. This section concludes with a comprehensive Food Allergy Management and Prevention Plan (FAMPP) Checklist for use in schools and ECE programs. This checklist can help schools and ECE programs improve their ability to manage the risk food allergies and assess whether their plans address all five priorities.\n\n# Priorities for Managing Food Allergies\n\n# Ensure the daily management of food allergies for individual children.\nTo protect the health and safety of an individual child with food allergies, school and ECE program staff must identify children with a history of food allergies and develop or obtain plans to manage their allergies.\na. Identify children with food allergies.\nSchools and ECE programs usually have forms and procedures to identify children with chronic conditions, including food allergies, when they enroll or transfer to the school-or when the condition is not initially reported but becomes evident during the academic year. Examples include health condition forms or parent interviews.\nChildren or parents may report a food allergy on the required forms, but this information may not be accurate or complete. Schools and ECE program staff must work with parents to obtain, directly from the child's healthcare provider, the medical information necessary to develop plans for managing the individual care and emergency actions.\nThe USDA requires a doctor's statement that a child has a food allergy disability before food service staff in the Child Nutrition Program can make meal accommodations and provide a safe meal for a child with a food allergy.\n\n# b. Develop a plan to manage and reduce the risk of food allergy reactions in individual children.\nParents and doctors should provide information and recommendations to help schools and ECE programs develop written plans to manage food allergies for children on a daily basis. This information may be provided on health condition forms, medical orders, doctor's statement, or diet orders. There are a variety of names used to label written plans for individual children with food allergies. It is essential for children to have a short, easy to follow plan for emergency care. This is usually a food allergy Emergency Care Plan (ECP). Other names used for the ECP can include a \"food allergy action plan, \"\"emergency action plan, \" or in ECE programs, an \"individual care plan\". Schools or ECE programs may need to establish additional plans, such as a Section 504 plan or, if appropriate, an Individualized Education Program (IEP), or may establish a nursing assessment and outcome-type Individualized Health Plan (IHP).\nThe ECP is the basic form used to collect food allergy information and it should be completed for every child identified as having a food allergy. 24,25,48, (If an ECP form is used by the Child Nutrition Program staff to make meal accommodations, it should include the medical information required by the USDA and must be signed by the doctor). This form should be kept in each child's school health record, and it may include the following:\n°°A recent photo of the child.\n°°Information about the food allergen, including a confirmed written diagnosis from the child's doctor or allergist.\n°°Information about signs and symptoms of the child's possible reactions to known allergens.\n°°Information about the possible severity of reactions, including any history of prior anaphylaxis (even though anaphylaxis can occur even in children without a history of prior anaphylaxis).\n°°A treatment plan for responding to a food allergy reaction or emergency, including whether an epinephrine auto-injector should be used.\n°°Information about other conditions, such as asthma or exercise-induced anaphylaxis that might affect food allergy management.\n°°Contact information for parents and doctors, including alternate phone numbers for notification in case of emergency.\nThe ECP should be written by the child's doctor and confirmed with the parents. In some cases, it can be written by a registered nurse, or school doctor, as long as the child's doctor is consulted and the parents confirm the plan. The child's doctor and parents should sign and date the ECP, and schools and ECE programs should not accept a child's ECP without confirmation and signature from the child's doctor. If a public elementary or secondary school maintains an ECP on an individual child, the ECP would be covered by FERPA as an \"education record. \" The ECP should specifically state who may have access to the information in the plan, and should ensure that any such access to this information is permissible under FERPA and any other applicable federal or state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.) Section 6 lists state and organizational resources that include examples of ECPs and suggested processes that schools and ECE programs might use to develop their ECPs.\nAn IHP is a written document that outlines how children will receive health care services at school and is developed and used by a registered nurse. The IHP documents a specific student's health needs and outlines specific health outcome expectations and plans for achieving these expectations. The use of an IHP is standard practice for schools with a full-time or part-time registered nurse and it is commonly used to document the progress of children with an identified chronic condition such as food allergies. 39,47,52,61 The IHP helps registered nurses manage the risk of food allergies, prevent allergic reactions, and coordinate care with other staff (such as food service staff ) and health service providers outside the school. Federal law does not require the use of an IHP, but its contents can be useful to the nurse in addressing the requirements of federal laws related to school responsibilities for children with food allergies. Section 6 lists state and organizational resources that include examples of an IHP.\nIf a doctor determines that a child's food allergy may result in anaphylaxis and if the child's food allergy constitutes a disability under applicable federal disability laws, school staff can integrate information from the ECP, doctor's statement, and IHP into a Section 504 plan or, if appropriate, into an IEP. (See Section 5 for more information on applicable federal laws.) Schools should still use an ECP with specific, easy-to-read information about how to respond to a food allergy reaction.\nFor children that are identified as having a food allergy disability and who attend a school or ECE program that participates in the U.S. Department of Agriculture's (USDA's) Child Nutrition Programs, a meal or food substitution or modification must be made when the diagnosis is supported by a doctors' signed statement. Before Child Nutrition Program food service staff can provide a safe meal accommodation, parents must provide a statement from a licensed doctor that identifies: °°The child's disability (according to pertinent statutes).\n°°An explanation of why the disability restricts the child's diet.\n°°The major life activity affected by the disability.\n°°The food or foods to be omitted from the child's diet.\n°°The food or choice of foods that must be substituted. 62 A child recognized by the Child Nutrition Program staff as having a food allergy disability does not have to have a Section 504 plan, ECP, IHP, or IEP in order for a meal accommodation to be provided.\nA statement signed by a licensed doctor addressing the points above is sufficient. However, the Child Nutrition Program-required doctor's statement can be integrated in any plan a school or ECE develops to meet a child's special dietary needs.\nIf a Section 504 plan or, if appropriate, an IEP, is developed in connection with the provision of services required under those laws to address the student's food allergy disability, information from the ECP is still useful and can be referenced in, or incorporated into, the Section 504 Plan or IEP. Note that a Section 504 plan or IEP is an education record subject to FERPA. For children not covered by Federal disability laws, schools can use the ECP and IHP to manage each child's food allergy. The IHP can include information about modifications and substitutions for meal and snack planning. An IHP or ECP developed for an individual student is also an education record subject to FERPA.\nIn ECE programs, every child with a food allergy should have an ECP or individual care plan, even if the child has a Section 504 plan or, if eligible for services under IDEA, has an IEP or, if appropriate, an individualized family service plan (IFSP). (See Section 5 for more information regarding these Federal laws.) Because most ECE programs do not have a registered nurse on staff to develop such a plan, the ECE program's health consultant, health manager, or administrator should review each child's health records and emergency information at enrollment and work with parents to obtain an ECP for each child diagnosed with a food allergy. The ECP should be updated at least once a year. Health consultants or managers can share information about any allergic reactions, changes in the child's health status, and exposure to allergens with parents and doctors (with the parents' permission). Working with parents and the child's healthcare provider is essential to make sure that children get the medical services and accommodations they need. Staff should consider referring children without access to health care to health services, when possible.\nECPs used by ECE programs should be signed and dated by the child's doctor and parents. The plan should specifically state who has access to the plan. The plan also should state which staff members are responsible for the care, transportation, and feeding of children with food allergies. 12,50 (See Section 5 for more information about applicable Federal laws.) c. Help students manage their own food allergies.\nYoung children in ECE programs and early elementary grades in schools generally cannot manage their own food allergies. However, some students, especially adolescents, can take responsibility for managing their own food allergies, including carrying and using epinephrine when needed. When medication is required by students who have chronic health conditions, especially when medication may be lifesaving, it is best practice to encourage and assist students to become educated and competent in their own care. 48,54,63,64 Students who can manage their own food allergies should have quick (within a few minutes) access to an epinephrine auto-injector, both at school and during school-related events. 13 Some schools allow students to carry prescribed epinephrine auto-injectors (e.g., in their pocket, backpack, or purse) at school. Some state laws, allow students to carry auto-injectors during activities on school property and during transportation to and from school or school-related events. 63 Federal law requires reasonable modifications of school policies when necessary to avoid disability discrimination, and in some cases, this may require allowing a student to carry an epinephrine auto-injector. School officials should check state and federal laws before setting their policies and practices. See Section 5 for more information about applicable Federal laws.\nBefore students are allowed to carry and use medication, school staff should assess students' knowledge, attitudes, behaviors, and skills to determine their ability to handle this responsibility. 64 This decision should be reassessed periodically, and the school nurse or another assigned staff member should randomly check to make sure students are carrying their epinephrine auto-injector. Some students with food allergies may choose to wear medical alert bracelets, which can aid emergency response. 13 School officials can encourage students to wear these bracelets, but they should not require them. Some students will not want to wear such jewelry because they fear being stigmatized.\nSchool nurses and other school staff members should reinforce self-management skills for students with food allergies. These skills include reading labels, asking questions about foods in the school meal and snack programs, avoiding unlabeled or unknown foods, using epinephrine auto-injectors when needed, and recognizing and reporting an allergic reaction to an adult.\nEven when students are able to manage their own food allergies, school staff need to know which students have allergies so they can have plans in place to monitor each student's condition and be able to respond in an emergency. Because some symptoms of anaphylaxis may continue after a dose of epinephrine is administered and because students might not always have their medication with them, schools should also keep a second epinephrine auto-injector (provided by parent or student) in a secure but rapidly accessible location. 63,65,66 (See the textbox on page 31 related to the justification for more than one dose of epinephrine.)\n\n# Prepare for food allergy emergencies.\nAll schools and ECE programs should anticipate and prepare for food allergy emergencies in the same ways they approach emergency preparedness for other hazards. Comprehensive emergency planning includes prevention, preparedness, response, and recovery for any type of emergency. This \"all-hazards\" model is often used to plan for natural disasters, weather-related emergencies, and pandemic influenza. A school's all-hazards emergency plan also should address potential crises caused by violence or food allergy emergencies. 67 This plan should go beyond each child's ECP to include building-level planning, communication, training, and emergency response procedures. 68 a. Set up communication systems that are easy to use.\nCommunication devices, such as intercoms, walkie-talkies, or cell phones, should be available at all times in case of an emergency. School and ECE program staff in classrooms, gymnasiums, cafeterias, playgrounds, and transportation vehicles should be able to communicate easily and quickly with the school nurse, school authorities, health consultants or managers, emergency responders and parents. Communication devices should be checked regularly to make sure they work.\nb. Make sure staff can get to epinephrine auto-injectors quickly and easily.\nQuick access to and immediate availability of epinephrine to respond to anaphylaxis emergencies is essential. 13 It is the parent's responsibility to provide at least one or two epinephrine auto-injectors for a child with food allergies if they are prescribed by a doctor. It is the school's or ECE program's responsibility to store epinephrine auto-injectors in a place that can be reached quickly and easily and to delegate and train staff to give epinephrine in response to allergic reactions.\nStudies have shown that quick access to epinephrine is critical to saving lives in episodes of anaphylaxis. 24,25,37 To ensure quick access to epinephrine, auto-injectors should be kept in a safe and secure place that trained staff members can get to quickly during school or ECE program hours. 63, At the same time, staff must also follow federal and state laws, including regulations, and local policies that may require medications to be locked in a secure place. For example, federal Head Start regulations require that all \"grantee and delegate agencies establish and maintain written procedures regarding the administration, handling, and storage of medication for every child,\" including \"labeling and storing, under lock and key, and refrigerating, if necessary, all medications, including those required for staff and volunteers. \" 51 State regulations and local policies may similarly require locking medications in a secure location. School and ECE program staff should seek guidance from federal and state regulatory agencies and local policy makers when deciding how to store epinephrine auto-injectors.\nThese decisions also must take into account the needs of each student and the specific characteristics of the school district, the staff, and the school building. Decisions on where to store medication, such as in a central location (office or health room), in the classroom, or in several locations (on a large school campus) may vary among school districts and schools. These decisions should be based on state and local laws and regulations and school policies. They also must ensure the safety of children with food allergies. The Guidelines for Managing Life-threatening Food Allergies in Connecticut Schools list some issues to consider, including the general safety standards for handling and storage of medication, developmental stage and competence of the student, size of the building, availability of a full-time school nurse in the building, availability of communication devices between teachers and paraprofessionals who are inside the building or on the playground and the school nurse, school nurse response time from the health office to the classroom, preferences and other responsibilities of the teacher, preferences of the parent, preferences of the student (as applicable), and movement of the student within the building. 54 The location(s) of medications should be listed in the school's overall emergency plan and in each child's ECP (and IHP, Section 504 plan, or IEP, if appropriate). Schools and ECE programs should also identify which staff members will be responsible for reviewing expiration dates and replacing outdated epinephrine auto-injectors and for carrying medication during field trips and other school events. 70 c. Make sure that epinephrine is used when needed and someone immediately contacts emergency medical services.\nDelays in using epinephrine have resulted in near fatal and fatal food allergy reactions in schools and ECE programs. 25,36,37 In a food allergy emergency, trained staff should give epinephrine immediately.\nEarly and appropriate administration of epinephrine can temporarily stop allergic reactions and provide the critical time needed to get medical help.\nState laws, state nursing regulations, and local school board policies direct the medication administration in school and ECE programs. They often define which medications nonhealth professionals are allowed to administer in schools, including who may administer epinephrine by auto-injector. If nonhealth staff members are permitted to administer epinephrine, training should be required. 39,71 When epinephrine is used, school or ECE program staff must call 911 or emergency medical services (EMS). EMS should be informed that the emergency is due to an allergic reaction, if epinephrine has been administered, when it was administered, and that an additional dose of epinephrine may be needed. The child should be transported quickly in an emergency vehicle to the nearest hospital emergency department for further medical treatment and observation. 13 Staff also should contact the child's parents to inform them of their child's food allergy emergency and tell them where the child is being transported. Because medical attention is needed urgently in this situation, staff must not wait for parents to come and pick up their children before calling EMS.\n\n# Justification for More Than One Dose of Epinephrine\nSchools and ECE programs should consider keeping multiple doses of epinephrine onsite so they can respond quickly to a food allergy emergency. Although some schools allow students to carry their own auto-injectors, a second auto-injector should be available at school in case a student does not have one at the time of the emergency. School and ECE program staff may also decide that having more than one auto-injector at different locations (especially for a large building or campus) will best meet a child's needs. In addition, some symptoms of anaphylaxis may continue after one dose of epinephrine, so a second dose may be needed at school if EMS does not arrive quickly. Some state laws allow for the prescribing of stock supply of non-patient specific epinephrine auto-injectors for use in schools, which may allow schools or ECE programs to acquire the needed additional doses of epinephrine. When allowed by state law and local policy, schools and ECE programs that have a doctor or nurse onsite can stock their emergency medical kits with epinephrine auto-injectors to be used for anaphylaxis emergencies. 63,65,66,72 In states where legislation does not exist or does not allow schools or ECE programs to stock epinephrine, staff will need to work with parents and their doctors to get additional epinephrine auto-injectors for students who need them.\n\n# d. Identify the role of each staff member in an emergency.\nAny plan for managing food allergies should state specifically what each staff member should do in an emergency. This information should be simple and easy to follow, particularly when a staff member who is not a licensed health professional is delegated to administer epinephrine. 24,68 Ideally, a registered nurse or doctor would be available to assess a food allergy emergency and decide if epinephrine is needed. When a nurse or doctor is not onsite, trained unlicensed assistive personnel or nonhealth professionals can recognize the signs and symptoms of an allergic reaction, have quick access to an epinephrine auto-injector, and administer epinephrine. 70,71 Examples of these staff members may include health aides and assistants, teachers, athletic coaches, food service staff, administrators, and parent or adult chaperones. A licensed health care professional such as a registered nurse, doctor, or allergist should train, evaluate, and supervise unlicensed assistive personnel or delegated nonhealth professionals. This training should teach staff how to recognize the signs and symptoms of a reaction, administer epinephrine, contact EMS, and understand state and local laws and regulations related to giving medication to students.\nECE programs that care for children with chronic conditions such as food allergies should seek the services of a trained health advocate or consultant to help staff develop emergency plans, write policies, and train staff. ECE programs are required to have a certified first aider present at all times. 50 All ECE program staff should get annual first aid training that teaches them how to recognize and respond to pediatric emergencies. 49 This training should include how to recognize the signs and symptoms of an allergic reaction and how to give epinephrine through an auto-injector. 23 ECE programs should keep records of all staff training.\n\n# e. Prepare for food allergy reactions in children without a prior history of food allergies.\nSchools and ECE programs should be ready to respond to severe allergic reactions in children with no history of anaphylaxis or no previously diagnosed food allergies. At a minimum, schools and ECE programs should establish a protocol for contacting emergency services when an allergic reaction is suspected and follow this protocol immediately when a child exhibits signs of anaphylaxis.\nIf allowed by state law, the school doctor or nurse may stock their emergency medical kits with epinephrine auto-injectors to be used for anaphylaxis emergencies. If the school or ECE program has a FAMPP, written protocol, and licensed or delegated trained staff, an epinephrine auto-injector may be used for anaphylaxis regardless of previous allergy history.\nf. Document the response to a food allergy emergency.\nEmergency response should include a protocol for documenting or recording each emergency incident and use of epinephrine. 12,65,68 Documentation should include the following:\n°°Time and location of the incident.\n°°Food allergen that triggered the reaction (if known).\n°°If epinephrine was used and the time it was used.\n°°Notification of parents and EMS.\n°°Staff members who responded to the emergency.\nSection 6 lists state and organizational resources that include examples of epinephrine administration reports.\nCorrective actions and lessons learned from an incident should be used to revise the child's individual plan and the school's or ECE program's FAMPP, if needed. School and ECE program administrators also should review the emergency response with the child's parents, the staff members involved in the response, local EMS responders, and the child. 63,70 See the Example Checklist for an example of steps to follow after a nonfatal food allergy emergency.\n\n# Example Checklist: Steps to Take Within 24 Hours of a Nonfatal Food Allergy Reaction\n- Call parent or guardian to follow up on student condition.\n- Review anaphylactic or allergic episode with parent or guardian and student.\n°°Identify allergen and route of exposure-discuss signs and symptoms with parent or guardian.\n°°Review actions taken.\n°°Discuss positive and negative outcomes.\n°°Discuss any needed revision to care plan based on experience or outcome.\n- Discuss family role with parent or guardian to improve outcomes.\n- Discuss school, ECE program, and home concerns to improve prevention, response, and student outcomes.\n- Ask parent or guardian to replace epinephrine dose that was given, if needed.\n- Ask parent or guardian to follow up with health care provider.\nSource: National Association of School Nurses, 2011.\n\n# Provide professional development on food allergies for staff.\nSchools and ECE programs should provide training to all staff members to increase their knowledge about food allergies and how to respond to food allergy emergencies. This training should focus on how to reduce the risk of an allergic reaction, respond to allergic reactions, and support the social and academic development of children with food allergies. 25,38,73 Schools and ECE programs should coordinate training activities with a licensed health care professional, such as a school nurse, public health nurse, public health educator, or school or community doctor. Training can include use of existing materials that provide general information about food allergies, as well as information and resources to help staff meet the specific needs of individual children. 23,24,39,49,73,74 Administrators should allow enough time for proper training, and all training should be evaluated to make sure it is effective.\nIn 2010, the National Diabetes Education Program updated their guidance to help students manage their diabetes in schools. 16 This updated guide outlines three levels of training that include basic training for all staff and specialized training for specific staff members. This approach provides a useful framework that has been adapted here to guide training on food allergy management in schools and ECE programs.\n\n# a. Provide general training on food allergies for all staff.\nAny staff member who might interact with children with food allergies or be asked to help respond to a food allergy emergency should be trained. Examples include administrators, nutrition and food service staff (including contract staff ), classroom and specialty teachers, athletic coaches, school counselors, bus drivers, custodial and maintenance staff, therapists, paraeducators, special education service providers, librarians and media specialists, security staff, substitute teachers, and volunteers such as playground monitors and field trip chaperones. General training content should include the following:\n°°School or ECE program policies and practices.\n°°An overview of food allergies.\n°°Definitions of key terms, including food allergy, major allergens, epinephrine, and anaphylaxis.\n°°The difference between potentially life-threatening food allergy and other food-related problems.\n°°Signs and symptoms of a food allergy reaction and anaphylaxis and information on common emergency medications.\n°°General strategies for reducing and preventing exposure to allergens (in food and nonfood items).\n°°Policies on bullying and harassment and how they apply to children with food allergies. °°How to respond to a food allergy emergency.\n°°Information about federal laws that could apply, such as the ADA, Section 504, and FERPA. (See Section 5 for more information about applicable federal laws.) Information about any state laws, including regulations, or district policies that apply.\n°°How to administer epinephrine with an auto-injector (for those formally delegated to do so).\n°°How to help children treat their own food allergy episodes.\n°°Effects of food allergies on children's behavior and ability to learn.\n°°Importance of giving emotional support to children with food allergies and to other children who might witness a severe food allergy reaction (anaphylaxis).\n°°Common risk factors, triggers, and areas of exposure to food allergens in schools or ECE programs.\n°°Specific strategies for fully integrating children with food allergies into school and class activities while reducing the risk of exposure to allergens in classrooms, during meals, during nonacademic outings, on field trips, during official activities before and after school or ECE programs, and during events sponsored by schools or ECE programs that are held outside of regular hours. These strategies could address (but are not limited to) the following: §°Special seating arrangements when age and circumstance appropriate (e.g., during meal times, birthday parties). §°Plans for keeping foods with allergens separated from foods provided to children with food allergies. §°Rules on how staff and students should wash their hands and clean surfaces to reduce the risk of exposure to food allergens. §°The importance of not sharing food. §°How to read food labels to identify food allergens.\n\n# c. Provide specialized training for staff who are responsible for managing the health of children with food allergies on a daily basis.\nThis training should be required for district nurses, school nurses, school doctors, and professionally qualified health coordinators or managers. In addition to the general and in-depth content described previously, this training should include information about how to:\n°°Create ECPs and review or develop other individual care plans as needed.\n°°Manage and store medication.\n°°Delegate and train unlicensed assistive personnel to administer epinephrine.\n°°Help children manage their own food allergies.\n°°Document the tasks performed as part of food allergy management.\n°°Evaluate emergency responses and staff members' ability to respond to food allergy emergencies.\nTraining should be conducted at least once a year, and should be reviewed after a food allergy reaction or anaphylaxis emergency for the purpose of improving prevention and response.\nSchools and ECE programs should consult with parents of children with food allergies when they design staff training. These parents have knowledge and experience on how to manage their child's food allergies, as well as information from their child's doctor. Parents do not need to participate in the delivery of training sessions or attend staff training.\n\n# Educate children and family members about food allergies.\na. Teach all children about food allergies.\nAll children need to learn about food allergies, but teaching methods will differ on the basis of their age and the setting. For example, schools can provide food allergy education as part of the health education or other curriculum topic, such as family and consumer sciences, general science, physical education, and character education. 41,45,67,69,75,76 ECE programs can provide food allergy education with help from certified health education specialists.\nFood allergy education should be appropriate for the developmental level and culture of the children in a particular school or ECE program. It should focus on increasing awareness and understanding of food allergies and building support and acceptance of people with food allergies. 59,76 At a minimum, all children should be able to:\n°°Identify signs and symptoms of anaphylaxis.\n°°Know and understand why it is wrong to tease or bully others, including people with food allergies.\n°°Know and understand the importance of finding a staff member who can help respond to suspected food allergy emergencies.\n°°Understand rules on hand washing, food sharing, allergen-safe zones, and personal conduct.\nFood allergy awareness is reinforced when staff members model behaviors and attitudes that comply with rules that reduce exposure to food allergens. 48 b. Teach all parents and families about food allergies.\nA successful FAMPP needs support and participation from parents of children with food allergies and from parents of children without food allergies. All parents should get information to increase their awareness and understanding of food allergies, the policies and practices that protect children with food allergies, the roles of all staff members in protecting children with food allergies, and the measures parents of children with and without food allergies can take to help ensure this protection. 45,76 School and ECE program administrators, working with school or district nurses or health consultants or managers, should educate families on food allergy policies and practices. Classroom teachers should provide information to all parents about what is being done to prevent food allergy reactions in the classroom. Food service staff should provide information to families about federal regulations of the U.S. Department of Agriculture's Food and Nutrition Service and practices that protect children, and manage food allergies during meals served under USDA meal programs. District and school policies and protocols to prevent bullying, respond to food allergy emergencies, and create a safe environment for all children should be shared with all families.\nSchools and ECE programs can share information in many ways, including through letters or e-mails to parents; updates on school Web sites; and announcements at parent-teacher association meetings, school nights, health fairs, and community events.\n\n# Create and maintain a healthy and safe educational environment.\nSchools, ECE programs, and communities have a shared responsibility to promote a safe physical environment that protects children with food allergies and climate that supports their positive psychological and social development. 77,78 a. Create an environment that is as safe as possible from exposure to food allergens.\nSchools and ECE programs can create a safer learning environment by reducing children's exposure to potential allergens. 24,39,74 When a child has a documented food allergy, staff should take active steps to reduce the risk of exposure in all common areas, such as classrooms and cafeterias. 12 Some schools or ECE programs have considered banning or have banned specific food across the entire school or ECE program setting in an attempt to eliminate exposing a child with a food allergy to that food. But, such an option cannot guarantee a totally safe environment because there is no reasonable or fail-safe way to prevent an allergen from inadvertently entering into a building. Even with such a ban in place, a school or ECE program still has a responsibility to properly plan for children with any life-threatening food allergies, to educate all school personnel accordingly, and ensure that school staff are trained and prepared to prevent and respond to a food allergy emergency.\nSchools or ECE programs may choose other alternatives to banning allergens including the designation of allergen-safe zones, such as an individual classroom or eating area in the cafeteria, or designation of food-free zones, such as a library, classroom, or buses. 45 79 provide school districts, schools, and ECE programs with requirements governing the cleaning and sanitizing of surfaces and other practices that can protect against the unintentional transfer of residue or trace amount of an allergic food into another food. Some practices to reduce this cross-contact include the following:\n°°Clean and sanitize with soap and water or all-purpose cleaning agents and sanitizers that meet state and local food safety regulations, all surfaces that come into contact with food in kitchens, classrooms, and other locations where food is prepared or eaten. Cleaning with water alone will not remove food allergens.\n°°Clean and sanitize food preparation equipment, such as food slicers, and utensils before and after use to prevent cross-contact.\n°°Clean and sanitize trays and baking sheets after each use. Oils can seep through wax paper or other liners and cause cross-contact.\n°°Prepare food separately for children with food allergies. Strategies should include preparing items without allergens first, using a separate work space and equipment, and labeling and storing items before preparing other foods.\n°°Train all staff who prepare, handle, or serve food how to read labels to identify food allergens. Make sure that staff members are knowledgeable about current labeling laws. Because food labels often change, they should be read every time the food is purchased. Ingredient lists posted on Web sites are not reliable. The manufacturer of the food should be contacted if clarification is needed.\n°°Use appropriate hand-washing procedures that emphasize the use of soap and water. Hand sanitizers are not effective in removing food allergens.\nNutrition and food service staff in schools and ECE programs are required to follow local food safety and sanitation laws and be trained in practices that prevent food, surface-to-food, and food-to-food contamination that also serve to help prevent cross-contact of food allergens. Meals and snacks may be served in locations other than cafeterias, handled by staff members other than the food service staff, or provided outside of a USDA Child Nutrition Program. When developing policies and procedures for food handling, consider all possible situations where food might be prepared or served, any staff members who might be involved, and the state and local food safety regulations that might be appropriate to help prevent the transfer of food allergens in these situations.\nIn ECE programs, additional precautions are recommended to reduce the risk of food allergy reactions, especially among children with a history of anaphylaxis. Many of these recommendations are consistent with common practices for managing any child in an ECE program.\n°°Make sure that all staff members can read product labels and identify food allergens.\n°°Recommend, but do not require, that children with known food allergies wear a medical alert bracelet.\n°°Promote good hand-washing practices before and after eating.\n°°Supervise children closely during mealtimes. Consider assigned seating for meals, especially in situations with family-style dining. Emphasize that children not share food.\n°°Put children's names on cups, plates, and utensils to avoid confusion and cross-contact.\n°°Designate food storage areas for foods brought from home. 6,45,77 c. Make outside groups aware of food allergy policies and rules when they use school or ECE program facilities before or after hours.\nLocal agencies, community groups, and community members who use school or ECE program facilities before or after operating hours should be aware of and comply with policies on food, cleaning, and sanitation procedures. If food is allowed in the building, consider banning food from specific classrooms or areas that children with food allergies use often. School and ECE program staff should be notified when outside groups are using their facilities.\n\n# d. Create a positive psychosocial climate.\nSchools and ECE programs should foster a climate that promotes positive psychological and social development; that actively promotes safety, respect, and acceptance of differences; and fosters positive interpersonal relationships between staff members and children and between the children themselves. The psychosocial climate is influenced by clear and consistent disciplinary policies, meaningful opportunities for participation, and supportive behaviors by staff members and parents. 78 Children with food allergies need an environment where they feel secure and can interact with caring people they trust. Bullying, teasing, and harassment can lead to psychological distress for children with food allergies which could lead to a more severe reaction when the allergen is present. 22,43,44 A positive psychosocial climate-coupled with food allergy education and awareness for all children, families, and staff members-can help remove feelings of anxiety and alienation among children with food allergies. 43,44 To create a positive psychosocial climate, staff members, children, and parents must all work together. School nurses, school counselors, or mental health consultants can provide leadership and guidance to set best practices and strategies for a positive psychosocial climate. Staff members should promote and reinforce expectations for a positive and supportive climate by making sure the needs of children with food allergies are addressed. For example, they can avoid using language and activities that isolate children with food allergies and encourage everyone's help in keeping the classroom safe from food allergens. Children can help develop classroom rules, rewards, and activities.\nAll children and staff members share responsibility for preventing bullying and social isolation of children with food allergies. School and ECE program staff should recognize that acceptance by peers is one of the most important influences on a child's emotional and social development. 78 Among adolescents, food allergy education and awareness can be an effective strategy to improve social interactions, reduce peer pressure, and decrease risk-taking behaviors that expose them to food allergens. 22 Children should be expected to treat others with respect and to be good citizens, not passive bystanders, when they are aware of bullying or peers who seem troubled. Children should understand the positive or negative consequences associated with their actions. Rules and policies against bullying behavior should be developed in partnership with staff members, families, and children. They should be posted in buildings; published in school handbooks; and discussed with staff members, children, and families. All children and staff members should be encouraged to report bullying and harassment of any child with food allergies. 80,81\n\n# Conclusion\nSchools and ECE programs are responsible for the health and safety of children with food allergies. The strategies presented in these guidelines can help schools and ECE programs take a comprehensive approach to managing food allergies. Through the collective efforts of school and ECE program staff members, parents, and health care providers, children with food allergies can be assured a safe place to thrive, learn, and succeed.\n\n# Meals and Snacks\n- Use nonfood incentives for prizes, gifts, and awards.\n- Help students with food allergies read labels of foods provided by others so they can avoid ingesting hidden food allergens.\n- Consider methods (such as assigned cubicles) to prevent cross-contact of food allergens from lunches and snacks stored in the classroom.\n- Support parents of children with food allergies who wish to provide safe snack items for their child in the event of unexpected circumstances.\n- Encourage children to wash hands before and after handling or consuming food.\n- - Designate an allergen-safe food preparation area.\n- Provide advanced copies of menus for parents to use in planning.\n- Be prepared to share food labels, recipes, or ingredient lists used to prepare meals and snacks with others.\n- Do not allow food to be eaten on buses except by children with special needs such as those with diabetes.\n- Encourage children to wash hands before and after handling or consuming food. - Identify special needs before field trips or events.\n- Package meals and snacks appropriately to prevent crosscontact.\n- Encourage children to wash hands before and after handling or consuming food.\n- Encourage hand washing before and after handling or consuming food.\n\n# Physical Education and Recess\n\n# Meals and Snacks\n- Keep food labels from all foods served to children with allergies for at least 24 hours after servicing the food in case the child has a reaction.\n- Keep current contact information for vendors and suppliers so you can get food ingredient information.\n- Read all food labels and recheck with each purchase for potential food allergens.\n- Report mistakes such as crosscontact with an allergen or errors in the ingredient list or menu immediately to administrators and parents.\n- Wash all tables and chairs with soap and water or all-purpose cleaning agents before each meal period.\n- Encourage children, school staff , and volunteers to wash hands before and after handling or consuming food.\na USDA Web site: www.fns.usda.gov/cnd/guidance/special_dietary_needs.pdf.\n\n# Food Allergy Management and Prevention Plan Checklist\nUse this checklist to determine if your school or ECE program has appropriate plans in place to promote the health and well-being of children with food allergies. For each priority, check the box to the left if you have plans and practices in place. Develop plans to address the priorities you did not check.\nYou can also use the checklist to evaluate your response to food allergy emergencies. Ongoing evaluation and improvement can help you improve your plans and actions.\nReview the full descriptions of the five priorities (pages to make sure that your plans and practices are complete and that your plans for improvement will meet the needs of children, their families, administrators, and staff. This section presents the actions that school district leaders can take to implement the voluntary recommendations in Section 1. Although the focus of the recommendations is on the management of food allergies at the school building level, district-level leadership and policy and staff support are essential for the success of school-level food allergy management.\n\n# School District Policy Support\nSchool boards can adopt written policies that direct and support clear, consistent, and effective practices for managing the risk of food allergies and response to food allergy emergencies. Data from CDC's 2006 School Health Policies and Programs Study indicate that only slightly more than 40% of school districts have model food allergy policies. 8 A comprehensive and uniform set of district policies for managing food allergies in schools can:\n- Communicate the district's commitment to effectively managing food allergies to school administrators and staff members, parents, and the community.\n- Promote consistency of priorities, actions, and options for managing food allergies across the district to avoid confusion and haphazard responses.\n- Align food allergy management plans in schools with federal and state laws, including regulations, and policies, as well as other established school policies.\n- Make protective practices and strategies for managing food allergies in schools an integral part of ongoing school activities.\n- Support the food allergy management decisions and practices of school administrators and staff members.\n- Increase public knowledge about food allergies and applicable laws and public support for implementation of effective food allergy management practices in schools. Section 6 provides a list of resources with more information and strategies to inform school policymakers.\n\n# School District Staff Support\nDistrict policies are implemented with the support of board members, the district superintendent, and district-level staff members. 82 District leaders and staff can:\n- Communicate policy requirements and school system directives.\n- Help schools implement and comply with applicable federal and state laws, including regulations, and policies.\n- Help communicate lines of authority for managing food allergies in school buildings.\n- Provide standardized forms, procedures, tools, and plans, including a sample Food Allergy Management and Prevention Plan (FAMPP), to schools.\n- Coordinate training to improve consistency of practices across the district.\n- Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n- Help schools plan and implement their FAMPPs.\nDistrict staff might also provide direct assistance to schools to help them meet the needs of students with food allergies, especially when the school does not have key staff, such as a doctor or full-time registered nurse, working at the building level. District staff sometimes communicate directly with parents and doctors who might need additional information about a school's food allergy policies and practices. They also may communicate directly with parents whose children need help managing their food allergy as they move from one school to the next within the district.\n\n# School Board Members\n1. Set the direction for the school district's coordinated approach to managing food allergies.\n- Develop a comprehensive set of school district policies to manage food allergies in school settings.\nWork with a variety of school staff, including school administrators, Section 504 coordinators, licensed health care professionals (e.g., doctors, registered nurses), school health advisory council members, teachers, paraeducators, school food service staff, bus drivers and other transportation staff, custodians and maintenance staff, after-school program staff, students, parents, community experts, and others who will implement policies. Section 6 provides a list of resources with more information and strategies to inform school policymakers.\n- Align food allergy policies and practices with the district's \"all-hazards\" approach to emergency planning and with policies on the care of students with chronic health conditions.\n- Be familiar with federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure local school policies and practices follow these laws and policies.\n- Use multiple mechanisms, such as newsletters and Web sites, to disseminate and communicate food allergy policies to appropriate district staff, families, and the community.\n- Give parents and students information about the school district's procedures they can use if they disagree with the food allergy policies and plans implemented by the school district.\n- On a regular schedule, review and evaluate the district's food allergy-related policies and revise as needed.\n\n# Prepare for food allergy emergencies.\n- Make sure that responding to life-threatening food allergy reactions is part of the school district's \"all-hazards\" approach to emergency planning.\n- Support and allocate resources to trained and appropriately certified or licensed staff members to respond to food allergy emergencies in all schools.\n- Review data and information (e.g., when and where medication was used) from incident reports of food allergy reactions and assess the effect of the incident on all students involved. Modify your policies as needed.\n\n# Support professional development on food allergies for staff.\n- Support and allocate resources and time for professional development and training on food allergies.\n- Identify professional development and training needs to make sure that district and school staff, especially those on food allergy management teams, are adequately trained, competent, and confident to perform assigned responsibilities to help students with life-threatening food allergies and respond to an emergency.\n\n# Educate students and family members about food allergies.\n- Encourage the inclusion of information about food allergies in the district's health education or other curriculum for students to raise awareness.\n- Support and allocate resources for awareness education for students and parents.\n\n# Create and maintain a healthy and safe school environment.\n- Endorse the use of signs and other strategies to increase awareness about food allergies throughout the school environment.\n- Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n- Support collaboration with district and community experts to integrate the management of food allergies with the management of other chronic health conditions.\n- Support collaboration with district and community experts to make sure schools have healthy and safe physical environments.\n- Develop and consistently enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n\n# School District Superintendent\n1. Lead the school district's coordinated approach to managing food allergies.\n- Provide leadership and designate school district resources to implement the school district's comprehensive approach to managing food allergies.\n- Promote, disseminate, and communicate food allergy-related policies to all school staff, families, and the community.\n- Make sure that each school has a team that is responsible for food allergy management.\n- Be familiar with federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure your policies and practices follow these laws and policies.\n- Give parents and students information about the school district's procedures they can use if they disagree with the food allergy policies and plans implemented by the school district.\n- On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n- Establish evaluation strategies for determining when the district's food allergy policies and practices or the school's FAMPP are not effectively implemented.\n\n# Prepare for food allergy emergencies.\n- Make sure that responding to life-threatening food allergy reactions is part of the school district's all-hazards approach to emergency planning.\n- Make sure that each school has trained and appropriately certified or licensed staff members develop and implement written Emergency Care Plans (ECPs) for students with food allergies. Additional plans can include Individualized Healthcare Plans (IHPs), Section 504 plans, or, if appropriate, Individualized Education Programs (IEPs).\n- Encourage periodic emergency response drills and practice on how to handle a food allergy emergency in schools.\n- Review data and information (e.g., when and where medication was administered) from incident reports of food allergy reactions and assess the effect of the incident on all students involved. Modify policies as needed.\n\n# Support professional development on food allergies for staff.\n- Make sure that district and school staff, especially those responsible for implementing the FAMPP, have professional development and training opportunities to become adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n\n# Educate students and family members about food allergies.\n- Help ensure that information about food allergies is included in the district's health education curriculum for students to raise awareness.\n- Communicate with parents about the district's policies and practices to protect the health of students with food allergies.\n\n# Create and maintain a healthy and safe school environment.\n- Increase awareness of food allergies throughout the school environment.\n- Collaborate with school board members, school administrators, and other school staff to create a safe environment for students with food allergies. Provide oversight of schools with children who have food allergies.\n- Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n- Consistently enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n\n# Health Services Director\nThe health services director can be a doctor or registered nurse working at the district level.\n\n# Participate in the school's coordinated approach to managing food allergies.\n- Help develop a school district's comprehensive approach to managing life-threatening food allergies that will support the FAMPP used in each school.\n- Provide leadership and obtain the resources needed to implement the district's comprehensive approach to managing food allergies.\n- Promote, disseminate, and communicate the food allergy policies and practices to all school staff, families, the school community, and the local medical community.\n- Know and educate others about federal and state laws, including regulations and policies relevant to the obligations of schools to students with food allergies and make sure policies and practices follow these laws.\n- Make sure a doctor or registered nurse reviews all FAMPPs and ECPs. Create other plans as needed.\n- Provide direct assistance to help schools develop procedures and plans for monitoring students with food allergies, including, if appropriate, through Section 504 plans, or IEPs.\n- Coordinate with other district staff, including the food service director, curriculum coordinator, and student support services director.\n- Make sure that food allergy policies and practices address competitive foods (foods and beverages sold outside of the federal reimbursable school meals program), such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n- On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n\n# Ensure the daily management of food allergies for individual students.\n- Help the school team responsible for the FAMPP write this plan. If a student is eligible to receive services under Section 504 or, if appropiate, IDEA, make sure all provisions of these federal laws are met.\n- Create standard forms, such as health forms, school registration forms, and ECPs, for schools to use to identify students e with food allergies and develop individual management plans for them. Establish protocols for tasks related to developing management plans, such as how to interview parents, get appropriate documentation from doctors, and coordinate meals with food service staff.\n- Help schools implement policies and procedures for managing student medications. These policies should include how epinephrine auto-injectors are stored and accessed, how their use is monitored, and the schedule for regularly inspecting auto-injector expiration dates. They should also include plans for supporting students who are permitted and capable of managing their own food allergies by carrying and using epinephrine auto-injectors.\n- Help schools that do not have a registered nurse on site develop plans to manage food allergies in individual students, provide health services when needed, and respond to food allergy emergencies.\n- Help schools link students with food allergies and their families to community health services and family support services when needed.\n\n# Prepare for food allergy emergencies.\n- Develop protocols for responding to food allergy emergencies that can guide practices at the building level.\n- If allowed by state laws, including regulations, and district policy, obtain or write nonpatient-specific prescriptions and standing orders for epinephrine auto-injectors that can be used to respond to anaphylaxis emergencies.\n- Work directly with local emergency responders to confirm that they carry epinephrine auto-injectors for anaphylaxis emergencies.\n- Review school emergency response plans to make sure they include the actions needed to respond to food allergy emergencies.\n- Help schools conduct periodic emergency response drills and practice how to handle food allergy emergencies.\n- Help schools conduct debriefing meetings after a food allergy reaction or emergency. - Review data and information (e.g., when and where medication was administered) from incident reports of food allergy reactions and assess the effect of the incident on all students involved. Provide input to modify policies and practices as needed.\n- Collect school data to monitor and track food allergy emergencies across the district. Use these data to guide improvements in policies and practices.\n\n# Support professional development on food allergies for staff.\n- Seek professional development opportunities to learn updated information about managing food allergies.\n- Educate district and school staff about food allergies so they are adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n- Coordinate district training for school nurses and others who might lead school teams responsible for implementing FAMPPs to make sure they have the information they need to develop effective plans.\n- Know and educate others about federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure district policies and practices follow these laws and policies.\n- Help school building leaders plan and provide food allergy training for staff, parents, and students.\n- Help train delegated staff members on how to store, access, and administer epinephrine autoinjectors.\n\n# Educate students and family members about food allergies.\n- Work collaboratively with the curriculum coordinator or health education coordinator at the district level to identify appropriate food allergy content for the district's health education curriculum.\n- Help school administrators communicate the district's policies and practices for managing food allergies to parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe school environment.\n- Work collaboratively with district staff to enforce policies that promote healthy physical environments.\n- Work collaboratively with student support services staff at the district level to enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n\n# Student Support Services Director\nThe student support services director can be a school psychologist, school counselor, or child and family services director.\n1. Participate in the school's coordinated approach to managing food allergies.\n- Help develop a school district's comprehensive approach to managing food allergies that will support the FAMPP used in each school.\n- Promote, disseminate, and communicate food allergy policies to all school staff, families, and the community.\n- Know and inform others about federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure district policies and practices follow these laws and policies.\n- Provide direct assistance to help schools establish procedures and plans for monitoring students with food allergies, including, if appropriate, through Section 504 plans or IEPs.\n- Coordinate with other district staff, including the food service director, curriculum coordinator, and health services director.\n- On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n\n# Ensure the daily management of food allergies for individual students.\n- Help the school team responsible for implementing the FAMPP write this plan. If a student is eligible to receive services under Section 504 or, if appropiate, IDEA, make sure all provisions of these federal laws are met.\n- Help schools link students with food allergies and their families to community health services and family support services when needed.\n\n# Prepare for food allergy emergencies.\n- Help develop protocols for responding to food allergy emergencies that can guide practices in district schools.\n- Review school emergency response plans to make sure they include the actions needed to respond to food allergy emergencies.\n- Help schools conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n- Review data and information (e.g., when and where medication was administered) from incident reports of food allergy reactions and assess the effect of the incident on affected students. Provide input to modify policies and practices as needed.\n\n# Support professional development on food allergies for staff.\n- Help educate district and school staff about food allergies so they are adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n- Help develop district training for all school staff to help them improve their FAMPPs.\n- Know and educate others about federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure district and school policies and practices follow these laws and policies.\n- Help school building leaders plan and provide food allergy training for staff, parents, and students.\n\n# Educate students and family members about food allergies.\n- Help school administrators communicate the district's policies and practices for preventing food allergy reactions to parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe school environment.\n- Work collaboratively with district staff to enforce policies that promote healthy physical environments.\n- Work collaboratively with district health services staff, school principals, school counselors, and others to help enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n\n# District Food Service Director\n1. Participate in the school's coordinated approach to managing food allergies.\n- Help develop a school district's comprehensive approach to managing food allergies that will support the FAMPP used in each school.\n- Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n- Access and use resources and guidance from local health departments and the state agency that administers child nutrition programs.\n- Promote, disseminate, and communicate the food allergy policies to school staff, families, and the community.\n- Know and educate others about federal and state laws, including regulations, and policies on food allergies and the need to follow these laws and policies, including those regulations that pertain to the U.S. Department of Agriculture's (USDA's) Child Nutrition Program.\n- Ensure that food service staff understand USDA's required doctor's statement as written and that the statement provides sufficient information to provide a safe meal.\n- Help establish school-level procedures and plans for monitoring students with food allergies, including plans for accommodating the special nutritional needs of individual students when necessary.\n- Coordinate with other district staff, including the student support services director, curriculum coordinator, and health services director.\n- On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n\n# Ensure the daily management of food allergies for individual students.\n- Develop and implement procedures in each school for identifying students with food allergies in school cafeterias. Make sure that procedures governing access to personally identifiable information from education records are consistent with student rights under the Family Educational Rights and Privacy Act of 1974 (FERPA) and any other federal and state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.)\n- Work with the health services director, principals and other school staff responsible for implementing FAMPPs to set up procedures for handling food allergies in the cafeteria. These plans should be consistent with the student's IHP, Section 504 plan, or, if appropriate, IEP, and USDA regulations on meals and food substitutions, as reflected in the USDA's Accommodating Children with Special Dietary Needs in the School Nutrition Programs. Procedures should be established for children who participate in school meals programs and those who bring food from home.\n- Work with school teams responsible for developing ECPs for students with food allergies. For schools that participate in the USDA's Child Nutrition programs, make sure that documents that list appropriate food substitutions for a student with a food allergy disability are signed by a licensed doctor. The doctor's statement must identify: °°The child's food allergy.\n°°An explanation of why the allergy restricts the child's diet.\n°°The major life activity affected by the allergy.\n°°The food or foods to be omitted from the child's diet and the foods or choices that can be substituted.\n- Establish procedures for obtaining information to clarify food substitutions and other relevant medical information from a student's doctor as needed.\n- Coordinate food substitutions for all schools with students who have food allergies, in consultation as necessary with each child's doctor, and manage the documentation of these activities.\nWhen possible, use foods that are already served in school meals or snacks to make appropriate substitutions.\n- Provide oversight and tracking of each student's dietary plans, including tracking allergic reactions that occur during school meals.\n- Develop and implement policies and procedures to prevent allergic reactions and cross-contact during meal preparation and service. Communicate these policies and procedures to school food service staff.\n- Keep information about ingredients for all foods bought and served by school food service programs and keep labels of foods given to food-allergic children for at least 24 hours so that the labels can be reviewed if needed.\n- Be prepared to share information about ingredients in recipes and foods served by food service programs with parents.\n\n# Prepare for food allergy emergencies.\n- Help develop protocols for responding to food allergy emergencies that can guide practices in district schools.\n- Help the health services director communicate the appropriate ways to avoid exposure to food allergens and respond to food allergy emergencies to all staff members who are involved in managing a student's food allergy in the cafeteria.\n- Make sure that food service staff are able to respond to a food allergy emergency in the cafeteria and implement an ECP.\n- Review school emergency response plans to make sure they include the actions needed to respond to food allergy emergencies during school meals.\n- Help schools conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n- Review data and information (e.g., when and where medication was administered) from incident reports on any food allergy reactions and assess the effect of the incident on affected students. Provide input to modify policies and practices as needed.\n\n# Support professional development on food allergies for staff.\n- Help educate district and school staff about food allergies so they are adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n- Provide training opportunities for school food service staff to help them understand how to follow policies and procedures for preparing and serving safe meals and snacks for students with food allergies.\n- Make sure that school food service staff participate in district training on food allergies.\n- Make sure that all school staff understand their role in preventing and responding to emergencies in the school cafeteria.\n- Help school building leaders plan and provide food allergy training for staff, parents, and students.\n\n# Educate students and family members about food allergies.\n- Help the curriculum coordinator or health education coordinator integrate food allergy lessons, such as how to read food labels, into the district's health education curriculum.\n- Communicate with parents about any foods that might be served as part of school meals programs such as the School Breakfast Program or the Fresh Fruit and Vegetable Program.\n- Share information about options for food substitutions with the parents of students with food allergies. Schools are encouraged to make substitutions with foods that have already been bought, when possible.\n- Work with administrators, classroom teachers, and parent-teacher organizations to offer food allergy education to parents in schools.\n- Help school administrators communicate the policies and procedures used in food service programs to prevent food allergy reactions to parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe school environment.\n- Work collaboratively with district staff to help enforce policies that promote healthy physical environments.\n- Work collaboratively with district health services staff, school principals, school food service staff, and others to help enforce policies that prohibit discrimination and bullying against students with food allergies.\n- Provide guidance to school food service staff that helps them to meet the dietary needs of students with food allergies and protect their health during school meals, while guarding against practices that could result in alienation of or discrimination against these students.\nSee Section 6 for more resources and tools that might assist in managing food allergies and allergy-related emergencies in schools.\n\n# Section 3. Putting Guidelines into Practice: Actions for School Administrators and Staff\nEffective management of food allergies in schools requires the participation of many people. This section presents the actions that school building administrators and staff can take to implement the recommendations in Section 1. Some actions duplicate responsibilities required under applicable federal and state laws, including regulations, and policies. Although many of the actions presented here are not required by statute, they can contribute to better management of food allergies in schools.\nSome actions are intentionally repeated for different staff positions to ensure that critical actions are addressed even if a particular position does not exist in the district or school (e.g., school doctor). This duplication also reinforces the need for different staff members to work together to manage food allergies effectively. All actions are important, but some will have a greater effect than others. Some actions may be most appropriately carried out by district-level staff members whose roles are to support food allergy management plans and practices across schools or to provide specific services to schools that do not have an on-site staff person to provide these services. Ultimately, each school district or school must determine which actions are most practical and necessary to implement and who should be responsible for those actions.\n\n# School Administrator\nThe school administrator can be a principal or assistant principal.\n\n# Lead the school's coordinated approach to managing food allergies.\n- Coordinate planning and implementation of a comprehensive Food Allergy Management and Prevention Plan (FAMPP) for your school. If your school has an on-site registered nurse, work with this person and the members of any relevant team-such as the school wellness team, school health team, or school improvement team-to plan and implement the FAMPP. Designate a qualified person (e.g., the registered nurse) to lead development of the FAMPP and designate responsibilities for implementing the plan as appropriate. If your school does not have an on-site nurse, ask for help from a registered nurse at the district level or from a public health nurse in the community.\n- Make sure staff understand the school's responsibilities under Section 504 of the Rehabilitation Act of 1973, the Americans with Disabilities Act (ADA), the Individuals with Disabilities Education Act (IDEA), and the Richard B. Russell National School Lunch Act to students who are or may be eligible for services under those laws. Make sure they understand the need to comply with the Family Educational Rights and Privacy Act of 1974 (FERPA) and any other federal and state laws that protect the privacy of student information. (See Section 5 for information about applicable federal laws.)\n- Communicate school district policies and the school's practices for managing food allergies to all school staff, substitute teachers, classroom volunteers, and families.\n- Make sure staff implement school district policies for managing food allergies.\n- Help staff implement the school's FAMPP.\n- On a regular basis, review and evaluate your school's FAMPP and revise as needed.\n\n# Ensure the daily management of food allergies for individual students.\n- Make sure that mechanisms-such as health forms, registration forms, and parent interviewsare in place to identify students with food allergies.\n- If your school does not have an on-site registered nurse, work with the parents of children with food allergies and their doctor to develop a written Emergency Care Plan (ECP) (sometimes called a Food Allergy Action Plan). This plan is needed to manage and monitor students with food allergies on a daily basis, whether they are at school or at school-sponsored events. If a student has been determined to be eligible for services under Section 504 or, if appropriate, IDEA, make sure that all provisions of these federal laws are met.\n- Share information about students with food allergies with all staff members who need to know, provided the exchange of information occurs in accordance with FERPA and any other federal and state laws that protect the confidentiality or privacy of student information. (See section 5 for more information about FERPA.) Make sure these staff members are aware of what actions are needed to manage each student's food allergy on a daily basis.\n\n# Prepare for and respond to food allergy emergencies.\n- Make sure that responding to life-threatening food allergy reactions is part of the school's \"all-hazards\" approach to emergency planning.\n- Make sure that parents of students with food allergies provide epinephrine auto-injectors to use in food allergy emergencies, if their use is called for in a student's ECP.\n- Set up communication systems that are easy to use for staff who need to respond to food allergy reactions and emergencies.\n- Make sure that staff who are delegated and trained to administer epinephrine auto-injectors can get to them quickly and easily.\n- Make sure that local emergency responders know that epinephrine may be needed when they are called to respond to a school emergency.\n- Prepare for food allergy reactions in students without a prior history of food allergies or anaphylaxis.\n- Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n- Conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n- Contact parents immediately after any suspected allergic reaction and after a child with a food allergy ingests or has contact with a food that may contain an allergen, even if an allergic reaction does not occur. If the child may need treatment, recommend that the parents notify the child's primary health care provider or allergist.\n- Document all responses to food allergy emergencies. Review data and information (e.g., when and where medication was used) from incident reports of food allergy emergencies and assess the effect on affected students. Provide input to modify your school district's emergency response policies and practices as needed.\n\n# Support professional development on food allergies for staff.\n- Make sure staff receive professional development and training on food allergies.\n- Coordinate training with licensed health care professionals, such as school or district doctors or nurses or local health department staff, and with other essential school or district professionals, such as the district's food service director, if appropriate. Invite parents of students with food allergies to help develop the content for this training.\n\n# Educate students and family members about food allergies.\n- Make sure that the school's curricular offerings include information about food allergies to raise awareness among students.\n- Communicate the school's responsibilities, expectations, and practices for managing food allergies to all parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe school environment.\n- Increase awareness of food allergies throughout the school environment.\n- Emphasize and support practices that protect and promote the health of students with food allergies across the school environment, during before-and after-school activities, and during transportation of students.\n- Make sure that students with food allergies have an equal opportunity to participate in all school activities and events.\n- Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n- Reinforce the school's rules that prohibit discrimination and bullying as they relate to students with food allergies.\n\n# Registered School Nurses\n\n# Participate in the school's coordinated approach to managing food allergies.\n- Take the lead in planning and implementing the school's FAMPP or help the school administrator with this task.\n- Support partnerships among school staff and the parents and doctors (e.g., pediatricians or allergists) of students with food allergies.\n- Consult state and local Nurse Practice Acts and guidelines to guide the roles and responsibilities of school nurses.\n\n# Supervise the daily management of food allergies for individual students.\n- Make sure that students with food allergies are identified. Share information with other staff members as needed, provided the exchange of information occurs in accordance with FERPA and any other federal and state laws that protect the confidentiality or privacy of student information.\n- Obtain or develop an ECP for each student with a food allergy or food allergy disability. Get the medical information needed to care for children with food allergies when they are at school, such as medical records and emergency information. Communicate with parents and health care providers (with parental consent) about known food allergies, signs of allergic reactions, relevant use of medications, complicating conditions, and other relevant health information.\n- Make sure that USDA's required doctor's statement is completed and provides clear information to assist in the preparation of a safe meal accommodation. This statement can be part of an ECP or a separate document.\n- Use a team approach to develop an Individualized Healthcare Plan (IHP) for each student with a food allergy, and, if required by Federal law, a Section 504 plan, or an Individualized Education Program (IEP), if appropriate.\n- Monitor each student's ECP or other relevant plan on a regular basis and modify plans when needed.\n- Refer parents of children who do not have access to health care to services in the community.\n- For students who have permission to carry and use their own epinephrine auto-injectors, regularly assess their ability to perform these tasks.\n\n# Prepare for and respond to food allergy emergencies.\n- Develop instructions for responding to an emergency if a school nurse is not immediately available. Add these instructions to the school's FAMPP.\n- File ECPs in a place where staff can get to them easily in an emergency. Distribute ECPs to staff on a need-to-know basis.\n- Make sure that the administration of an epinephrine auto-injector follows school policies and state mandates. Make sure that medications are kept in a secure place that staff can get to quickly and easily. Keep back-up epinephrine auto-injectors for students who carry their own. Regularly inspect the expiration date on all stored epinephrine auto-injectors.\n- Train and supervise delegated staff members how to administer an epinephrine auto-injector and recognize the signs and symptoms of food allergy reactions and anaphylaxis.\n- If allowed by state and local laws, work with school leaders to get extra epinephrine auto-injectors or nonpatient-specific prescriptions or standing orders for auto-injectors to keep at school for use by staff delegated and trained to administer epinephrine in an anaphylaxis emergency.\n- Assess whether students can reliably carry and use their own epinephrine auto-injectors and encourage self-directed care when appropriate.\n- Make sure that school emergency plans include procedures for responding to any student who experiences signs of anaphylaxis, whether the student has been identified as having a food allergy or not.\n- Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n- Contact parents immediately after any suspected allergic reaction and after a child with a food allergy ingests or has contact with a food that may contain an allergen, even if an allergic reaction does not occur. If the child may need treatment, recommend that the parents notify the child's primary health care provider or allergist.\n- After each food allergy emergency, review how it was handled with the school administrator, school doctor or nurse (if applicable), parents, staff members involved in the response, emergency medical services (EMS) responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n- Help students with food allergies transition back to school after an emergency.\n- Talk with students who may have witnessed a life-threatening allergic reaction in a way that does not violate the privacy rights of the student with the food allergy.\n\n# Help provide professional development on food allergies for staff.\n- Stay up-to-date on best practices for managing food allergies. Sources for this information include allergists or other doctors who are treating students with food allergies, local health department staff, national school nursing resources, and the district's food service director or registered dietitian.\n- Educate teachers and other school staff about food allergies and the needs of specific students with food allergies in a manner consistent with FERPA, USDA, and any other federal and state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.)\n- Advise staff to refer students to the school nurse when food allergy symptoms or side effects interfere with school activities so that medical and educational services can be properly coordinated.\n\n# Provide food allergy education to students and parents.\n- Teach students with food allergies about food allergies and help them develop self-management skills.\n- Make sure that students who are able to manage their own food allergies know how to recognize the signs and symptoms of their own allergic reactions, are capable of using an epinephrine auto-injector, and know how to notify an adult who can respond to a food allergy reaction.\n- Help classroom teachers add food allergy lessons to their health and education curricula.\n- Find ways for the parents of students with food allergies to share their knowledge and experience with other parents.\n- Work with administrators, classroom teachers, and parent-teacher organizations to offer food allergy education for parents at school.\n- Help the school administrator communicate the school's policies and practices for preventing food allergy reactions to parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe school environment.\n- Work with other school staff and parents to create a safe environment for students with food allergies. On a regular basis, assess the school environment, including the cafeteria and classrooms, to identify allergens in the environment that could lead to allergic reactions. Work with appropriate staff to develop strategies to help children avoid identified allergens.\n- Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n- Work with school counselors and other school staff to provide emotional support to students with food allergies.\n- Promote an environment that encourages students with food allergies to tell a staff member if they are bullied because of their allergy.\n\n# School Doctors\nA school doctor works full-time or part-time to provide consultation and a wide range of health services to the school population.\n\n# Participate in the school's coordinated approach to managing food allergies.\n- Lead or help plan and implement the school's FAMPP.\n- Support partnerships among school staff and the parents and doctors (e.g., allergists, pediatricians) of students with food allergies.\n- Keep current on federal, state, and local guidance on food allergy management.\n- Consult state and local Nurse Practice Acts to make sure the roles and responsibilities of school nurses are appropriate.\n- Guide and support the food allergy management practices of school nursing staff.\n- Help evaluate school FAMPPs.\n\n# Ensure the daily management of food allergies for individual students.\n- Help the school nurse perform the actions necessary to manage students with food allergies on a daily basis. (See the items under Action 2 for Registered School Nurses.)\n3. Prepare for and respond to food allergy emergencies.\n- Help the school nurse make sure that all students with food allergies have an ECP.\n- If allowed by state and local laws, write prescriptions or standing orders for nonpatient-specific epinephrine auto-injectors so the school can stock back-up medication for use in food allergy emergencies.\n- Help the school nurse assess whether students can reliably carry and use their own epinephrine auto-injector and encourage self-directed care when appropriate.\n- Help the school nurse train staff how to use epinephrine auto-injectors and recognize the signs and symptoms of food allergy reactions and anaphylaxis.\n- Help the school nurse and health assistants regularly inspect the expiration date on all stored epinephrine auto-injectors.\n- Make sure that school emergency plans include procedures for responding to any student who experiences signs of anaphylaxis, whether diagnosed with a food allergy or not.\n- Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n- Contact parents immediately after any suspected allergic reaction and after a child with a food allergy ingests or has contact with a food that may contain an allergen, even if an allergic reaction does not occur. If the child may need treatment, recommend that the parents notify the child's primary health care provider or allergist.\n- After each food allergy emergency, review how it was handled with the school administrator, school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n\n# Help provide professional development on food allergies for staff.\n- Share current and relevant knowledge of best practices for managing food allergies with school leaders (e.g., school administrator, school nurse).\n- Help educate teachers and other school staff about food allergies and the needs of specific students with food allergies, in a manner consistent with FERPA, USDA, and any other federal and state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.)\n- Advise staff to refer students to the school doctor or nurse when symptoms or side effects of a food allergy interfere with school activities so that medical and educational services can be coordinated.\n\n# Provide food allergy education to students and parents.\n- Help teach students with food allergies about food allergies and help them develop selfmanagement skills.\n- Help the school nurse make sure that students who are able to manage their food allergies know how to recognize the signs and symptoms of their own allergic reactions, are capable of using an epinephrine auto-injector, and know how to notify an adult who can respond to a food allergy reaction.\n- Help classroom teachers add food allergy lessons to their health and education curricula.\n- Help find ways for parents of students with food allergies to share their knowledge and experience with other parents.\n- Work with administrators, the school nurse, classroom teachers, and parent-teacher organizations to offer food allergy education for parents at school.\n- Help the school administrator communicate the school's policies and practices for preventing food allergy reactions to parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe school environment.\n- Work with other school staff and parents to create a safe environment for students with food allergies.\n- On a regular basis, assess the school environment, including the cafeteria and classrooms, to identify allergens in the environment that could lead to allergic reactions. Work with appropriate staff to manage identified allergens.\n- Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n- Work with school counselors, the school nurse, and other school staff to provide emotional support to students with food allergies.\n- Promote an environment that encourages students with food allergies to tell a staff member if they are bullied or harassed because of their allergy.\n\n# Health Assistants, Health Aides, or Other Unlicensed Personnel\nThese staff members work with the school or district nurse or doctor.\n\n# Help with the daily management of food allergies for individual students.\n- Help the school nurse identify students with food allergies. Review the medical records and emergency information of all students.\n- Talk with the school nurse about any allergic reactions and changes in a student's health status.\n\n# Prepare for and respond to food allergy emergencies.\n- Get a copy of the ECP for every student with food allergies. Make sure the plan includes information about signs and symptoms of an allergic reaction, how to respond, and whether medications should be given.\n- File ECPs in a place where staff can get to them easily in an emergency.\n- Be ready to respond to a food allergy emergency if a nurse is not immediately available. If school policies and state mandates allow you to give medication and you are delegated to perform this task, complete training on how to administer epinephrine, regularly review instructions, and practice this task. Make sure that medications are kept in a secure place that you or other delegated staff members can get to quickly and easily. Regularly inspect the expiration date on all stored epinephrine auto-injectors.\n- After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n\n# Participate in professional development on food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of allergic reactions and how they are communicated by students.\n°°How to read food labels and identify allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in the school in ways that are consistent with a student's ECP.\n°°Your role in implementing a student's ECP.\n°°When and how to call EMS and parents.\n°°How FERPA, USDA, and other federal and state laws that protect the privacy and confidentiality of student information apply to students with food allergies and food allergy disabilities.\n°°General strategies for reducing or preventing exposure to food allergens in the classroom, such as cleaning surfaces, using nonfood items for celebrations, and getting rid of nonfood items that contain food allergens (e.g., clay, paste).\n°°Policies on bullying and discrimination against all students, including those with food allergies.\n\n# Provide food allergy education to students and parents.\n- Get help from the school counselor or other mental health professionals to teach students about bullying of and discrimination against students with food allergies.\n- Help communicate policies on bullying and discrimination to parents.\n\n# Create and maintain a healthy and safe school environment.\n- Work with other school staff and parents to create a safe environment for students with food allergies.\n- Promote an environment that encourages support for students with food allergies and promotes positive interactions between students.\n- Report all cases of bullying against students, including those with food allergies, to the school administrator, school nurse, or school counselor.\n\n# Classroom Teachers\nThis category includes classroom teachers in all basic subjects, as well as physical education teachers, instructional specialists such as music or art teachers, paraeducators, student teachers, long-term substitute teachers, classroom aides, and classroom volunteers.\n\n# Participate in the school's coordinated approach to managing food allergies.\n- Ask the school nurse or school administrator for information on current policies and practices for managing students with food allergies, including how to manage medications and respond to a food allergy reaction.\n- Help plan and implement the school's FAMPP.\n\n# Help with the daily management of food allergies for individual students.\n- Make sure you understand the essential actions that you need to take to help manage food allergies when students with food allergies are under your supervision, including when meals or snacks are served in the classroom, on field trips, or during extracurricular activities. Seek guidance and help from the school administrator, school nurse, or school food service director as needed.\n- Be available and willing to help students who manage their own food allergies.\n- Work with parents and the school nurse and other appropriate school personnel to determine if any classroom modifications are needed to make sure that students with food allergies can participate fully in class activities.\n- With parental consent, share information and responsibilities with substitute teachers and other adults who regularly help in the classroom (e.g., paraeducators, volunteers, instructional specialists).\n(Depending on a school district's FERPA notice as to which individuals would constitute school officials with legitimate educational interests, FERPA may not require parental consent in these circumstances. FERPA also includes an emergency exception to the prior consent requirement if there is an articulable and significant threat to the health or safety of the student or others. See Section 5 for more information about FERPA.)\n- Refer students with undiagnosed but suspected food allergies to the school nurse for follow-up. f f. See footnote e. infra.\n- If your school does not have a nurse on-site, talk with parents about the signs and symptoms you have seen and recommend that they discuss them with their primary health care provider.\n- If you suspect a severe food allergy reaction or anaphylaxis, take immediate action, consistent with your school's FAMPP or \"all-hazards\" emergency response protocol.\n\n# Prepare for and respond to food allergy emergencies.\n- Read and regularly review each student's ECP. Never hesitate to activate the plan in an emergency.\nIf you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n- Keep copies of ECPs for your students in a secure place that you can get to easily in an emergency.\nWith parental consent, share information from the ECP with substitute teachers and other adults who regularly help in the classroom to help them know how to respond to a food allergy emergency.\n(Depending on a school district's FERPA notice as to which individuals would constitute school officials with legitimate educational interests, FERPA may not require parental consent in these circumstances. FERPA also includes an emergency exception to the prior consent requirement if there is an articulable and significant threat to the health or safety of the student or others. See Section 5 for more information about FERPA.)\n- Support and help students who have permission to carry and use their own epinephrine in cases of an allergic reaction.\n- Make sure that the needs of students with food allergies are met during class field trips and during other extracurricular activities.\n- Immediately contact the school administrator and if available, the school nurse after any suspected allergic reaction.\n- After each food allergy emergency, review how it was handled with the school administrator, school nurse, parents, other staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n- Help students with food allergies transition back to school after an emergency.\n- Address concerns with students who witness a life-threatening allergic reaction in a way that does not compromise the confidentiality rights of the student with the allergy.\n\n# Participate in professional development on food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are manifested in and communicated by students.\n°°How to read food labels and identify allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to respond to food allergy emergencies in ways that are consistent with a student's ECP, if appropriate, a Section 504 Plan, or IEP, if appropriate.\n°°When and how to call EMS and parents.\n°°Your role in implementing a student's ECP.\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information, and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°General strategies for reducing or preventing exposure to food allergens in the classroom, such as cleaning surfaces, using nonfood items for celebrations, getting rid of nonfood materials that contain food allergens (e.g., clay, paste), and preventing cross contact of allergens when meals or snacks are served in the classroom.\n°°Policies that prohibit discrimination and bullying against all students, including those with food allergies.\n\n# Provide food allergy education to students and parents.\n- Look for ways to add information about food allergies to your curriculum. Work with other teachers to plan lessons and activities to teach students how they can prevent allergic reactions.\n- Work with the school nurse to educate parents about the presence and needs of students with food allergies in the classroom. Raise awareness and educate the parents of children without food allergies about \"food rules\" for the classroom. Ask parents to help you keep certain foods out of the classroom during meals, celebrations, and other activities that might include food.\n- Ask the school counselor or other mental health professionals for help or resources to teach students about policies that prohibit discrimination and bullying against all students, including those with food allergies.\n- Communicate policies on bullying and discrimination to all parents.\n\n# Create and maintain a healthy and safe school environment.\n- Promote a safe physical environment through the following actions:\n°°Create classroom rules and practices for dealing with food allergies. Tell parents about these rules and practices at the beginning of the school year or when you find out that a student with a food allergy will be in your class.\n°°Create ways for students with food allergies to participate in all class activities.\n°°Avoid using known allergens in classroom activities, such as arts and crafts, counting, science projects, parties, holidays and celebrations, or cooking.\n°°Enforce hand washing before and after eating, particularly for younger students.\n°°Use nonfood items for rewards or incentives.\n°°Encourage the use of allergen-safe foods or nonfood items for birthday parties or other celebrations in the classroom. Support parents of students with food allergies who wish to send allergen-safe snacks for their children.\n°°Discourage trading or sharing of food with a student with a food allergy in the classroom, particularly for younger students.\n°°Enforce food allergy prevention practices while supervising students in the cafeteria.\n- Manage food allergies on field trips through the following actions:\n°°Determine if the intended location is safe for students with food allergies. If it is not safe, the field trip might have to be changed or cancelled if accommodations cannot be made.\nStudents cannot be excluded from field trips because of food allergies.\n°°Invite the parents of students with food allergies to chaperone or go with their child on the field trip. Many parents may want to go, but they cannot be required to go.\n°°Work with school food service staff to plan meals and snacks.\n°°Make sure you include someone who is delegated and trained to administer epinephrine, that you have quick access to an epinephrine auto-injector, and that you know where the nearest medical facilities are located. If a food allergy emergency occurs, activate the student's ECP and notify the parents.\n°°Make sure there are appropriate emergency protocols and mechanisms in place to respond to a food allergy emergency when away from the school.\n°°Make sure that communication devices are working so you can respond quickly during an emergency.\n- Promote a positive psychosocial climate through the following actions:\n°°Be a role model by respecting the needs of students with food allergies.\n°°Help students make decisions about and manage their own food allergies.\n°°Encourage supportive and positive interactions between students.\n°°Reinforce the school's rules against discrimination and bullying.\n°°Take action to address all reports of bullying or harassment of a student with a food allergy.\n°°Tell parents if their child has been bullied, and report all cases of bullying to the school administrator.\n°°Tell parents and the school nurse if you see negative changes in a student's academic performance or behavior.\n\n# School Food Service Managers and Staff\n1. Participate in the school's coordinated approach to managing food allergies.\n- Use resources and guidance from the district food service director, local board of health, USDA, and dietitians to reduce exposure to food allergens.\n- Help plan and implement the school's FAMPP. Make sure that it includes specific practices for managing food allergens in school meals served inside and outside of the cafeteria.\n\n# Help with the daily management of food allergies for individual students.\n- Identify students with food allergies in a way that does not compromise students' privacy or confidentiality rights.\n- Make sure you have and understand dietary orders, or the doctor's statement, and other relevant medical information that you need to make meal accommodations for students with food allergies and food allergy disabilities.\n- Consult with the district foodservice director to help develop individual dietary and cafeteria management plans for each student with a food allergy and food allergy disability. These plans should be consistent with the student's IHP, and if the student has a food allergy, the student's Section 504 plan, or, if appropriate, IEP, and USDA regulations on meals and food substitutions, as reflected in the USDA's Accommodating Children with Special Dietary Needs in the School Nutrition Programs.\n- Help communicate appropriate actions to avoid allergic reactions and respond to food allergy emergencies to all staff members and food service staff who are expected to help manage a student's food allergy in the cafeteria.\n- Follow policies and procedures to prevent allergic reactions and cross-contact of potential food allergens during food preparation and service.\n- Understand how to read labels to identify allergens in foods and beverages served in school meals. Work with the school foodservice director, the district food service director, or the food manufacturer if additional information or clarification is needed on the product's ingredients.\n- Manage food substitutions for students with food allergies and food allergy disabilities and manage the documentation of these activities. Work with the school administrator or school nurse and the district food service director to make sure that the information needed to meet USDA and state regulations for food service is documented as required.\n- Be prepared to share information about ingredients in recipes and foods served by the school food service program with parents.\n\n# Prepare for and respond to food allergy emergencies.\n- Be familiar with student's ECPs and the doctor's statement required by USDA, what actions must be taken if a food allergy emergency occurs in the cafeteria. Make sure that food service staff are able to respond to a food allergy emergency in the cafeteria and implement an ECP.\n- If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n- If appropriate and allowed by state laws, including regulations, school policy, and the school's FAMPP, keep an epinephrine auto-injector in a secure place in the cafeteria that you can get to quickly and easily.\n- Provide support and help to students who carry and use their own medication.\n- After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n\n# Participate in professional development on food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by student.\n°°How to read food labels and identify allergens.\n°°How to plan meals for students with food allergies and allergy disabilities and how to prevent cross-contact of allergens. Consult with the district school food service director when necessary.\n°°How to deal with emergencies in the school in ways that are consistent with a student's ECP.\n°°The role of the food service manager and staff in implementing a child's doctor statement under USDA requirements and ECP, if applicable.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°General strategies for reducing or preventing allergic reactions in the cafeteria.\n°°Policies on bullying and discrimination against all students, including those with food allergies.\n\n# Provide food allergy education to students and parents.\n- Help classroom teachers add food allergy lessons into their health and education curriculum, including teaching students how to read food labels.\n- Share menu ideas with parents of students with food allergies to identify potential allergens and improve healthy eating.\n- Find ways for parents of students with food allergies to share their knowledge and experience with other parents.\n- Help the school administrator communicate the policies and practices used by the food service staff to prevent food allergy reactions to parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe school environment.\n- Reduce the potential for allergic reactions through the following actions:\n°°Be able to recognize students with food allergies and food allergy disabilities in the cafeteria.\n°°Follow procedures for handling food allergies in the cafeteria, even if a student is not participating in the Child Nutrition Program school meals program.\n°°Read food labels to identify allergens.\n°°Follow policies and procedures to prevent cross-contact of potential food allergens during food preparation and service.\n°°Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n- Promote a positive psychosocial climate in the cafeteria through the following actions:\n°°Encourage supportive and positive interactions between students.\n°°Reinforce the school's rules against bullying and discrimination.\n°°Take action to address all reports of bullying or harassment of a student with a food allergy.\n°°Report all cases of bullying and harassment against students, including those with food allergies, to the school administrator, school nurse, or school counselor.\n\n# School Counselors and Other Mental Health Services Staff\nThis category includes school psychologists and school social workers.\n1. Participate in the school's coordinated approach to managing food allergies.\n- Help plan and implement the school's FAMPP.\n\n# Help with the daily management of food allergies for individual students.\n- Address immediate and long-term mental health problems, such as anxiety, depression, low self-esteem, negative behavior, or eating disorders, among students with food allergies.\n- Address adolescent oppositional behavior, such as noncompliance with IHPs.\n- Make referrals to mental health services and professionals outside the school for students who need them, consistent with applicable requirements of Section 504 and IDEA, if appropriate.\n- Work with school health service staff (e.g., school doctor, school nurse) to develop consistent protocols for referrals.\n- Read and regularly review each student's ECP. Never hesitate to activate the plan in an emergency.\nIf you are the person delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector if needed.\n- After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future allergic reactions and to improve emergency response.\n- Help students with food allergies transition back to school after an emergency.\n- Be prepared to respond to the emotional needs of students who witness a life-threatening allergic reaction in a way that does not compromise the students' privacy or confidentiality rights.\n\n# Participate in professional development on food allergies.\n- Work with the school or district nurse and other health professionals to support training and education for staff on the mental and emotional health issues faced by a student with food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by students.\n°°How to read food labels and identify allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in the school in ways that are consistent with a student's ECP.\n°°Your role in implementing a child's ECP.\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°Policies that prohibit discrimination and bullying against students with food allergies.\n\n# Provide food allergy education to students and parents.\n- Work with classroom teachers and other school staff to educate parents and students about bullying and discrimination against students with food allergies.\n\n# Create and maintain a healthy and safe school environment.\n- Encourage staff to support a broad range of school-based mental health promotion efforts to support all students that promote positive interactions between students, build a positive school climate, encourage diversity and acceptance, discourage bullying, and promote student independence.\n- Reinforce the school's rules against bullying and discrimination.\n- Take action to address all reports of bullying or harassment of a student with a food allergy.\n- Tell parents if their child has been bullied, and report all cases of bullying to school administrators.\n\n# Bus Drivers and School Transportation Staff\n1. Participate in the school's coordinated approach to managing food allergies.\n- Ask the school nurse or school administrator for information on current policies and practices for managing students with food allergies, including how to manage medications and respond to a food allergy reaction.\n- Support school's FAMPPs.\n\n# Help with the daily management of food allergies for individual students.\n- Be aware of students with food allergies and know how to respond to an allergic reaction if it occurs while the student is being transported to or from school.\n- Enforce district food policies for all students riding a school bus.\n\n# Prepare for and respond to food allergy emergencies.\n- Read and regularly review the ECP for any student riding to and from school on a bus. Never hesitate to activate the plan in an emergency. If you are the person delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector if needed.\n- Know procedures for communicating an emergency during the transporting of children to and from school. Make sure that other adults on the bus are aware of emergency communication protocol.\n- Make sure communication devices are working so you can reach school officials, EMS, and others during a food allergy emergency.\n- Call 911 or EMS to ask for emergency transportation of any student exhibiting signs of anaphylaxis. Notify the school administrator of your actions and the need for someone to contact the student's parents.\n- After any food allergy emergency that occurs while a student is being transported to or from school, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future allergic reactions and improve emergency response.\n\n# Participate in professional development on food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by students.\n°°How to respond to a food allergy emergency while transporting children to and from school. How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in a way that is consistent with a student's ECP or transportation emergency protocol.\n°°Your role in implementing a child's ECP.\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°Policies that prohibit discrimination and bullying against all students, including those with food allergies.\n\n# Create a healthy and safe environment.\n- Advocate for two-way communication systems between schools and transportation vehicles that are kept in working order.\n- Enforce district food policies for all students riding a school bus.\n- Encourage supportive and positive interactions between students.\n- Reinforce the school's rules against discrimination and bullying.\n- Report all cases of bullying or harassment of students, including those with food allergies, to the school administrator.\n\n# Facilities and Maintenance Staff\nThis category includes custodial staff.\n\n# Participate in the school's coordinated approach to managing food allergies.\n- Help plan and implement the school's FAMPP.\n\n# Help with the daily management of food allergies for individual students.\n- Be aware of students with food allergies and know how to respond to an allergic reaction if it occurs while the student is at school.\n- Help create a safe and healthy environment to prevent allergic reactions.\n\n# Prepare for and respond to food allergy emergencies.\n- Activate your school's \"all-hazard\" emergency response practices if a student displays signs or symptoms of an allergic reaction.\n- Know and understand your school's communication protocols for an emergency.\n- Make sure communication devices are working.\n- After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future allergic reactions and improve emergency response.\n\n# Participate in professional development on food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by students.\n°°How to respond to emergencies at the school.\n°°Your role in supporting a child's ECP.\n°°Policies that prohibit discrimination and bullying against all students, including those with food allergies.\n°°Policies and standards for washing hands and cleaning surfaces to reduce food allergens on surfaces.\n\n# Create and maintain a healthy and safe environment.\n- Promote a safe and healthy physical environment through the following actions:\n°°Advocate for two-way communication systems throughout school buildings that are kept in working order.\n°°Enforce district food policies.\n°°Clean floors, surfaces, and food-handling areas with approved soap and water or all-purpose cleaning products.\n- Promote a positive psychosocial climate through the following actions:\n°°Encourage supportive and positive interactions between students.\n°°Reinforce the school's rules against discrimination and bullying.\n°°Report all cases of bullying or harassment of students, including those with food allergies, to the school administrator.\nSee Section 6 for more resources and tools that might assist in managing food allergies and allergy-related emergencies in schools.\n\n# Section 4. Putting Guidelines into Practice: Actions for Early Care and Education Administrators and Staff\nEffective management of food allergies in early care and education (ECE) programs requires the participation of many people. This section presents the actions that ECE program staff can take to implement the recommendations in Section 1. Some actions duplicate responsibilities required under applicable federal and state laws, including regulations, and policies. Although many responsibilities presented here are not required by statute, they can contribute to better management of food allergies in ECE programs.\nIf the ECE program participates in USDA's Child Nutrition Programs, the ECE program must follow USDA statutes, regulations, and guidance for providing meal accommodations for children with food allergy disabilities.\nSome actions are intentionally repeated for different staff positions to ensure that critical actions are addressed even if a particular position does not exist in the ECE program. This duplication also reinforces the need for different staff members to work together to manage food allergies effectively. All actions are important, but some will have a greater effect than others. Ultimately, each ECE program must determine which actions are most practical and necessary to implement and who should be responsible for those actions.\nAlthough these guidelines are specifically for licensed ECE programs, many of the recommendations can be used in unlicensed child care settings.\n\n# Program Directors and Family Child Care Providers\n\n# Lead the ECE program's coordinated approach to managing food allergies.\n- Coordinate planning and implementation of a comprehensive Food Allergy Management and Prevention Plan (FAMPP). Work with staff, parents, food services, and the children's health care providers.\n- Designate a qualified person (e.g., health manager, health consultant) to lead development of the program's FAMPP and designate responsibilities for implementing the plan as appropriate.\n\n# Ensure the daily management of food allergies for individual children.\n- Make sure that mechanisms-such as health forms, registration forms, USDA-required doctor's statement and parent interviews-are in place to identify children with food allergies.\n- Work with the parents of children with food allergies and the child's primary health care provider or allergist to obtain a written Emergency Care Plan (ECP) to manage and monitor children with food allergies on a daily basis.\n- Share information about children with food allergies with all staff who need to know. Make sure they are aware of what actions are needed to manage each child's food allergy on a daily basis.\n\n# Prepare for and respond to food allergy emergencies.\n- Make sure that all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medications and how they should be used. It should also include specific symptoms that would indicate the need to give one or more medications or take the child to an emergency medical facility.\n- Make sure that parents of children with food allergies provide epinephrine auto-injectors to use in food allergy emergencies if their use is called for in the child's ECP.\n- Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily.\n- Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n- Contact parents immediately after any suspected allergic reaction. You also should contact parents immediately after a child ingests a potential allergen or has contact with a potential allergen, even if an allergic reaction does not occur. If the child needed treatment, recommend that the parents notify the child's primary health care provider or allergist.\n- If epinephrine is given, contact emergency medical services (EMS) and have the child transported to an emergency room by ambulance. Contact the parents to tell them the child's location and condition.\n- Conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n- Be ready to respond to severe allergic reactions in children with no history of diagnosed food allergies or anaphylaxis.\n- Review data and information (e.g., when and where medication was used) from incident reports of food allergy emergencies and assess the effect on affected children. Modify policies and practices as needed.\n\n# Support professional development on food allergies for staff.\n- Make sure staff receive professional development and training on food allergies.\n- Make sure that training helps your program meet any applicable Head Start Program Performance Standards and Other Regulations.\n- Coordinate training with licensed health care professionals.\n- Invite parents of children with food allergies to participate in training for staff.\n\n# Educate children and family members about food allergies.\n- Communicate your program's responsibilities, expectations, and practices for managing food allergies to all parents through newsletters, announcements, and other methods.\n\n# Create and maintain a healthy and safe ECE program environment.\n- Increase awareness of food allergies and food allergy disabilities throughout the program environment.\n- Make sure that children with food allergies have an equal opportunity to participate in all program activities and events.\nChild Care Providers, Preschool Teachers, Teaching Assistants, Volunteers, Aides, and Other Staff\n\n# Participate in the ECE program's coordinated approach to managing food allergies.\n- Help plan and implement the program's FAMPP.\n\n# Help with the daily management of food allergies for individual children.\n- Make sure all children with food allergies have an ECP. In programs that participate in USDA's Child Nutrition Programs, include a doctor's statement of disability.\n- Make sure you understand the essential actions that you need to take to help manage food allergies and food allergy disabilities in children when they are under your supervision.\n- Enforce hand washing practices and make sure tables and surfaces are cleaned before and after meals with approved soap and water or all-purpose cleaning products to reduce cross-contact of allergens.\n- Work with parents to determine if any modifications are needed to make sure that children with food allergies can participate fully in all program activities.\n\n# Prepare for and respond to food allergy emergencies.\n- Make sure that all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medications and how they should be used. It should also include specific symptoms that would indicate the need to give one or more medications or take the child to an emergency medical facility.\n- Make sure that parents of children with food allergies provide epinephrine auto-injectors to use in food allergy emergencies if their use is called for in the child's ECP.\n- Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily.\n- Never hesitate to activate a child's ECP in an emergency. If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n- Keep copies of ECPs for children in your care in a secure place that you can get to quickly and easily in an emergency.\n- Provide feedback on the child's ECP and participate in a debriefing meeting after a food allergy reaction or emergency.\n- Contact parents immediately after any suspected allergic reactions. You also should contact parents immediately after a child ingests a potential allergen or has contact with a potential allergen, even if an allergic reaction does not occur. If the child needed treatment, recommend that the parents notify the child's primary health care provider or allergist.\n- If epinephrine is given, contact EMS, tell them when epinephrine was administered, and have the child transported to an emergency room by ambulance. Contact the parents to tell them the child's location and condition.\n- After each food allergy emergency, review how it was handled with the ECE program administrator, registered nurse, parents, staff members involved in the response, EMS responders, and the child to identify ways to prevent future emergencies and improve emergency response.\n\n# Participate in professional development on food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of allergic reactions and how they are communicated by young children.\n°°How to read food label and identify allergens.\n°°Your role in implementing a child's ECP.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°General strategies for reducing or preventing exposure to food allergens in the program setting and during field trips or other program-sponsored events.\n°°Policies that prohibit discrimination and bullying against children with food allergies.\n\n# Create and maintain a healthy and safe ECE program environment.\n- Promote a safe physical environment through the following actions:\n°°Create rules and practices for dealing with food allergies, including preventing exposure to allergens. Tell parents about these rules and practices each year or when you find out that a child with a food allergy will be in your care.\n°°Create ways for children with food allergies to participate in all class activities.\n°°Avoid using known allergens in program activities, such as arts and crafts, counting, science projects, parties, holidays and celebrations, or cooking.\n°°Enforce hand washing before and after eating.\n°°Clean tables and chairs before and after eating with approved soap and water or all-purpose cleaning products.\n°°Use nonfood items for rewards or incentives.\n°°Encourage the use of allergen-safe foods or nonfood items for birthday parties or other celebrations. Support parents of children with food allergies who wish to send allergen-safe snacks for their children.\n°°Discourage trading or sharing of food.\n- Manage food allergies on field trips through the following actions:\n°°Determine if the intended location is safe for children with food allergies.\n°°Make sure that field trips and other events are consistent with the program's food allergy policies.\n°°Plan for meals and snacks.\n°°Make sure you have quick access to an epinephrine auto-injector or other medications and that you know where the nearest medical facilities are located. If a food allergy emergency occurs, activate the child's ECP and notify the parents.\n°°Make sure that a person who is certified in first aid and trained to use an epinephrine auto-injector is available.\n- Promote a positive psychosocial climate through the following actions:\n°°Be a role model by respecting the needs of children with food allergies.\n°°Encourage supportive and positive interactions between children.\n°°Take action to address all reports of bullying or harassment of a child with a food allergy.\n°°Tell parents if you see negative changes in their child's behavior.\n\n# Nutrition Services Staff\n1. Participate in the ECE program's coordinated approach to managing food allergies.\n- Help plan and implement the program's FAMPP.\n\n# Help with the daily management of food allergies for individual children.\n- Read and regularly review each child's ECP. Make sure you understand the essential actions that you need to take to help manage food allergies in children during meals.\n- Make sure you get the dietary orders and other relevant medical information that you need to accommodate children with food allergies.\n- Document information about meal substitutions as outlined in each child's ECP. Make sure that the information needed to meet the U.S. Department of Agriculture's (USDA's) Child Nutrition Program regulations and state regulations is documented.\n- Work with the state agency that administers USDA programs, the local health department, and dietitians in the community to get the information and resources you need to make sure your program is following all federal and state regulations and you are responding to a child's dietary requirements.\n- Take the food allergies of the children in your program into account when you buy food and formula.\n- Establish and follow policies and procedures to prevent allergic reactions and cross-contact of potential food allergens during food preparation and service.\n\n# Prepare for and respond to food allergy emergencies.\n- Make sure all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food. If your program participates in the USDA's Child Nutrition Program, make sure you have the proper documentation to meet USDA and state regulations.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medication and how they should be used.\n- Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily.\n- Never hesitate to activate a child's ECP in an emergency. If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n- Keep copies of ECP for children in your care in a secure place that you can get to quickly and easily in an emergency.\n- Provide feedback on the child's ECP and participate in a debriefing meeting after a food allergy reaction or emergency.\n- Contact parents immediately after any suspected allergic reactions. You also should contact parents immediately after a child ingests a potential allergen or has contact with a potential allergen, even if an allergic reaction does not occur. If the child needed treatment, recommend that the parents notify the child's primary health care provider or allergist.\n- If epinephrine is given, contact EMS, tell them when epinephrine was administered, and have the child transported to an emergency room by ambulance. Contact the parents to tell them the child's location and condition.\n- Make sure that a food service staff member who has been trained to respond to a food allergy reaction is available during all meals and snack times.\n\n# Participate in professional development on food allergies.\n- Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by young children.\n°°How to read food labels and identify food allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in the ECE program setting in ways that are consistent with a child's ECP.\n°°Legal rights of children with food allergies.\n°°USDA's statutes, regulations, and guidance (for ECE programs participating in USDA's Child Nutrition Programs).\n°°State, and local laws and policies for food services and food safety.\n°°General strategies for reducing or preventing exposure to food allergens in the kitchen or area where food is served.\n°°The role of nutrition staff in implementing a child's ECP, including the specific duties outlined in Head Start Program Performance Standards and Other Regulations.\n\n# Health Services Staff\n\n# Participate in the ECE program's coordinated approach to managing food allergies.\n- Help plan and implement the program's FAMPP.\n\n# Ensure the daily management of food allergies for individual children.\n- Make sure children with food allergies are identified in a way that complies with Head Start Program Performance Standards and Other Regulations and established enrollment practices but does not compromise their confidentiality rights.\n- Read and regularly review medical records and emergency information for all children with food allergies.\n- Communicate with parents and health care providers (with parental consent) about any allergic reactions, changes in a child's health, and exposures to allergens.\n- Read and regularly review each child's ECP. Make sure that all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medications and how they should be used. It should also include specific symptoms that would indicate the need to give one or more medications or take the child to an emergency medical facility.\n- Work with parents and health care providers to make sure that the medical needs of children with food allergies are met and that all necessary accommodations are made.\n- Refer parents of children who do not have access to health care to State Children's Health Insurance Program providers.\n\n# Prepare for and respond to food allergy emergencies.\n- Keep copies of ECPs for children in your care in a secure place that you can get to quickly and easily in an emergency.\n- Make sure that parents of children with food allergies provide epinephrine auto-injectors to use in food allergy emergencies if their use is called for in the child's ECP.\n- Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily. Regularly inspect the expiration date of epinephrine auto-injectors.\n- Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n- If allowed by state and local laws, work with the program director to get extra epinephrine autoinjectors or nonpatient-specific prescriptions or standing orders for auto-injectors that can be used by a registered nurse and those delegated and trained to administer epinephrine during allergy emergencies.\n- Never hesitate to activate a child's ECP in an emergency. If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n- After each food allergy emergency, review how it was handled with the ECE program administrator, parents, staff members involved in the response, EMS responders, and the child to identify ways to prevent future emergencies and improve emergency response. Make revisions to the child's ECP as appropriate.\n\n# Help provide professional development on food allergies for staff.\n- Stay up-to-date on best practices for managing food allergies. Sources for this information include allergists who are treating children with food allergies and local health departments.\n- Educate other staff about food allergies and the needs of children with food allergies in a way that does not compromise their confidentiality rights.\n- Use each child's ECP to train other staff members how to recognize the specific signs of an allergic reaction in each child and how to respond to a food allergy emergency.\n- Coordinate annual training for all staff on relevant federal and state regulations for managing food allergies in children.\n- Coordinate annual training for all staff on emergency response protocol and practices, including how to respond to food allergy emergencies.\n- Provide or coordinate training for delegated staff on how to use an epinephrine auto-injector.\nSee Section 6 for more resources and tools that might assist in managing food allergies and allergy-related emergencies in ECE programs.\n\n# Section 5. Federal Laws and Regulations that Govern Food Allergies in Schools and Early Care and Education Programs\nThe federal laws and regulations described in this section address the responsibilities of schools and early care and education (ECE) programs to help children and adolescents manage food allergies that may constitute a disability under federal law and to ensure that children are not subject to discrimination on the basis of their disability. This section also addresses privacy and confidentiality requirements that apply to the education records of students with food allergies, regardless of whether they have been found to have a disability under federal law. Schools and ECE programs are encouraged to copy and distribute relevant laws to appropriate staff and to reinforce relevant laws and regulations in all training provided to staff. For information on how to get copies of relevant federal laws and regulations, see Section 6. g\nThe federal laws described in this section are enforced or administered by the U.S. Department of Education (ED), the U.S. Department of Justice (DOJ), and the U.S. Department of Agriculture (USDA).\n\n# Section 504 of the Rehabilitation Act of 1973 (Section 504) and the Americans with Disabilities Act of 1990 (ADA) h\nSection 504 is a federal law that prohibits discrimination on the basis of disability in programs and activities that receive federal financial assistance. Recipients of federal financial assistance from ED include public school districts, other state and local educational agencies, and postsecondary educational institutions. The Department of Education's Office for Civil Rights (OCR) enforces Section 504 as it applies to these recipients. The USDA enforces Section 504 as it applies to recipients of federal financial assistance from USDA.\nTitle II of the ADA prohibits discrimination on the basis of disability by public entities, including public elementary, secondary, and postsecondary educational institutions, whether or not they receive federal financial assistance. For public schools, OCR shares Title II enforcement responsibilities with the U.S. Department of Justice (DOJ).\nSection 504 and Title II of the ADA require that qualified individuals with disabilities, including students, parents, and other program participants, not be excluded from or denied the benefits of services, programs, or activities or otherwise subjected to discrimination by reason of a disability. Public school districts that receive federal financial assistance are covered by both Section 504 and Title II. As a general rule, because Title II does not provide less protection than Section 504, violations of Section 504 also constitute violations of Title II. To the extent that Title II provides greater protections, schools must also comply with Title II and provide those additional protections.\ng. In addition to becoming familiar with these relevant federal laws, schools and ECE programs should determine which applicable state statutes, policies, and regulations and local statues and policies should be considered when developing management plans for children with food allergies. If a student's food allergy is a disability, that student is entitled to the protections of Section 504 and the ADA. Both laws define a disability as a physical or mental impairment that substantially limits a major life activity. Children with food allergies may be substantially limited in major life activities such as eating, breathing, or the operation of major bodily functions such as the respiratory or gastrointestinal system. The U.S. Congress has made clear that the definition of disability under Section 504 and the ADA is to be construed broadly. i\nUnder both Section 504 and Title II, students with disabilities in public schools must be given an equal opportunity to participate in academic, nonacademic, and extracurricular activities. ED's Section 504 regulation outlines a process for schools to use to determine whether a student has a disability and to determine what services a student with a disability needs. j This evaluation process must be tailored individually because each student is different, and his or her needs will vary. The Section 504 regulations specify that school districts must identify all students with disabilities and provide them with a free appropriate public education (FAPE).\nUnder ED's Section 504 regulation, FAPE is the provision of regular or special education and related aids and services designed to meet the individual educational needs of students with disabilities as adequately as the needs of students who do not have disabilities are met. A student does not have to receive special education services, however, in order to receive related aids and services under Section 504. The most common practice is to include these related aids and services, as well as any needed special education services, in a written document, sometimes called a Section 504 plan. Even if a school district does not believe that a student needs special education or related aids and services, Section 504 and Title II require the district to consider whether it can reasonably modify policies, practices, or procedures to ensure that a student with a disability has an equal opportunity to participate in and benefit from the school's services and programs. ED's Section 504 regulation also states that public preschool and day care programs operated by recipients of federal funds may not, on the basis of disability, exclude students with disabilities and must take their needs into account when determining the aid, benefits, or services to be provided. k Under ED's Section 504 regulation, private schools that receive federal financial assistance may not exclude an individual student with a disability if the school can, with minor adjustments; provide an appropriate education to that student. Private, nonreligious schools and ECE programs are covered by Title III of the ADA. Title III prohibits public accommodations such as these from discriminating against individuals with disabilities in the full and equal enjoyment of the entity's services and activities. Under Title III, private schools and ECE programs must make reasonable modifications to policies, practices, and procedures when necessary to give children with disabilities, including those with food allergies, full and equal access to and participation in programs and services unless the entity can show that the modification would result in a fundamental alteration of those programs and services.\nUnder Section 504 and the ADA, children with food allergy disabilities in schools and ECE programs must be provided with the services and modifications they need in order to attend. Examples of these services and modifications might include implementing allergen-safe food plans, administering epinephrine according to a doctor's orders (even if the school or ECE program has a no-medication policy), allowing students to carry their own medication, and providing an allergen-safe environment in which the student can eat meals. Disability harassment is a form of discrimination prohibited by Section 504 and Titles II and III of the ADA.\nHarassment creates a hostile environment when the conduct is sufficiently serious so as to interfere with or limit a student's ability to participate in or benefit from the services, activities, or opportunities offered by a school. When student-on-student disability harassment occurs and the school knows or reasonably should know about the harassment, a school must take prompt and effective steps reasonably calculated to end the harassment, prevent its recurrence, and eliminate any hostile environment created by the harassment. Section 504 and Title II require schools to take such steps and prohibit schools from encouraging, tolerating, or ignoring peer harassment based on disability that creates a hostile environment. Bullying, teasing, or harassment about an allergy can lead to psychological distress for children with food allergies which could lead to a more severe reaction when the allergen is present. And exposing an allergic child to the allergen (e.g., putting the allergen in the child's food or forcing the child to ingest the allergen) can have very serious-even fatal-consequences. School districts, in developing and implementing policies on bullying and harassment, should instruct staff and students as to how such policies apply to children with food allergies, including the possible disciplinary consequences for bullying and harassment that target or place food-allergic children at risk. Additional consequences could be to separate the harasser from the target and to provide counseling for the target or the harasser. Finally, a school should take steps to stop further harassment and prevent any retaliation against the person who made the complaint (or was the subject of the harassment) or against those who provided information as witnesses. The ADA, as amended, Section 504 of the Rehabilitation Act, The Richard B. Russell National School Lunch Act 42 USC 1758(a), the Child Nutrition Act, CNP regulations, and USDA's Non-discrimination regulations at 7 CFR 15b, govern meal accommodations for children with food related disabilities in schools and ECE programs that participate in the CNPs. USDA has oversight for providing meals in these programs. Program operators in the CNPs must make meal accommodations to regular program meals for children identified by a licensed doctor as having a food allergy disability that prevents them from consuming a meal as prepared. For purposes of discussion in these guidelines, if a child has a food allergy that is identified as a disability by a licensed doctor, meal accommodations must be provided.\nAdditionally, a school, institution, and site participating in USDA's Child Nutrition Programs, is not required to establish a Section 504 plan, IEP, IHP, ICP (or any plan that may be used by a child with special dietary needs) to make an accommodation to a program meal for a child with a food related disability. Instead, the CNPs require a written statement from a licensed doctor which identifies the following requirements:\n- The child's disability (according to pertinent statutes).\n- An explanation of why the disability restricts the child's diet.\n- The major life activity affected by the disability.\n- The food or foods to be omitted from the child's diet.\n- The food or choice of foods that must be substituted. 62 A statement signed by a licensed doctor addressing the points above is sufficient. However, the written statement from a licensed doctor may be incorporated in any of the plans discussed above.\n\n# Individuals with Disabilities Education Act (IDEA)\nIDEA Part B l provides federal funds to help states make FAPE available to eligible children with disabilities in the least restrictive environment. The obligation to make FAPE available in the least restrictive environment begins at the child's third birthday and could last until the child's twenty-second birthday, depending on state law or practice. m FAPE under IDEA Part B refers to the provision of special education and related services at no cost to the parents that include an appropriate preschool, elementary school, or secondary school education at the state level. Eligibility determinations under IDEA Part B are made at the state and local school district level on an individual, case-by-case basis in light of applicable IDEA Part B requirements and state education standards. At the federal level, IDEA is administered by the Office of Special Education Programs in the Office of Special Education and Rehabilitative Services in the ED.\nA child could be found eligible for services under IDEA Part B because of a food allergy only if it adversely affects the child's educational performance, and the child needs special education and related services because of the food allergy. If determined eligible, the school district must develop an Individualized Education Program (IEP) for the child, or if appropriate, an Individualized Family Service Plan (IFSP) for a child age three through five. n An IEP is a written document developed by a team that includes the child's parents and school officials. It sets out, among other elements, the special education and related services and supplementary aids and services to be provided to the child. If parents place their disabled child at a private school at their own expense, IDEA Part B generally would not require the school district to develop an IEP for the child at the private school. In general, if a child with a food allergy only needs a related service and does not need special education, that child would not be eligible for services under IDEA Part B. Such a child might still be eligible for services or modifications under Section 504 or Title II.\nIn addition, IDEA Part C provides federal funds to assist states in identifying and providing early intervention services to children with disabilities from birth to age three and, at the state's discretion, through five or when the child enters kindergarten. Under IDEA Part C, a child is eligible based on a developmental delay, diagnosed condition, or, at the state's discretion, at-risk status. An IFSP is a document written by a team that includes the child's parents that identifies the specific early intervention services needed by the child. o\n\n# Family Educational Rights and Privacy Act (FERPA) of 1974\nFERPA applies to educational agencies or institutions that receive federal funds under a program administered by ED. p FERPA generally prohibits schools and school districts from disclosing personally identifiable information from a student's education record unless the student's parent or the eligible student (a student who is aged 18 years or older or who attends an institution of postsecondary education) provides prior, written consent for the disclosure. This requirement has several exceptions. q One exception permits schools to disclose personally identifiable information from a student's education record without obtaining prior written consent to school officials, including teachers, who have legitimate educational interests in the information, including the educational interests of the child. Schools must use reasonable methods, such as physical, technological, or administrative access controls, to ensure that school officials obtain access only to those education records in which they have legitimate educational interests. To use this exception, schools must include in their annual notification of FERPA rights to parents and eligible students the criteria for determining who constitutes a school official and what constitutes a legitimate educational interest.\nThis exception for school officials also applies to a contractor, consultant, volunteer, or other party to whom a school has outsourced institutional services or functions provided that the outside party:\n- Performs an institutional service or function for which the school would otherwise use employees.\n- Is under the direct control of the school with respect to the use and maintenance of education records.\n- Is subject to the requirements in FERPA that govern the use and redisclosure of personally identifiable information from education records.\nAnother exception to the requirement of prior written consent permits schools to disclose personally identifiable information from an education record to appropriate parties, including the parent of an eligible student, in connection with an emergency if knowledge of the information is necessary to protect the health or safety of the student or other individuals. Under this exception, a school may take into account the totality of the circumstances pertaining to a threat to the health or safety of a student or other individuals. If a school determines that there is an articulable and significant threat to the health or safety of a student or other individuals, it may disclose information from education records to any person whose knowledge of the information is necessary to protect the health or safety of the student or other individuals. If the information available at the time of the incident forms a rational basis for the decision to disclose information, ED will not substitute its judgment for that of the school in evaluating the circumstances and making its determination. When disclosures are made under this exception, a school must record the articulable and significant threat to the health or safety of a student or other individual that formed the basis for the disclosure and the parties to whom the information was disclosed.\nIn addition, under FERPA, the parent or eligible student must be given the opportunity to inspect and review the student's education records. A school must comply with a request for access to the student's education records within a reasonable period of time, but not more than 45 days after it has received the request.\nAdditional information and resources, including how to access copies of federal laws, are provided in Section 6."},"raw_text":{"kind":"string","value":"Services (HHS), including the Administration for Children and Families (ACF), Food and Drug Administration (FDA), and National Institutes of Health (NIH). CDC acknowledges Mr. Pete Hunt (HHS/CDC) for his role as lead author of these guidelines. CDC also acknowledges Dr.# Introduction\n\n# Overview\nFood allergies are a growing food safety and public health concern that affect an estimated 4%-6% of children in the United States. 1,2 Children with food allergies are two to four times more likely to have asthma or other allergic conditions than those without food allergies. 1 The prevalence of food allergies among children increased 18% during 1997-2007, and allergic reactions to foods have become the most common cause of anaphylaxis in community health settings. 1,3 In 2006, about 88% of schools had one or more students with a food allergy. 4 Staff who work in schools and early care and education (ECE) programs should develop plans for how they will respond effectively to children with food allergies.\nAlthough the number of children with food allergies in any one school or ECE program may seem small, allergic reactions can be life-threatening and have far-reaching effects on children and their families, as well as on the schools or ECE programs they attend. Any child with a food allergy deserves attention and the school or ECE program should create a plan for preventing an allergic reaction and responding to a food allergy emergency.\nStudies show that 16%-18% of children with food allergies have had a reaction from accidentally eating food allergens while at school. 5,6 In addition, 25% of the severe and potentially life-threatening reactions (anaphylaxis) reported at schools happened in children with no previous diagnosis of food allergy. 5,7 School and ECE program staff should be ready to address the needs of children with known food allergies. They also should be prepared to respond effectively to the emergency needs of children who are not known to have food allergies but who exhibit allergic signs and symptoms.\nUntil now, no national guidelines had been developed to help schools and ECE programs address the needs of the growing numbers of children with food allergies. However, 14 states and many school districts have formal policies or guidelines to improve the management of food allergies in schools. 8,9 Many schools and ECE programs have implemented some of the steps needed to manage food allergies effectively. 4 Yet systematic planning for managing the risk of food allergies and responding to food allergy emergencies in schools and ECE programs remain incomplete and inconsistent. 10,11 \n# FDA Food Safety Modernization Act\nThese guidelines, Voluntary Guidelines for Managing Food Allergies in Schools and Early Care and Education Programs (hereafter called the Voluntary Guidelines for Managing Food Allergies), were developed in response to Section 112 of the FDA Food Safety Modernization Act, which was enacted in 2011. 12 This act is designed to improve food safety in the United States by shifting the focus from response to prevention. Section 112(b) calls for the Secretary of Health and Human Services, in consultation with the Secretary of Education, to \"develop guidelines to be used on a voluntary basis to develop plans for individuals to manage the risk of food allergy and anaphylaxis in schools a and early childhood education programs b \" and \"make such guidelines available to local educational agencies, schools, early childhood education programs, and other interested entities and individuals to be implemented on a voluntary basis only. \" 12 Each plan, described in the act to manage the risk of food allergy and anaphylaxis in schools and early childhood education programs, that is developed for an individual shall be considered an education record for the purpose of Section 444 of the General Education Provisions Act (commonly referred to as the Family Educational Rights and Privacy Act). The act specifies that nothing in the guidelines developed under its auspices should be construed to preempt state law. (A link to FDA Food Safety Modernization Act, including Section 112 statutory language is provided in Section 6, Resources.) Specifically, the content of these guidelines should address the following:\n• Parental obligation to provide the school or early childhood education program, prior to the start of every school year, with documentation from their child's physician or nurse supporting a diagnosis of food allergy, and any risk of anaphylaxis, if applicable; identifying any food to which the child is allergic; describing, if appropriate, any prior history of anaphylaxis; listing any medication prescribed for the child for the treatment of anaphylaxis; detailing emergency treatment procedures in the event of a reaction; listing the signs and symptoms of a reaction; assessing the child's readiness for self-administration of prescription medication; and a list of substitute meals that may be offered to the child by school or early childhood education program food service personnel.\n• The creation and maintenance of an individual plan for food allergy management, in consultation with the parent, tailored to the needs of each child with a documented risk for anaphylaxis, including any procedures for the self-administration of medication by such children in instances where the children are capable of self-administering medication; and such administration is not prohibited by state law.\n• Communication strategies between individual schools or early childhood education programs and providers of emergency medical services, including appropriate instructions for emergency medical response.\n• Strategies to reduce the risk of exposure to anaphylactic causative agents in classrooms and common school or early childhood education program areas such as cafeterias.\na. The term school is defined in the FDA Food Safety Modernization Act (FDA FSMA) to include public kindergartens, elementary schools, and secondary schools. 12 b. The term early childhood education program is defined in the FDA Food Safety Modernization Act to include a Head Start program or an Early Head Start program carried out under the Head Start Act (42 U.S.C. 9831 et seq.), a statelicensed or state-regulated child care program or school, or a state prekindergarten program that serves children from birth through kindergarten. 12 Some of these early childhood education programs may provide early intervention and preschool services under the Individuals with Disabilities Education Act (IDEA). Some programs that provide these IDEA early intervention and preschool services may not fall under the FDA FSMA, but may still wish to consider these voluntary guidelines when developing procedures for children with food allergies.\n• The dissemination of general information on life threatening food allergies to school or early childhood education program staff, parents, and children.\n• Food allergy management training of school or early childhood education program personnel who regularly come into contact with children with life-threatening food allergies.\n• The authorization and training of school or early childhood education program personnel to administer epinephrine when the nurse is not immediately available.\n• The timely accessibility of epinephrine by school or early childhood education program personnel when the nurse is not immediately available.\n• The creation of a plan contained in each individual plan for food allergy management that addresses the appropriate response to an incident of anaphylaxis of a child while such child is engaged in extracurricular programs of a school or early childhood education program, such as non-academic outings and field trips, before-and afterschool programs or before-and after-early childhood education programs, and schoolsponsored or early childhood education program-sponsored programs held on weekends.\n• Maintenance of information for each administration of epinephrine to a child at risk for anaphylaxis and prompt notification to parents.\n• Other elements determined necessary for the management of food allergies and anaphylaxis in schools and early childhood education programs. 12 Section 1 of the Voluntary Guidelines for Managing Food Allergies addresses these content requirements. Section 2 provides a list of recommended actions for school board members and administrators and staff at the district level. Section 3 provides a list of recommended actions for administrators and staff in schools, while Section 4 provides recommended actions for administrators and staff in ECE programs. Section 5 provides information about relevant federal laws that are enforced or administered by the U.S. Department of Education (ED), the U.S. Department of Justice (DOJ), and the U.S. Department of Agriculture (USDA). Section 6 provides a list of resources with more information and strategies.\n# Methods\nTo develop these guidelines, staff at the Centers for Disease Control and Prevention (CDC) created a systematic process to collect, review, and compile expert advice, scientific literature, state guidelines, best practice documents, and position statements from individuals, agencies, and organizations.\nIn January 2010, CDC sponsored a meeting of experts to gather their input into the critical processes and actions needed to protect students with food allergies and to respond to food allergy emergencies in schools. This meeting included representatives from the following groups (see Acknowledgements for details):\n• Federal agencies with expertise in food allergy management in the public health sector, including in schools (CDC, Food and Drug Administration, U.S. National Institute of Allergy and Infectious Diseases, U.S. Department of Education [ED], U.S. Department of Agriculture [USDA]).\n• Organizations with expertise or experience in clinical food allergy management and food allergy advice to consumers (Food Allergy and Anaphylaxis Network, Food Allergy Initiative, Asthma and Allergy Foundation of America, American Academy of Pediatrics, and the American College of Asthma, Allergy, and Immunology).\n• Organizations representing professionals who work in schools (National School Boards Association, National Education Association, National Association of School Nurses, National Association of School Administrators, National Association of Elementary School Principals, National Association of Secondary School Principals, School Nutrition Association, American School Counseling Association, and the American School Health Association).\n• One state educational agency.\n• One local school district.\n• Two parents of children with food allergies.\nMeeting participants provided input on the organization and content for food allergy guidelines.\nIn terms of organization, they recommended that the guidelines should:\n• Use a management framework that is similar to the framework used to address other chronic conditions in schools and ECE programs. This framework should include creation of a building-wide team and essential elements of a plan to manage food allergies.\n• Make sure that management and support systems address the needs of children with food allergies and promote an allergen-safe c school or ECE program.\n• Promote partnerships among schools and ECE programs, children with food allergies and their families, and health care providers.\nc. The term allergen-safe refers to an environment that is made as safe as possible from food allergens. The phrase should not be interpreted to mean an allergen-free environment totally safe from food allergens. There is no failsafe way to prevent an allergen from inadvertently entering a school or ECE program facility. When guarding against exposures to food allergens, a school or ECE program should still properly plan for children with any life-threatening food allergies, to educate all school personnel accordingly, and ensure that school staff are trained and prepared to prevent and respond to a food allergy emergency.\n• Emphasize the value of an onsite, full-time registered nurse to manage food allergies in children, but provide guidance for schools and ECE programs that don't have a full-time or part-time registered nurse.\n• Convey scientific evidence and established clinical practice in terms that leaders and staff in schools and ECE programs understand. Make sure this information is consistent with regulatory and planning guidelines from other federal agencies.\n• Emphasize the need to follow state laws, including regulations (such as Nurse Practice Acts and state food safety regulations) and school or ECE program policies when deciding which procedures and actions are permissible or allowed.\nIn terms of content, meeting participants recommended that the guidelines should:\n• Recommend that children with food allergies be identified so an individual plan for managing their food allergies can be developed.\n• Include essential practices for protecting children from allergic reactions and responding to reactions that occur at schools or ECE programs, at sponsored events, or during transport to and from schools or ECE programs.\n• Develop strategies to reduce the risk of exposure to food allergens in classrooms, cafeterias, and other school or ECE program settings.\n• Develop steps for responding to food allergy emergencies, including the administration of epinephrine, that are consistent with a school's or ECE program's \"all-hazards\" plan.\n• Emphasize training for staff to improve their understanding of food allergies, their ability to help children prevent exposure to food allergens, and their ability to respond to food allergy emergencies (including administration of epinephrine). This training can help to create an environment of acceptance and support for children with food allergies.\n• Emphasize the need to teach children about food allergies as part of the school's or ECE program's health education curriculum.\n• Address the need to teach all parents about food allergies.\n• Address the physical safety and emotional needs of children with food allergies (i.e., stigma, bullying, harassment).\n• Include a list of actions for all staff working in schools and ECE programs that may have a role in managing risk of food allergy, including administrators, registered nurses, teachers, paraprofessional staff, counselors, food service staff, and custodial staff.\nMeeting participants provided an initial set of data and literature sources for analysis. CDC staff then reviewed published literature from peer-reviewed and nonpeer-reviewed sources, including descriptive studies, epidemiologic studies, expert statements, policy statements, and relevant Web-based content from federal agencies. CDC scientists conducted an extensive search for scientific reports, using four electronic citation databases: PubMed, Medline, Web of Science, and ERIC. To ensure a comprehensive review of food allergy sources, CDC used search terms that included a combination of terms, such as \"food allergy, \" \"school, \" \"anaphylaxis, \" \"epinephrine, \" \"peanut allergy, \" \"child, \" \"pediatric, \" \"food allergy and bullying, \" \"emergencies, \" \"life-threatening allergy, \" \"school nurse, \" and \"food allergy and child care. \" CDC staff reviewed all recommended documents and eliminated sources that were outdated (earlier than 2000), were superseded by more current data or recommendations, in conflict with current standards of clinical and school-based practice, reflected international recommendations not relevant to U.S. schools or ECE programs, or were limited to adult food allergies.\nCDC staff relied heavily on the content and references in the 2010 Guidelines for the Diagnosis and Management of Food Allergy in the United States. 13 These 2010 guidelines reflect the most up-to-date, extensive systematic review of the literature and assessment of the body of evidence on the science of food allergies. They met the standards of rigorous systematic search and review methods, and they provide clear recommendations that are based on consensus among researchers, scientists, clinical practitioners, and the public. While the 2010 guidelines did not address the management of patients with food allergies outside of clinical settings (and thus did not directly address the management of food allergies in schools), they were deemed an important source for informing the clinical practice recommendations for managing risks for children with food allergies in the Voluntary Guidelines for Managing Food Allergies.\nTo ensure that recommendations for managing the risk of food allergies were consistent with those recommended for other chronic conditions, CDC staff added search terms that included \"school\" and \"asthma, \"\"diabetes, \"\"epilepsy, \"\"chronic condition, \" and \"management. \" In particular, they used information from the following three documents: Students with Chronic Illness: Guidance for Families, Schools, and Students, 14 Managing Asthma: A Guide for Schools, 15 and Helping the Student with Diabetes Succeed: A Guide for School Personnel. 16 CDC staff analyzed best practice documents, state school food allergy guidelines (n = 14), and relevant health and education organizations' position statements for compatibility with the priorities outlined by experts, common themes, and the accuracy and clarity of recommendations or positions based on clinical standards and scientific evidence.\nTo ensure that these Voluntary Guidelines for Managing Food Allergies were compatible with existing federal laws, federal regulations, and current guidelines for schools and ECE programs, CDC solicited expertise and input from the following sources:\n• Office of the General Counsel; Office of Safe and Healthy Students, Office of Elementary and Secondary Education; Office for Civil Rights; and Office of Special Education and Rehabilitative Services, U.S. Department of Education (ED).\n• Civil Rights Division, U.S. Department of Justice (DOJ).\n• Office of the Deputy Assistant Secretary for Early Childhood, Administration for Children and Families, U.S. Department of Health and Human Services (HHS).\nIn addition to the input from the experts meeting, the analysis of research and practice documents, and the technical advice and assistance provided by regulatory federal agencies, CDC conducted three formal rounds of expert review and comment. During the first round, CDC staff worked with meeting participants and agency partners to get concurrence with recommendations. Second and third round reviews were used to refine the content. Reviewers included participants from the first meeting and additional reviewers added after each round to ensure input from at least one new person who had not previously reviewed the document. In addition to these formal reviews, CDC staff asked for multiple reviews from select experts in food allergy management, schools, and ECE programs to ensure the accuracy of the information and relevance of the recommendations to professional practice. During the review process, CDC staff reviewed and accepted additional references that supported changes made in draft recommendations.\nThe resulting Voluntary Guidelines for Managing Food Allergies include recommendations for practice in the following five priority areas that should be addressed in each school's or ECE program's Food Allergy Management Prevention Plan:\n1. Ensure the daily management of food allergies in individual children.\n2. Prepare for food allergy emergencies.\n3. Provide professional development on food allergies for staff members.\n4. Educate children and family members about food allergies.\n5. Create and maintain a healthy and safe educational environment.\n# Purpose\nThe Voluntary Guidelines for Managing Food Allergies are intended to support implementation of food allergy management and prevention plans and practices in schools and ECE programs. They provide practical information, planning steps, and strategies for reducing allergic reactions and responding to life-threatening reactions for parents, district administrators, school administrators and staff, and ECE program administrators and staff. They can guide improvements in existing food allergy management plans and practices. They can help schools and ECE programs develop a plan where none currently exists. Schools and ECE programs will not need to change their organization or structure or incorporate burdensome practices to respond effectively. They also should not have to incur significant financial costs where basic health and emergency services are already provided.\nAlthough the practices in these guidelines are voluntary, any actions taken for individual children must be implemented consistent with applicable federal and state laws and local policies. Many of the practices reinforce relevant federal laws and regulations administered or enforced by ED, HHS, DOJ, and USDA. How these laws apply case by case will depend upon the facts in each situation. These guidelines also do not address state and local laws or local school district policies because the requirements of these laws and policies vary from state to state and from school district to school district. References to state guidelines reflect support for and consistency with the recommendations in the Voluntary Food Allergy Guidelines, but do not suggest federal endorsement of state guidelines. While these guidelines provide information related to certain applicable laws, they should not be construed as giving legal advice. Schools and ECE programs should consult local legal professionals for such advice. Although schools and ECE programs have some common characteristics, they operate under different laws and regulations and serve children with different developmental and supervisory needs. Different practices are needed in each setting to manage the risk of food allergies. These guidelines include recommendations that apply to both settings, and they identify how the recommendations should be applied differently in each setting when appropriate. These guidelines do not provide specific guidance for unlicensed child care settings, although many recommendations can be used in these settings.\nIf a school or ECE program participates in the Child Nutrition Programs (CNPs), then USDA Food and Nutrition Service is the federal agency with oversight of the meals served. The CNPs include the National School Lunch and School Breakfast Programs, the Special Milk Program, the Fresh Fruit and Vegetable Program, the Child and Adult Care Food Program, and the Summer Food Service Program. Schools, institutions, and sites participating in the CNPs are required under relevant statutes to make accommodations to program meals for children that are determined to have a food allergy disability.\nA food related disability can be a food allergy if the allergy is acknowledged to be a disability by a licensed doctor. These guidelines can assist CNP program operators in providing safe meals and a safe environment for this population of children. \n# About Food Allergies\nA food allergy is defined as an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. 13 The immune response can be severe and life-threatening. Although the immune system normally protects people from germs, in people with food allergies, the immune system mistakenly responds to food as if it were harmful. One way that the immune system causes food allergies is by making a protein antibody called immunoglobulin E (IgE) to the food. The substance in foods that cause this reaction is called the food allergen. When exposed to the food allergen, the IgE antibodies alert cells to release powerful substances, such as histamine, that cause symptoms that can affect the respiratory system, gastrointestinal tract, skin, or cardiovascular system and lead to a lifethreatening reaction called anaphylaxis. 17 The Voluntary Guidelines for Managing Food Allergies focuses not on all food allergies but on food allergies associated with IgE because those are the food allergies that are associated with the risk of anaphylaxis.\nThere are other types of food-related conditions and diseases that range from the frequent problem of digesting lactose in milk, resulting in gas, bloating, and diarrhea, to reactions caused by cereal grains (celiac disease) that can result in severe malabsorption and a variety of other serious health problems. These conditions and diseases may be serious but are not immediately life-threatening and are not addressed in these guidelines. 13,[17][18][19] More than 170 foods are known to cause IgE mediated food allergies. In the United States, the following eight foods or food groups account for 90% of serious allergic reactions: milk, eggs, fish, crustacean shellfish, wheat, soy, peanuts, and tree nuts. 13 Federal law requires food labels in the United States to clearly identify the food allergen source of all foods and ingredients that are (or contain any protein derived from) these common allergens. 20 Some nonfood products used in schools and ECE programssuch as clay, paste, or finger paints-can also contain allergens that may or may not be identified as ingredients on product labels. 21 The symptoms of allergic reactions to food vary both in type and severity among individuals and even in one individual over time. Symptoms associated with an allergic reaction to food include the following:\n• Mucous Membrane Symptoms: red watery eyes or swollen lips, tongue, or eyes.\n• Skin Symptoms: itchiness, flushing, rash, or hives.\n• Gastrointestinal Symptoms: nausea, pain, cramping, vomiting, diarrhea, or acid reflux.\n• Upper Respiratory Symptoms: nasal congestion, sneezing, hoarse voice, trouble swallowing, dry staccato cough, or numbness around mouth.\n• Lower Respiratory Symptoms: deep cough, wheezing, shortness of breath or difficulty breathing, or chest tightness.\n• Cardiovascular Symptoms: pale or blue skin color, weak pulse, dizziness or fainting, confusion or shock, hypotension (decrease in blood pressure), or loss of consciousness.\n• Mental or Emotional Symptoms: sense of \"impending doom, \" irritability, change in alertness, mood change, or confusion.\n# Food Allergy Symptoms in Children\nChildren with food allergies might communicate their symptoms in the following ways:\n• It feels like something is poking my tongue.\n• My tongue (or mouth) is tingling (or burning).\n• My tongue (or mouth) itches.\n• My tongue feels like there is hair on it.\n• My mouth feels funny.\n• There's a frog in my throat; there's something stuck in my throat.\n• My tongue feels full (or heavy).\n• My lips feel tight.\n• It feels like there are bugs in there (to describe itchy ears).\n• It (my throat) feels thick.\n• It feels like a bump is on the back of my tongue (throat).\nSource: The Food Allergy & Anaphylaxis Network. Food Allergy News. 2003;13 (2).\nChildren sometimes do not exhibit overt and visible symptoms after ingesting an allergen, making early diagnosis difficult. 13,22 Some children may not be able to communicate their symptoms clearly because of their age or developmental challenges. Complaints such as abdominal pain, itchiness, or other discomforts may be the first signs of an allergic reaction (see Food Allergy Symptoms in Children).\nSigns and symptoms can become evident within a few minutes or up to 1-2 hours after ingestion of the allergen, and rarely, several hours after ingestion. Symptoms of breathing difficulty, voice hoarseness, or faintness associated with change in mood or alertness or rapid progression of symptoms that involve a combination of the skin, gastrointestinal tract, or cardiovascular symptoms signal a more severe allergic reaction (anaphylaxis) and require immediate attention.\nThe severity of reactions to food allergens is difficult to predict and varies depending on the child's particular sensitivity to the food and on the type and amount of exposure to the food. Ingesting a food allergen triggers most severe reactions, while inhaling or having skin contact with food allergens generally causes mild reactions. 23,24,25 The severity of reaction from food ingestion also can be influenced by the child's age, how quickly the allergen is absorbed (e.g., absorption is faster if food is taken on an empty stomach or ingestion is associated with exercise), and by co-existing health conditions or factors. 17 For example, a person with asthma might be at greater risk of having a more severe anaphylactic reaction. Exercise and certain medications also can increase the harmful effects of certain food allergens. 13,26,27 \n# Allergic Reactions and Anaphylaxis\nAnaphylaxis is best described as a severe allergic reaction that is rapid in onset and may cause death. 31 Not all allergic reactions will develop\n# Food Allergies and Asthma\nOne-third of children with food allergies also have asthma, which increases their risk of experiencing a severe or fatal reaction. 28 Data also suggest that children with asthma and food allergies have more visits to hospitals and emergency departments than children who don't have asthma. 2,29,30 Because asthma can pose serious risks to the health of children with food allergies, schools and ECE programs must consider these risks when they develop plans for managing food allergies.\ninto anaphylaxis. In fact, most are mild and resolve without problems. However, early signs of anaphylaxis can resemble a mild allergic reaction. Unless obvious symptoms-such as throat hoarseness or swelling, persistent wheezing, or fainting or low blood pressure-are present, it is not easy to predict whether these initial, mild symptoms will progress to become an anaphylactic reaction that can result in death. 13 Therefore, all children with known or suspected ingestion of a food allergen and the appearance of symptoms consistent with an allergic reaction must be closely monitored and possibly treated for early signs of anaphylaxis.\n# Characteristics and Risk Factors\nFood allergies account for 35%-50% of all cases of anaphylaxis in emergency care settings .32 Many different food allergens (e.g., milk, egg, fish, shellfish) can cause anaphylaxis.\nIn the United States, fatal or near fatal reactions are most often caused by peanuts (50%-62%) and tree nuts (15%-30%). 33 Results of studies of fatal allergic reactions to food found that a delay in administering epinephrine was one of the most significant risk factors associated with fatal outcomes. 13,26 Some population groups, including children with a history of anaphylaxis, are at higher risk of having a severe reaction to food (see Fatal Food Allergy Reactions).\n# Fatal Food Allergy Reactions\n\n# Risk Factors\n• Delayed administration of epinephrine.\n• Reliance on oral antihistamines alone to treat symptoms.\n• Consuming alcohol and the food allergen at the same time.\n# Groups at Higher Risk\n• Adolescents and young adults.\n• Children with a known food allergy.\n• Children with a prior history of anaphylaxis.\n• Children with asthma, particularly those with poorly controlled asthma.\n# Timing of Symptoms\nIn general, anaphylaxis caused by a food allergen occurs within minutes to several hours after food ingestion . 13 Death due to food-induced anaphylaxis may occur within 30 minutes to 2 hours of exposure, usually from cardiorespiratory compromise. 13 By the time symptoms of an allergic reaction are recognized, a child is likely to already be experiencing anaphylaxis. Symptoms of anaphylaxis can begin with mild skin symptoms (e.g., hives, flushing) that progress slowly, appear rapidly with more severe symptoms, or appear (in rare circumstances) with shock in the absence of other symptoms. In fact, many fatal anaphylaxis cases caused by food do not follow a predictable pattern that starts with mild skin symptoms.\nEven if initial symptoms are successfully treated or resolve completely, up to 20% of anaphylactic reactions recur within 4-8 hours (called biphasic reaction). In other cases, symptoms do not completely resolve and require additional emergency care. For these reasons, children with food-induced anaphylaxis must be monitored closely and evaluated as soon as possible in an emergency care setting.\n# Treatment of Anaphylaxis and Use of Epinephrine\nNo treatment exists to prevent reactions to food allergies or anaphylaxis. Strict avoidance of the food allergen\n# Allergens that May Result\nis the only way to prevent a reaction. However, avoidance in Anaphylaxis that Require Use is not always easy or possible, and staff in schools and ECE of Epinephrine programs must be prepared to deal with allergic reactions,\n• Foods such as peanuts, tree nuts, including anaphylaxis. Early and quick recognition and milk, eggs, fish, or shellfish. treatment of allergic reactions that may lead to anaphylaxis can prevent serious health problems or death.\n• Medications such as penicillin or aspirin. The recommended first line of treatment for anaphylaxis is the prompt use of epinephrine. Early use of epinephrine\n• Bee venom or insect stings, such to treat anaphylaxis improves a person's chance of survival as from yellow jackets, wasps, and quick recovery. 13,34 hornets, or fire ant).\nEpinephrine, also called adrenaline, is naturally produced • Latex, such as from gloves. by the body. When given by injection, it rapidly improves breathing, increases heart rate, and reduces swelling of the face, lips, and throat. Epinephrine is typically available in the form of an autoinjector, a spring loaded syringe used to deliver a measured dose of epinephrine, designed for self-administration by patients, or administration by persons untrained in other needle-based forms of epinephrine delivery. In a clinical setting, patients may receive epinephrine through other needle-based delivery methods.\nEpinephrine can quickly improve a person's symptoms, but the effects are not long lasting. If symptoms recur (biphasic reaction), additional doses of epinephrine are needed. Even when epinephrine is used, 911 or other emergency medical services (EMS) must be called so the person can be transported quickly in an emergency vehicle to the nearest hospital emergency department for further medical treatment and observation. 13 It is not possible to set one guideline for when to use epinephrine to treat allergic reactions caused by food. A person needs clinical experience and judgment to recognize the symptoms associated with anaphylaxis, and not all school or ECE program staff have this experience. Clinical guidelines for how to manage food-induced allergic reactions have mainly focused on the health care setting. They emphasize the need to watch patients closely and give the proper treatment, including epinephrine.\nTreatment decisions are based on the progression or increased severity of symptoms and whether the patient has a history of risk factors for anaphylaxis (see Fatal Food Allergy Reactions). 13 For example, the clinical guidelines favor quick and early use of epinephrine as soon as even mild symptoms appear for children who have had severe allergic reactions in the past. Some schools and ECE programs offer clinical services from a doctor or registered nurse. In these cases, the doctor or nurse can use the clinical guidelines to assess children and make decisions about treatment, including if or when to use epinephrine. However, many schools and most ECE programs do not have a doctor or nurse onsite to make such an assessment. In these cases, a staff person at the scene should call 911 or EMS immediately. If staff are trained to recognize symptoms of an allergic reaction or anaphylaxis and are delegated and trained to administer epinephrine, they also should administer epinephrine by auto-injector at the first signs of an allergic reaction, especially if the child's breathing changes. In addition, school or ECE program staff should make sure that the child is transported without delay in an emergency vehicle to the nearest hospital emergency department for further medical treatment and observation. 24,35 These actions may result in administering epinephrine and activating emergency response systems for a child whose allergic reaction does not progress to life-threatening anaphylaxis. However, the delay or failure to administer epinephrine and the lack of medical attention have contributed to many fatal anaphylaxis cases from food allergies. 25,[36][37][38] The risk of death from untreated anaphylaxis outweighs the risk of adverse side effects from using epinephrine in these cases.\n# Emotional Impact on Children with Food Allergies and Their Parents d\nThe health of a child with a food allergy can be compromised at any time by an allergic reaction to food that is severe or life threatening. Many studies have shown that food allergies have a significant effect on the psychosocial well-being of children with food allergies and their families. [39][40][41][42][43][44][45] Parents of a child with a food allergy may have constant fear about the possibility of a life-threatening reaction and stress from constant vigilance needed to prevent a reaction. They also have to trust their child to the care of others, make sure their child is safe outside the home, and help their child have a normal sense of identity.\nChildren with food allergies may also have constant fear and stress about the possibility of a lifethreatening reaction. The fear of ingesting a food allergen without knowing it can lead to coping strategies that limit social and other daily activities. Children can carry emotional burdens because they are not accepted by other people, they are socially isolated, or they believe they are a burden to others. They also may have anxiety and distress that is caused by teasing, taunting, harassment, or bullying by peers, teachers, or other adults. School and ECE program staff must consider these factors as they develop plans for managing the risk of food allergy for children with food allergies. d. For the purposes of this document, the word parent is used to refer to the adult primary caregiver(s) of a child's basic needs (e.g., feeding, safety). This includes biological parents; other biological relatives such as grandparents, aunts, uncles, or siblings; and non-biological parents such as adoptive, foster, or stepparents.\n# Section 1. Food Allergy Management in Schools and Early Care and Education Programs\n\n# Essential First Steps\nSchool and ECE program staff should develop a comprehensive strategy to manage the risk of food allergy reactions in children. This strategy should include (1) a coordinated approach, (2) strong leadership, and\n(3) a specific and comprehensive plan for managing food allergies.\n# Use a coordinated approach that is based on effective partnerships.\nThe management of any chronic health condition should be based on a partnership among school or ECE program staff, children and their families, and the family's allergist or other doctor. 11,42,46 School or ECE Program Staff\n# Child with Food Allergy and Parent\n\n# Effective Management of Food Allergies\n\n# Allergist or Other Doctor\nThe collective knowledge and experience of a licensed doctor, children with food allergies, and their families can guide the most effective management of food allergies in schools or ECE programs for each child. Close working relationships can help ease anxiety among parents, build trust, and improve the knowledge and skill of school or ECE program staff members. 10,14,42 In schools, all staff members play a part in protecting the health and safety of children with chronic conditions. These staff members include administrators, school nurses or school doctors, food service staff (including food service contract staff ), classroom and specialty teachers, athletic coaches, school counselors, bus drivers, custodial and maintenance staff, therapists, paraeducators, special education service providers, librarians and media specialists, security staff, substitute teachers, and volunteers, such as playground monitors and field trip chaperones. In ECE programs, staff members include the center director, health consultants, nutrition and food service staff, Head Start and child care providers, preschool teachers, teaching assistants, aides, volunteers, and transportation staff.\nA team structure allows for collective management of food allergies, with coordinated planning and communication to ensure that staff responsibilities are carried out in a clear and consistent manner. Instead of creating a new team to address the food allergy-related needs of a particular student with a food allergy, schools and ECE programs can use an existing team such as the student's Section 504 committee (which addresses Section 504 of the Rehabilitation Act of 1973), the student's Individualized Education Program (IEP) team [which addresses special education and related services under Part B of the Individuals With Disabilities Education Act (IDEA)], the school improvement team, child and learning support team, school health or wellness team, or Head Start Health Services Advisory Committee.\nInvolving the school doctor (if applicable), an allergist in the community, or the child's doctor can help the school or ECE program reduce the risk of accidental exposure to allergens. 47 A doctor's diagnosis of a food allergy is necessary to accurately inform plans for avoiding food allergens and managing allergic reactions. The doctor can also give advice on the best practices to control or manage food allergies. 24,25 An allergist is a licensed doctor with specialty training in the diagnosis and treatment of allergic diseases, asthma, and diseases of the immune system.\nChildren with food allergies and their parents have firsthand experience with allergic reactions and are most familiar with a child's unique signs and symptoms. Parents should give the school or ECE program documentation that supports a doctor's diagnosis of food allergy, as well as information about prior history and current risk of anaphylaxis. This information is critical to preventing risk of exposure to allergens and outlining the actions that must be taken if a food allergen exposure occurs. Parents should be continually involved in helping to build a learning environment that is responsive to their child's unique health condition. 47 By working together, parents and school or ECE program staff can communicate better and make sure they have the same expectations. This partnership also shows a shared commitment to the child's well-being and builds parental support and confidence in the ability of school or ECE program staff to manage food allergies.\nMany parents give their ECE program an Emergency Care Plan (ECP) developed by the child's allergist or other doctor. This plan may be the only information ECE program staff members have to manage the child's food allergy. When multiple children have food allergies, the result can be multiple approaches for addressing and managing food allergies and reactions. Instead, ECE programs should use a coordinated approach that is built on partnerships among ECE program staff, parents, and doctors. With a coordinated approach, staff can create one consistent plan of action for responding to any child with a food allergy and to any allergic reaction. 10,44,48 \n# Provide clear leadership to guide planning and ensure implementation of food allergy management plans and practices.\nSuccessful coordination of food allergy planning requires strong school and ECE program leadership. The support of school principals and ECE program administrators is critical, but it may make more sense for the person who provides or coordinates health services for children to lead the food allergy planning process. 49,50 For example, most schools and some ECE programs have a school or district nurse, school doctor, or health consultant or manager. Nationwide, about 85% of schools have either a part-time or full-time nurse to provide health services to students (37% have a full-time nurse). 8 In Head Start programs, health services must be supervised by staff members or consultants with training in health-related fields. 50,51 School nurses, school doctors, and health consultants or managers should have the expertise to help schools and ECE programs develop plans to manage food allergies. Specifically, these staff members can:\n• Work with families and doctors to obtain or create an Emergency Care Plan (ECP) for children with food allergies.\n• Make sure that each child's plan for managing food allergies is consistent with federal laws and regulations, state laws, including regulations, local policies, and standards of professional practices.\n• Act as a liaison between school and district policy makers, ECE program administrators, health services staff members, food service staff members, community health service providers, and emergency responders.\n• Make sure that education records that include personally-identifiable information about a student's food allergy are generally not disclosed without the prior written consent of the parent (or eligible student) in compliance with the Family Educational Rights and Privacy Act of 1974 (FERPA), 20 U.S.C. 1232g and its implementing regulations in 34 CFR part 99, and any other applicable federal and state laws that protect the privacy or confidentiality of student information. (FERPA may not require parental consent in all circumstances.) FERPA also includes an emergency exception to the prior consent requirement if there is an articulable and significant threat to the health or safety of the student or others. (See Section 5 for more information about FERPA.)\n• Monitor the use of medication in the school or ECE program setting.\n• Obtain an epinephrine auto-injector and make sure it is rapidly available to designated and trained staff members to respond to a child's food allergy emergency.\n• Recognize and handle medical emergencies.\n• Learn about best practices for managing food allergies.\n• Help schools and ECE programs develop a comprehensive approach to managing food allergies. Coordinate a team to put the resulting plan into action.\n• Work with food service staff on parts of the plan that involve meal and snack preparation and services.\n• Identify internal resources and community partners that can support the planning process.\n• Share general information about food allergies with staff members, parents, and others who need it.\n• Make sure staff receive the training they need, including how to administer an epinephrine auto-injector. A doctor or registered nurse can provide this training.\n• Talk with staff members, doctors, children, and their families about food allergies and how they should be managed. Share concerns from parents and children with the food allergy management team.\n• Review the school or ECE program plan on a regular basis to look for ways to reduce exposure to food allergens and better manage allergic reactions. Recommend changes when needed to make the plans better. 49,50,52 The many responsibilities outlined in this section demonstrate the benefit of having a full-or parttime registered nurse (and a doctor part-time) and ECE programs having a medically trained and knowledgeable health consultant or manager. However, if a registered nurse, doctor, or health consultant or manager is not available, the school or ECE program administrator can develop a comprehensive plan that may include delegating some critical responsibilities to other trained professional staff. This plan should also include seeking advice from the child's primary doctor or allergist and training guidance and assistance from health services staff at the district level 47 (See Sections 2 and 3.)\n# Develop and implement a comprehensive plan for managing food allergies.\nTo effectively manage food allergies and the risks associated with these conditions, many people inside and outside the school or ECE program must come together to develop a comprehensive plan, called the Food Allergy Management and Prevention Plan (FAMPP). This plan should include all strategies and actions needed to manage food allergies in the school or ECE program. It also should be compatible with the approach used to address other chronic conditions in each individual setting. 14 The FAMPP should reinforce the efforts of each school or ECE program to create a safe learning environment for all children. It should address systemwide planning, implementation, and follow-up and include specific actions for each individual child with a food allergy. The FAMPP should:\n• Meet the requirements of federal laws and regulations, such as Section 504 of the Rehabilitation Act of 1973, the Americans with Disabilities Act (ADA) and the Richard B. Russell National School Lunch Act, if applicable. An explanation of how these federal laws could apply to students with food allergies is provided in Section 5. Among other things, these federal laws address individualized assessment of each child's needs and parental participation in the development of any plan or program designed to meet these dietary needs. An effective FAMPP also would need to meet the requirements of state and local laws and regulations and district policies.\n• Reflect clear goals, purposes, and expectations for food allergy management that are consistent with the school's or ECE program's mission and policies.\n• Be clear and easy to understand and implement.\n• Be responsive to the needs of any child with food allergies by taking into account the different and unique needs of each child.\n• Be adaptable and updated regularly on the basis of experiences, best practices, current research, and changes in district policy or state or county law.\nThe FAMPP should address the following five priorities:\n1. Ensure the daily management of food allergies for individual children.\n2. Prepare for food allergy emergencies.\n3. Provide professional development on food allergies for staff members.\n4. Educate children and family members about food allergies.\n5. Create and maintain a healthy and safe educational environment.\nThe remainder of this section provides more detail and specific recommendations for each priority. This section concludes with a comprehensive Food Allergy Management and Prevention Plan (FAMPP) Checklist for use in schools and ECE programs. This checklist can help schools and ECE programs improve their ability to manage the risk food allergies and assess whether their plans address all five priorities.\n# Priorities for Managing Food Allergies\n\n# Ensure the daily management of food allergies for individual children.\nTo protect the health and safety of an individual child with food allergies, school and ECE program staff must identify children with a history of food allergies and develop or obtain plans to manage their allergies.\na. Identify children with food allergies.\nSchools and ECE programs usually have forms and procedures to identify children with chronic conditions, including food allergies, when they enroll or transfer to the school-or when the condition is not initially reported but becomes evident during the academic year. Examples include health condition forms or parent interviews.\nChildren or parents may report a food allergy on the required forms, but this information may not be accurate or complete. Schools and ECE program staff must work with parents to obtain, directly from the child's healthcare provider, the medical information necessary to develop plans for managing the individual care and emergency actions.\nThe USDA requires a doctor's statement that a child has a food allergy disability before food service staff in the Child Nutrition Program can make meal accommodations and provide a safe meal for a child with a food allergy.\n# b. Develop a plan to manage and reduce the risk of food allergy reactions in individual children.\nParents and doctors should provide information and recommendations to help schools and ECE programs develop written plans to manage food allergies for children on a daily basis. This information may be provided on health condition forms, medical orders, doctor's statement, or diet orders. There are a variety of names used to label written plans for individual children with food allergies. It is essential for children to have a short, easy to follow plan for emergency care. This is usually a food allergy Emergency Care Plan (ECP). Other names used for the ECP can include a \"food allergy action plan, \"\"emergency action plan, \" or in ECE programs, an \"individual care plan\". Schools or ECE programs may need to establish additional plans, such as a Section 504 plan or, if appropriate, an Individualized Education Program (IEP), or may establish a nursing assessment and outcome-type Individualized Health Plan (IHP).\nThe ECP is the basic form used to collect food allergy information and it should be completed for every child identified as having a food allergy. 24,25,48,[52][53][54][55][56][57][58][59][60] (If an ECP form is used by the Child Nutrition Program staff to make meal accommodations, it should include the medical information required by the USDA and must be signed by the doctor). This form should be kept in each child's school health record, and it may include the following:\n°°A recent photo of the child.\n°°Information about the food allergen, including a confirmed written diagnosis from the child's doctor or allergist.\n°°Information about signs and symptoms of the child's possible reactions to known allergens.\n°°Information about the possible severity of reactions, including any history of prior anaphylaxis (even though anaphylaxis can occur even in children without a history of prior anaphylaxis).\n°°A treatment plan for responding to a food allergy reaction or emergency, including whether an epinephrine auto-injector should be used.\n°°Information about other conditions, such as asthma or exercise-induced anaphylaxis that might affect food allergy management.\n°°Contact information for parents and doctors, including alternate phone numbers for notification in case of emergency.\nThe ECP should be written by the child's doctor and confirmed with the parents. In some cases, it can be written by a registered nurse, or school doctor, as long as the child's doctor is consulted and the parents confirm the plan. The child's doctor and parents should sign and date the ECP, and schools and ECE programs should not accept a child's ECP without confirmation and signature from the child's doctor. If a public elementary or secondary school maintains an ECP on an individual child, the ECP would be covered by FERPA as an \"education record. \" The ECP should specifically state who may have access to the information in the plan, and should ensure that any such access to this information is permissible under FERPA and any other applicable federal or state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.) Section 6 lists state and organizational resources that include examples of ECPs and suggested processes that schools and ECE programs might use to develop their ECPs.\nAn IHP is a written document that outlines how children will receive health care services at school and is developed and used by a registered nurse. The IHP documents a specific student's health needs and outlines specific health outcome expectations and plans for achieving these expectations. The use of an IHP is standard practice for schools with a full-time or part-time registered nurse and it is commonly used to document the progress of children with an identified chronic condition such as food allergies. 39,47,52,61 The IHP helps registered nurses manage the risk of food allergies, prevent allergic reactions, and coordinate care with other staff (such as food service staff ) and health service providers outside the school. Federal law does not require the use of an IHP, but its contents can be useful to the nurse in addressing the requirements of federal laws related to school responsibilities for children with food allergies. Section 6 lists state and organizational resources that include examples of an IHP.\nIf a doctor determines that a child's food allergy may result in anaphylaxis and if the child's food allergy constitutes a disability under applicable federal disability laws, school staff can integrate information from the ECP, doctor's statement, and IHP into a Section 504 plan or, if appropriate, into an IEP. (See Section 5 for more information on applicable federal laws.) Schools should still use an ECP with specific, easy-to-read information about how to respond to a food allergy reaction.\nFor children that are identified as having a food allergy disability and who attend a school or ECE program that participates in the U.S. Department of Agriculture's (USDA's) Child Nutrition Programs, a meal or food substitution or modification must be made when the diagnosis is supported by a doctors' signed statement. Before Child Nutrition Program food service staff can provide a safe meal accommodation, parents must provide a statement from a licensed doctor that identifies: °°The child's disability (according to pertinent statutes).\n°°An explanation of why the disability restricts the child's diet.\n°°The major life activity affected by the disability.\n°°The food or foods to be omitted from the child's diet.\n°°The food or choice of foods that must be substituted. 62 A child recognized by the Child Nutrition Program staff as having a food allergy disability does not have to have a Section 504 plan, ECP, IHP, or IEP in order for a meal accommodation to be provided.\nA statement signed by a licensed doctor addressing the points above is sufficient. However, the Child Nutrition Program-required doctor's statement can be integrated in any plan a school or ECE develops to meet a child's special dietary needs.\nIf a Section 504 plan or, if appropriate, an IEP, is developed in connection with the provision of services required under those laws to address the student's food allergy disability, information from the ECP is still useful and can be referenced in, or incorporated into, the Section 504 Plan or IEP. Note that a Section 504 plan or IEP is an education record subject to FERPA. For children not covered by Federal disability laws, schools can use the ECP and IHP to manage each child's food allergy. The IHP can include information about modifications and substitutions for meal and snack planning. An IHP or ECP developed for an individual student is also an education record subject to FERPA.\nIn ECE programs, every child with a food allergy should have an ECP or individual care plan, even if the child has a Section 504 plan or, if eligible for services under IDEA, has an IEP or, if appropriate, an individualized family service plan (IFSP). (See Section 5 for more information regarding these Federal laws.) Because most ECE programs do not have a registered nurse on staff to develop such a plan, the ECE program's health consultant, health manager, or administrator should review each child's health records and emergency information at enrollment and work with parents to obtain an ECP for each child diagnosed with a food allergy. The ECP should be updated at least once a year. Health consultants or managers can share information about any allergic reactions, changes in the child's health status, and exposure to allergens with parents and doctors (with the parents' permission). Working with parents and the child's healthcare provider is essential to make sure that children get the medical services and accommodations they need. Staff should consider referring children without access to health care to health services, when possible.\nECPs used by ECE programs should be signed and dated by the child's doctor and parents. The plan should specifically state who has access to the plan. The plan also should state which staff members are responsible for the care, transportation, and feeding of children with food allergies. 12,50 (See Section 5 for more information about applicable Federal laws.) c. Help students manage their own food allergies.\nYoung children in ECE programs and early elementary grades in schools generally cannot manage their own food allergies. However, some students, especially adolescents, can take responsibility for managing their own food allergies, including carrying and using epinephrine when needed. When medication is required by students who have chronic health conditions, especially when medication may be lifesaving, it is best practice to encourage and assist students to become educated and competent in their own care. 48,54,63,64 Students who can manage their own food allergies should have quick (within a few minutes) access to an epinephrine auto-injector, both at school and during school-related events. 13 Some schools allow students to carry prescribed epinephrine auto-injectors (e.g., in their pocket, backpack, or purse) at school. Some state laws, allow students to carry auto-injectors during activities on school property and during transportation to and from school or school-related events. 63 Federal law requires reasonable modifications of school policies when necessary to avoid disability discrimination, and in some cases, this may require allowing a student to carry an epinephrine auto-injector. School officials should check state and federal laws before setting their policies and practices. See Section 5 for more information about applicable Federal laws.\nBefore students are allowed to carry and use medication, school staff should assess students' knowledge, attitudes, behaviors, and skills to determine their ability to handle this responsibility. 64 This decision should be reassessed periodically, and the school nurse or another assigned staff member should randomly check to make sure students are carrying their epinephrine auto-injector. Some students with food allergies may choose to wear medical alert bracelets, which can aid emergency response. 13 School officials can encourage students to wear these bracelets, but they should not require them. Some students will not want to wear such jewelry because they fear being stigmatized.\nSchool nurses and other school staff members should reinforce self-management skills for students with food allergies. These skills include reading labels, asking questions about foods in the school meal and snack programs, avoiding unlabeled or unknown foods, using epinephrine auto-injectors when needed, and recognizing and reporting an allergic reaction to an adult.\nEven when students are able to manage their own food allergies, school staff need to know which students have allergies so they can have plans in place to monitor each student's condition and be able to respond in an emergency. Because some symptoms of anaphylaxis may continue after a dose of epinephrine is administered and because students might not always have their medication with them, schools should also keep a second epinephrine auto-injector (provided by parent or student) in a secure but rapidly accessible location. 63,65,66 (See the textbox on page 31 related to the justification for more than one dose of epinephrine.)\n# Prepare for food allergy emergencies.\nAll schools and ECE programs should anticipate and prepare for food allergy emergencies in the same ways they approach emergency preparedness for other hazards. Comprehensive emergency planning includes prevention, preparedness, response, and recovery for any type of emergency. This \"all-hazards\" model is often used to plan for natural disasters, weather-related emergencies, and pandemic influenza. A school's all-hazards emergency plan also should address potential crises caused by violence or food allergy emergencies. 67 This plan should go beyond each child's ECP to include building-level planning, communication, training, and emergency response procedures. 68 a. Set up communication systems that are easy to use.\nCommunication devices, such as intercoms, walkie-talkies, or cell phones, should be available at all times in case of an emergency. School and ECE program staff in classrooms, gymnasiums, cafeterias, playgrounds, and transportation vehicles should be able to communicate easily and quickly with the school nurse, school authorities, health consultants or managers, emergency responders and parents. Communication devices should be checked regularly to make sure they work.\nb. Make sure staff can get to epinephrine auto-injectors quickly and easily.\nQuick access to and immediate availability of epinephrine to respond to anaphylaxis emergencies is essential. 13 It is the parent's responsibility to provide at least one or two epinephrine auto-injectors for a child with food allergies if they are prescribed by a doctor. It is the school's or ECE program's responsibility to store epinephrine auto-injectors in a place that can be reached quickly and easily and to delegate and train staff to give epinephrine in response to allergic reactions.\nStudies have shown that quick access to epinephrine is critical to saving lives in episodes of anaphylaxis. 24,25,37 To ensure quick access to epinephrine, auto-injectors should be kept in a safe and secure place that trained staff members can get to quickly during school or ECE program hours. 63,[68][69][70] At the same time, staff must also follow federal and state laws, including regulations, and local policies that may require medications to be locked in a secure place. For example, federal Head Start regulations require that all \"grantee and delegate agencies establish and maintain written procedures regarding the administration, handling, and storage of medication for every child,\" including \"labeling and storing, under lock and key, and refrigerating, if necessary, all medications, including those required for staff and volunteers. \" 51 State regulations and local policies may similarly require locking medications in a secure location. School and ECE program staff should seek guidance from federal and state regulatory agencies and local policy makers when deciding how to store epinephrine auto-injectors.\nThese decisions also must take into account the needs of each student and the specific characteristics of the school district, the staff, and the school building. Decisions on where to store medication, such as in a central location (office or health room), in the classroom, or in several locations (on a large school campus) may vary among school districts and schools. These decisions should be based on state and local laws and regulations and school policies. They also must ensure the safety of children with food allergies. The Guidelines for Managing Life-threatening Food Allergies in Connecticut Schools list some issues to consider, including the general safety standards for handling and storage of medication, developmental stage and competence of the student, size of the building, availability of a full-time school nurse in the building, availability of communication devices between teachers and paraprofessionals who are inside the building or on the playground and the school nurse, school nurse response time from the health office to the classroom, preferences and other responsibilities of the teacher, preferences of the parent, preferences of the student (as applicable), and movement of the student within the building. 54 The location(s) of medications should be listed in the school's overall emergency plan and in each child's ECP (and IHP, Section 504 plan, or IEP, if appropriate). Schools and ECE programs should also identify which staff members will be responsible for reviewing expiration dates and replacing outdated epinephrine auto-injectors and for carrying medication during field trips and other school events. 70 c. Make sure that epinephrine is used when needed and someone immediately contacts emergency medical services.\nDelays in using epinephrine have resulted in near fatal and fatal food allergy reactions in schools and ECE programs. 25,36,37 In a food allergy emergency, trained staff should give epinephrine immediately.\nEarly and appropriate administration of epinephrine can temporarily stop allergic reactions and provide the critical time needed to get medical help.\nState laws, state nursing regulations, and local school board policies direct the medication administration in school and ECE programs. They often define which medications nonhealth professionals are allowed to administer in schools, including who may administer epinephrine by auto-injector. If nonhealth staff members are permitted to administer epinephrine, training should be required. 39,71 When epinephrine is used, school or ECE program staff must call 911 or emergency medical services (EMS). EMS should be informed that the emergency is due to an allergic reaction, if epinephrine has been administered, when it was administered, and that an additional dose of epinephrine may be needed. The child should be transported quickly in an emergency vehicle to the nearest hospital emergency department for further medical treatment and observation. 13 Staff also should contact the child's parents to inform them of their child's food allergy emergency and tell them where the child is being transported. Because medical attention is needed urgently in this situation, staff must not wait for parents to come and pick up their children before calling EMS.\n# Justification for More Than One Dose of Epinephrine\nSchools and ECE programs should consider keeping multiple doses of epinephrine onsite so they can respond quickly to a food allergy emergency. Although some schools allow students to carry their own auto-injectors, a second auto-injector should be available at school in case a student does not have one at the time of the emergency. School and ECE program staff may also decide that having more than one auto-injector at different locations (especially for a large building or campus) will best meet a child's needs. In addition, some symptoms of anaphylaxis may continue after one dose of epinephrine, so a second dose may be needed at school if EMS does not arrive quickly. Some state laws allow for the prescribing of stock supply of non-patient specific epinephrine auto-injectors for use in schools, which may allow schools or ECE programs to acquire the needed additional doses of epinephrine. When allowed by state law and local policy, schools and ECE programs that have a doctor or nurse onsite can stock their emergency medical kits with epinephrine auto-injectors to be used for anaphylaxis emergencies. 63,65,66,72 In states where legislation does not exist or does not allow schools or ECE programs to stock epinephrine, staff will need to work with parents and their doctors to get additional epinephrine auto-injectors for students who need them.\n# d. Identify the role of each staff member in an emergency.\nAny plan for managing food allergies should state specifically what each staff member should do in an emergency. This information should be simple and easy to follow, particularly when a staff member who is not a licensed health professional is delegated to administer epinephrine. 24,68 Ideally, a registered nurse or doctor would be available to assess a food allergy emergency and decide if epinephrine is needed. When a nurse or doctor is not onsite, trained unlicensed assistive personnel or nonhealth professionals can recognize the signs and symptoms of an allergic reaction, have quick access to an epinephrine auto-injector, and administer epinephrine. 70,71 Examples of these staff members may include health aides and assistants, teachers, athletic coaches, food service staff, administrators, and parent or adult chaperones. A licensed health care professional such as a registered nurse, doctor, or allergist should train, evaluate, and supervise unlicensed assistive personnel or delegated nonhealth professionals. This training should teach staff how to recognize the signs and symptoms of a reaction, administer epinephrine, contact EMS, and understand state and local laws and regulations related to giving medication to students.\nECE programs that care for children with chronic conditions such as food allergies should seek the services of a trained health advocate or consultant to help staff develop emergency plans, write policies, and train staff. ECE programs are required to have a certified first aider present at all times. 50 All ECE program staff should get annual first aid training that teaches them how to recognize and respond to pediatric emergencies. 49 This training should include how to recognize the signs and symptoms of an allergic reaction and how to give epinephrine through an auto-injector. 23 ECE programs should keep records of all staff training.\n# e. Prepare for food allergy reactions in children without a prior history of food allergies.\nSchools and ECE programs should be ready to respond to severe allergic reactions in children with no history of anaphylaxis or no previously diagnosed food allergies. At a minimum, schools and ECE programs should establish a protocol for contacting emergency services when an allergic reaction is suspected and follow this protocol immediately when a child exhibits signs of anaphylaxis.\nIf allowed by state law, the school doctor or nurse may stock their emergency medical kits with epinephrine auto-injectors to be used for anaphylaxis emergencies. If the school or ECE program has a FAMPP, written protocol, and licensed or delegated trained staff, an epinephrine auto-injector may be used for anaphylaxis regardless of previous allergy history.\nf. Document the response to a food allergy emergency.\nEmergency response should include a protocol for documenting or recording each emergency incident and use of epinephrine. 12,65,68 Documentation should include the following:\n°°Time and location of the incident.\n°°Food allergen that triggered the reaction (if known).\n°°If epinephrine was used and the time it was used.\n°°Notification of parents and EMS.\n°°Staff members who responded to the emergency.\nSection 6 lists state and organizational resources that include examples of epinephrine administration reports.\nCorrective actions and lessons learned from an incident should be used to revise the child's individual plan and the school's or ECE program's FAMPP, if needed. School and ECE program administrators also should review the emergency response with the child's parents, the staff members involved in the response, local EMS responders, and the child. 63,70 See the Example Checklist for an example of steps to follow after a nonfatal food allergy emergency.\n# Example Checklist: Steps to Take Within 24 Hours of a Nonfatal Food Allergy Reaction\n• Call parent or guardian to follow up on student condition.\n• Review anaphylactic or allergic episode with parent or guardian and student.\n°°Identify allergen and route of exposure-discuss signs and symptoms with parent or guardian.\n°°Review actions taken.\n°°Discuss positive and negative outcomes.\n°°Discuss any needed revision to care plan based on experience or outcome.\n• Discuss family role with parent or guardian to improve outcomes.\n• Discuss school, ECE program, and home concerns to improve prevention, response, and student outcomes.\n• Ask parent or guardian to replace epinephrine dose that was given, if needed.\n• Ask parent or guardian to follow up with health care provider.\nSource: National Association of School Nurses, 2011.\n# Provide professional development on food allergies for staff.\nSchools and ECE programs should provide training to all staff members to increase their knowledge about food allergies and how to respond to food allergy emergencies. This training should focus on how to reduce the risk of an allergic reaction, respond to allergic reactions, and support the social and academic development of children with food allergies. 25,38,73 Schools and ECE programs should coordinate training activities with a licensed health care professional, such as a school nurse, public health nurse, public health educator, or school or community doctor. Training can include use of existing materials that provide general information about food allergies, as well as information and resources to help staff meet the specific needs of individual children. 23,24,39,49,[54][55][56][57][58][59][60]73,74 Administrators should allow enough time for proper training, and all training should be evaluated to make sure it is effective.\nIn 2010, the National Diabetes Education Program updated their guidance to help students manage their diabetes in schools. 16 This updated guide outlines three levels of training that include basic training for all staff and specialized training for specific staff members. This approach provides a useful framework that has been adapted here to guide training on food allergy management in schools and ECE programs.\n# a. Provide general training on food allergies for all staff.\nAny staff member who might interact with children with food allergies or be asked to help respond to a food allergy emergency should be trained. Examples include administrators, nutrition and food service staff (including contract staff ), classroom and specialty teachers, athletic coaches, school counselors, bus drivers, custodial and maintenance staff, therapists, paraeducators, special education service providers, librarians and media specialists, security staff, substitute teachers, and volunteers such as playground monitors and field trip chaperones. General training content should include the following:\n°°School or ECE program policies and practices.\n°°An overview of food allergies.\n°°Definitions of key terms, including food allergy, major allergens, epinephrine, and anaphylaxis.\n°°The difference between potentially life-threatening food allergy and other food-related problems.\n°°Signs and symptoms of a food allergy reaction and anaphylaxis and information on common emergency medications.\n°°General strategies for reducing and preventing exposure to allergens (in food and nonfood items).\n°°Policies on bullying and harassment and how they apply to children with food allergies. °°How to respond to a food allergy emergency.\n°°Information about federal laws that could apply, such as the ADA, Section 504, and FERPA. (See Section 5 for more information about applicable federal laws.) Information about any state laws, including regulations, or district policies that apply.\n°°How to administer epinephrine with an auto-injector (for those formally delegated to do so).\n°°How to help children treat their own food allergy episodes.\n°°Effects of food allergies on children's behavior and ability to learn.\n°°Importance of giving emotional support to children with food allergies and to other children who might witness a severe food allergy reaction (anaphylaxis).\n°°Common risk factors, triggers, and areas of exposure to food allergens in schools or ECE programs.\n°°Specific strategies for fully integrating children with food allergies into school and class activities while reducing the risk of exposure to allergens in classrooms, during meals, during nonacademic outings, on field trips, during official activities before and after school or ECE programs, and during events sponsored by schools or ECE programs that are held outside of regular hours. These strategies could address (but are not limited to) the following: §°Special seating arrangements when age and circumstance appropriate (e.g., during meal times, birthday parties). §°Plans for keeping foods with allergens separated from foods provided to children with food allergies. §°Rules on how staff and students should wash their hands and clean surfaces to reduce the risk of exposure to food allergens. §°The importance of not sharing food. §°How to read food labels to identify food allergens.\n# c. Provide specialized training for staff who are responsible for managing the health of children with food allergies on a daily basis.\nThis training should be required for district nurses, school nurses, school doctors, and professionally qualified health coordinators or managers. In addition to the general and in-depth content described previously, this training should include information about how to:\n°°Create ECPs and review or develop other individual care plans as needed.\n°°Manage and store medication.\n°°Delegate and train unlicensed assistive personnel to administer epinephrine.\n°°Help children manage their own food allergies.\n°°Document the tasks performed as part of food allergy management.\n°°Evaluate emergency responses and staff members' ability to respond to food allergy emergencies.\nTraining should be conducted at least once a year, and should be reviewed after a food allergy reaction or anaphylaxis emergency for the purpose of improving prevention and response.\nSchools and ECE programs should consult with parents of children with food allergies when they design staff training. These parents have knowledge and experience on how to manage their child's food allergies, as well as information from their child's doctor. Parents do not need to participate in the delivery of training sessions or attend staff training.\n# Educate children and family members about food allergies.\na. Teach all children about food allergies.\nAll children need to learn about food allergies, but teaching methods will differ on the basis of their age and the setting. For example, schools can provide food allergy education as part of the health education or other curriculum topic, such as family and consumer sciences, general science, physical education, and character education. 41,45,67,69,75,76 ECE programs can provide food allergy education with help from certified health education specialists.\nFood allergy education should be appropriate for the developmental level and culture of the children in a particular school or ECE program. It should focus on increasing awareness and understanding of food allergies and building support and acceptance of people with food allergies. 59,76 At a minimum, all children should be able to:\n°°Identify signs and symptoms of anaphylaxis.\n°°Know and understand why it is wrong to tease or bully others, including people with food allergies.\n°°Know and understand the importance of finding a staff member who can help respond to suspected food allergy emergencies.\n°°Understand rules on hand washing, food sharing, allergen-safe zones, and personal conduct.\nFood allergy awareness is reinforced when staff members model behaviors and attitudes that comply with rules that reduce exposure to food allergens. 48 b. Teach all parents and families about food allergies.\nA successful FAMPP needs support and participation from parents of children with food allergies and from parents of children without food allergies. All parents should get information to increase their awareness and understanding of food allergies, the policies and practices that protect children with food allergies, the roles of all staff members in protecting children with food allergies, and the measures parents of children with and without food allergies can take to help ensure this protection. 45,76 School and ECE program administrators, working with school or district nurses or health consultants or managers, should educate families on food allergy policies and practices. Classroom teachers should provide information to all parents about what is being done to prevent food allergy reactions in the classroom. Food service staff should provide information to families about federal regulations of the U.S. Department of Agriculture's Food and Nutrition Service and practices that protect children, and manage food allergies during meals served under USDA meal programs. District and school policies and protocols to prevent bullying, respond to food allergy emergencies, and create a safe environment for all children should be shared with all families.\nSchools and ECE programs can share information in many ways, including through letters or e-mails to parents; updates on school Web sites; and announcements at parent-teacher association meetings, school nights, health fairs, and community events.\n# Create and maintain a healthy and safe educational environment.\nSchools, ECE programs, and communities have a shared responsibility to promote a safe physical environment that protects children with food allergies and climate that supports their positive psychological and social development. 77,78 a. Create an environment that is as safe as possible from exposure to food allergens.\nSchools and ECE programs can create a safer learning environment by reducing children's exposure to potential allergens. 24,39,[54][55][56][57][58][59]74 When a child has a documented food allergy, staff should take active steps to reduce the risk of exposure in all common areas, such as classrooms and cafeterias. 12 Some schools or ECE programs have considered banning or have banned specific food across the entire school or ECE program setting in an attempt to eliminate exposing a child with a food allergy to that food. But, such an option cannot guarantee a totally safe environment because there is no reasonable or fail-safe way to prevent an allergen from inadvertently entering into a building. Even with such a ban in place, a school or ECE program still has a responsibility to properly plan for children with any life-threatening food allergies, to educate all school personnel accordingly, and ensure that school staff are trained and prepared to prevent and respond to a food allergy emergency.\nSchools or ECE programs may choose other alternatives to banning allergens including the designation of allergen-safe zones, such as an individual classroom or eating area in the cafeteria, or designation of food-free zones, such as a library, classroom, or buses. 45 79 provide school districts, schools, and ECE programs with requirements governing the cleaning and sanitizing of surfaces and other practices that can protect against the unintentional transfer of residue or trace amount of an allergic food into another food. Some practices to reduce this cross-contact include the following:\n°°Clean and sanitize with soap and water or all-purpose cleaning agents and sanitizers that meet state and local food safety regulations, all surfaces that come into contact with food in kitchens, classrooms, and other locations where food is prepared or eaten. Cleaning with water alone will not remove food allergens.\n°°Clean and sanitize food preparation equipment, such as food slicers, and utensils before and after use to prevent cross-contact.\n°°Clean and sanitize trays and baking sheets after each use. Oils can seep through wax paper or other liners and cause cross-contact.\n°°Prepare food separately for children with food allergies. Strategies should include preparing items without allergens first, using a separate work space and equipment, and labeling and storing items before preparing other foods.\n°°Train all staff who prepare, handle, or serve food how to read labels to identify food allergens. Make sure that staff members are knowledgeable about current labeling laws. Because food labels often change, they should be read every time the food is purchased. Ingredient lists posted on Web sites are not reliable. The manufacturer of the food should be contacted if clarification is needed.\n°°Use appropriate hand-washing procedures that emphasize the use of soap and water. Hand sanitizers are not effective in removing food allergens.\nNutrition and food service staff in schools and ECE programs are required to follow local food safety and sanitation laws and be trained in practices that prevent food, surface-to-food, and food-to-food contamination that also serve to help prevent cross-contact of food allergens. Meals and snacks may be served in locations other than cafeterias, handled by staff members other than the food service staff, or provided outside of a USDA Child Nutrition Program. When developing policies and procedures for food handling, consider all possible situations where food might be prepared or served, any staff members who might be involved, and the state and local food safety regulations that might be appropriate to help prevent the transfer of food allergens in these situations.\nIn ECE programs, additional precautions are recommended to reduce the risk of food allergy reactions, especially among children with a history of anaphylaxis. Many of these recommendations are consistent with common practices for managing any child in an ECE program.\n°°Make sure that all staff members can read product labels and identify food allergens.\n°°Recommend, but do not require, that children with known food allergies wear a medical alert bracelet.\n°°Promote good hand-washing practices before and after eating.\n°°Supervise children closely during mealtimes. Consider assigned seating for meals, especially in situations with family-style dining. Emphasize that children not share food.\n°°Put children's names on cups, plates, and utensils to avoid confusion and cross-contact.\n°°Designate food storage areas for foods brought from home. 6,45,77 c. Make outside groups aware of food allergy policies and rules when they use school or ECE program facilities before or after hours.\nLocal agencies, community groups, and community members who use school or ECE program facilities before or after operating hours should be aware of and comply with policies on food, cleaning, and sanitation procedures. If food is allowed in the building, consider banning food from specific classrooms or areas that children with food allergies use often. School and ECE program staff should be notified when outside groups are using their facilities.\n# d. Create a positive psychosocial climate.\nSchools and ECE programs should foster a climate that promotes positive psychological and social development; that actively promotes safety, respect, and acceptance of differences; and fosters positive interpersonal relationships between staff members and children and between the children themselves. The psychosocial climate is influenced by clear and consistent disciplinary policies, meaningful opportunities for participation, and supportive behaviors by staff members and parents. 78 Children with food allergies need an environment where they feel secure and can interact with caring people they trust. Bullying, teasing, and harassment can lead to psychological distress for children with food allergies which could lead to a more severe reaction when the allergen is present. 22,43,44 A positive psychosocial climate-coupled with food allergy education and awareness for all children, families, and staff members-can help remove feelings of anxiety and alienation among children with food allergies. 43,44 To create a positive psychosocial climate, staff members, children, and parents must all work together. School nurses, school counselors, or mental health consultants can provide leadership and guidance to set best practices and strategies for a positive psychosocial climate. Staff members should promote and reinforce expectations for a positive and supportive climate by making sure the needs of children with food allergies are addressed. For example, they can avoid using language and activities that isolate children with food allergies and encourage everyone's help in keeping the classroom safe from food allergens. Children can help develop classroom rules, rewards, and activities.\nAll children and staff members share responsibility for preventing bullying and social isolation of children with food allergies. School and ECE program staff should recognize that acceptance by peers is one of the most important influences on a child's emotional and social development. 78 Among adolescents, food allergy education and awareness can be an effective strategy to improve social interactions, reduce peer pressure, and decrease risk-taking behaviors that expose them to food allergens. 22 Children should be expected to treat others with respect and to be good citizens, not passive bystanders, when they are aware of bullying or peers who seem troubled. Children should understand the positive or negative consequences associated with their actions. Rules and policies against bullying behavior should be developed in partnership with staff members, families, and children. They should be posted in buildings; published in school handbooks; and discussed with staff members, children, and families. All children and staff members should be encouraged to report bullying and harassment of any child with food allergies. 80,81 \n# Conclusion\nSchools and ECE programs are responsible for the health and safety of children with food allergies. The strategies presented in these guidelines can help schools and ECE programs take a comprehensive approach to managing food allergies. Through the collective efforts of school and ECE program staff members, parents, and health care providers, children with food allergies can be assured a safe place to thrive, learn, and succeed. \n# Meals and Snacks\n• Use nonfood incentives for prizes, gifts, and awards.\n• Help students with food allergies read labels of foods provided by others so they can avoid ingesting hidden food allergens.\n• Consider methods (such as assigned cubicles) to prevent cross-contact of food allergens from lunches and snacks stored in the classroom.\n• Support parents of children with food allergies who wish to provide safe snack items for their child in the event of unexpected circumstances.\n• Encourage children to wash hands before and after handling or consuming food.\n• • Designate an allergen-safe food preparation area.\n• Provide advanced copies of menus for parents to use in planning.\n• Be prepared to share food labels, recipes, or ingredient lists used to prepare meals and snacks with others.\n• Do not allow food to be eaten on buses except by children with special needs such as those with diabetes.\n• Encourage children to wash hands before and after handling or consuming food. • Identify special needs before field trips or events.\n• Package meals and snacks appropriately to prevent crosscontact.\n• Encourage children to wash hands before and after handling or consuming food.\n• Encourage hand washing before and after handling or consuming food. \n# Physical Education and Recess\n\n# Meals and Snacks\n• Keep food labels from all foods served to children with allergies for at least 24 hours after servicing the food in case the child has a reaction.\n• Keep current contact information for vendors and suppliers so you can get food ingredient information.\n• Read all food labels and recheck with each purchase for potential food allergens.\n• Report mistakes such as crosscontact with an allergen or errors in the ingredient list or menu immediately to administrators and parents.\n• Wash all tables and chairs with soap and water or all-purpose cleaning agents before each meal period.\n• Encourage children, school staff , and volunteers to wash hands before and after handling or consuming food.\na USDA Web site: www.fns.usda.gov/cnd/guidance/special_dietary_needs.pdf.\n# Food Allergy Management and Prevention Plan Checklist\nUse this checklist to determine if your school or ECE program has appropriate plans in place to promote the health and well-being of children with food allergies. For each priority, check the box to the left if you have plans and practices in place. Develop plans to address the priorities you did not check.\nYou can also use the checklist to evaluate your response to food allergy emergencies. Ongoing evaluation and improvement can help you improve your plans and actions.\nReview the full descriptions of the five priorities (pages [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] to make sure that your plans and practices are complete and that your plans for improvement will meet the needs of children, their families, administrators, and staff. This section presents the actions that school district leaders can take to implement the voluntary recommendations in Section 1. Although the focus of the recommendations is on the management of food allergies at the school building level, district-level leadership and policy and staff support are essential for the success of school-level food allergy management.\n# School District Policy Support\nSchool boards can adopt written policies that direct and support clear, consistent, and effective practices for managing the risk of food allergies and response to food allergy emergencies. Data from CDC's 2006 School Health Policies and Programs Study indicate that only slightly more than 40% of school districts have model food allergy policies. 8 A comprehensive and uniform set of district policies for managing food allergies in schools can:\n• Communicate the district's commitment to effectively managing food allergies to school administrators and staff members, parents, and the community.\n• Promote consistency of priorities, actions, and options for managing food allergies across the district to avoid confusion and haphazard responses.\n• Align food allergy management plans in schools with federal and state laws, including regulations, and policies, as well as other established school policies.\n• Make protective practices and strategies for managing food allergies in schools an integral part of ongoing school activities.\n• Support the food allergy management decisions and practices of school administrators and staff members.\n• Increase public knowledge about food allergies and applicable laws and public support for implementation of effective food allergy management practices in schools. [82][83][84][85] Section 6 provides a list of resources with more information and strategies to inform school policymakers.\n# School District Staff Support\nDistrict policies are implemented with the support of board members, the district superintendent, and district-level staff members. 82 District leaders and staff can:\n• Communicate policy requirements and school system directives.\n• Help schools implement and comply with applicable federal and state laws, including regulations, and policies.\n• Help communicate lines of authority for managing food allergies in school buildings.\n• Provide standardized forms, procedures, tools, and plans, including a sample Food Allergy Management and Prevention Plan (FAMPP), to schools.\n• Coordinate training to improve consistency of practices across the district.\n• Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n• Help schools plan and implement their FAMPPs.\nDistrict staff might also provide direct assistance to schools to help them meet the needs of students with food allergies, especially when the school does not have key staff, such as a doctor or full-time registered nurse, working at the building level. District staff sometimes communicate directly with parents and doctors who might need additional information about a school's food allergy policies and practices. They also may communicate directly with parents whose children need help managing their food allergy as they move from one school to the next within the district.\n# School Board Members\n1. Set the direction for the school district's coordinated approach to managing food allergies.\n• Develop a comprehensive set of school district policies to manage food allergies in school settings.\nWork with a variety of school staff, including school administrators, Section 504 coordinators, licensed health care professionals (e.g., doctors, registered nurses), school health advisory council members, teachers, paraeducators, school food service staff, bus drivers and other transportation staff, custodians and maintenance staff, after-school program staff, students, parents, community experts, and others who will implement policies. Section 6 provides a list of resources with more information and strategies to inform school policymakers.\n• Align food allergy policies and practices with the district's \"all-hazards\" approach to emergency planning and with policies on the care of students with chronic health conditions.\n• Be familiar with federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure local school policies and practices follow these laws and policies.\n• Use multiple mechanisms, such as newsletters and Web sites, to disseminate and communicate food allergy policies to appropriate district staff, families, and the community.\n• Give parents and students information about the school district's procedures they can use if they disagree with the food allergy policies and plans implemented by the school district.\n• On a regular schedule, review and evaluate the district's food allergy-related policies and revise as needed.\n# Prepare for food allergy emergencies.\n• Make sure that responding to life-threatening food allergy reactions is part of the school district's \"all-hazards\" approach to emergency planning.\n• Support and allocate resources to trained and appropriately certified or licensed staff members to respond to food allergy emergencies in all schools.\n• Review data and information (e.g., when and where medication was used) from incident reports of food allergy reactions and assess the effect of the incident on all students involved. Modify your policies as needed.\n# Support professional development on food allergies for staff.\n• Support and allocate resources and time for professional development and training on food allergies.\n• Identify professional development and training needs to make sure that district and school staff, especially those on food allergy management teams, are adequately trained, competent, and confident to perform assigned responsibilities to help students with life-threatening food allergies and respond to an emergency.\n# Educate students and family members about food allergies.\n• Encourage the inclusion of information about food allergies in the district's health education or other curriculum for students to raise awareness.\n• Support and allocate resources for awareness education for students and parents.\n# Create and maintain a healthy and safe school environment.\n• Endorse the use of signs and other strategies to increase awareness about food allergies throughout the school environment.\n• Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n• Support collaboration with district and community experts to integrate the management of food allergies with the management of other chronic health conditions.\n• Support collaboration with district and community experts to make sure schools have healthy and safe physical environments.\n• Develop and consistently enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n# School District Superintendent\n1. Lead the school district's coordinated approach to managing food allergies.\n• Provide leadership and designate school district resources to implement the school district's comprehensive approach to managing food allergies.\n• Promote, disseminate, and communicate food allergy-related policies to all school staff, families, and the community.\n• Make sure that each school has a team that is responsible for food allergy management.\n• Be familiar with federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure your policies and practices follow these laws and policies.\n• Give parents and students information about the school district's procedures they can use if they disagree with the food allergy policies and plans implemented by the school district.\n• On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n• Establish evaluation strategies for determining when the district's food allergy policies and practices or the school's FAMPP are not effectively implemented.\n# Prepare for food allergy emergencies.\n• Make sure that responding to life-threatening food allergy reactions is part of the school district's all-hazards approach to emergency planning.\n• Make sure that each school has trained and appropriately certified or licensed staff members develop and implement written Emergency Care Plans (ECPs) for students with food allergies. Additional plans can include Individualized Healthcare Plans (IHPs), Section 504 plans, or, if appropriate, Individualized Education Programs (IEPs).\n• Encourage periodic emergency response drills and practice on how to handle a food allergy emergency in schools.\n• Review data and information (e.g., when and where medication was administered) from incident reports of food allergy reactions and assess the effect of the incident on all students involved. Modify policies as needed.\n# Support professional development on food allergies for staff.\n• Make sure that district and school staff, especially those responsible for implementing the FAMPP, have professional development and training opportunities to become adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n# Educate students and family members about food allergies.\n• Help ensure that information about food allergies is included in the district's health education curriculum for students to raise awareness.\n• Communicate with parents about the district's policies and practices to protect the health of students with food allergies.\n# Create and maintain a healthy and safe school environment.\n• Increase awareness of food allergies throughout the school environment.\n• Collaborate with school board members, school administrators, and other school staff to create a safe environment for students with food allergies. Provide oversight of schools with children who have food allergies.\n• Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n• Consistently enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n# Health Services Director\nThe health services director can be a doctor or registered nurse working at the district level.\n# Participate in the school's coordinated approach to managing food allergies.\n• Help develop a school district's comprehensive approach to managing life-threatening food allergies that will support the FAMPP used in each school.\n• Provide leadership and obtain the resources needed to implement the district's comprehensive approach to managing food allergies.\n• Promote, disseminate, and communicate the food allergy policies and practices to all school staff, families, the school community, and the local medical community.\n• Know and educate others about federal and state laws, including regulations and policies relevant to the obligations of schools to students with food allergies and make sure policies and practices follow these laws.\n• Make sure a doctor or registered nurse reviews all FAMPPs and ECPs. Create other plans as needed.\n• Provide direct assistance to help schools develop procedures and plans for monitoring students with food allergies, including, if appropriate, through Section 504 plans, or IEPs.\n• Coordinate with other district staff, including the food service director, curriculum coordinator, and student support services director.\n• Make sure that food allergy policies and practices address competitive foods (foods and beverages sold outside of the federal reimbursable school meals program), such as those available in vending machines, in school stores, during class parties, at athletic events, and during after-school programs.\n• On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n# Ensure the daily management of food allergies for individual students.\n• Help the school team responsible for the FAMPP write this plan. If a student is eligible to receive services under Section 504 or, if appropiate, IDEA, make sure all provisions of these federal laws are met.\n• Create standard forms, such as health forms, school registration forms, and ECPs, for schools to use to identify students e with food allergies and develop individual management plans for them. Establish protocols for tasks related to developing management plans, such as how to interview parents, get appropriate documentation from doctors, and coordinate meals with food service staff.\n• Help schools implement policies and procedures for managing student medications. These policies should include how epinephrine auto-injectors are stored and accessed, how their use is monitored, and the schedule for regularly inspecting auto-injector expiration dates. They should also include plans for supporting students who are permitted and capable of managing their own food allergies by carrying and using epinephrine auto-injectors.\n• Help schools that do not have a registered nurse on site develop plans to manage food allergies in individual students, provide health services when needed, and respond to food allergy emergencies.\n• Help schools link students with food allergies and their families to community health services and family support services when needed.\n# Prepare for food allergy emergencies.\n• Develop protocols for responding to food allergy emergencies that can guide practices at the building level.\n• If allowed by state laws, including regulations, and district policy, obtain or write nonpatient-specific prescriptions and standing orders for epinephrine auto-injectors that can be used to respond to anaphylaxis emergencies.\n• Work directly with local emergency responders to confirm that they carry epinephrine auto-injectors for anaphylaxis emergencies.\n• Review school emergency response plans to make sure they include the actions needed to respond to food allergy emergencies.\n• Help schools conduct periodic emergency response drills and practice how to handle food allergy emergencies.\n• Help schools conduct debriefing meetings after a food allergy reaction or emergency. • Review data and information (e.g., when and where medication was administered) from incident reports of food allergy reactions and assess the effect of the incident on all students involved. Provide input to modify policies and practices as needed.\n• Collect school data to monitor and track food allergy emergencies across the district. Use these data to guide improvements in policies and practices.\n# Support professional development on food allergies for staff.\n• Seek professional development opportunities to learn updated information about managing food allergies.\n• Educate district and school staff about food allergies so they are adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n• Coordinate district training for school nurses and others who might lead school teams responsible for implementing FAMPPs to make sure they have the information they need to develop effective plans.\n• Know and educate others about federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure district policies and practices follow these laws and policies.\n• Help school building leaders plan and provide food allergy training for staff, parents, and students.\n• Help train delegated staff members on how to store, access, and administer epinephrine autoinjectors.\n# Educate students and family members about food allergies.\n• Work collaboratively with the curriculum coordinator or health education coordinator at the district level to identify appropriate food allergy content for the district's health education curriculum.\n• Help school administrators communicate the district's policies and practices for managing food allergies to parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe school environment.\n• Work collaboratively with district staff to enforce policies that promote healthy physical environments.\n• Work collaboratively with student support services staff at the district level to enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n# Student Support Services Director\nThe student support services director can be a school psychologist, school counselor, or child and family services director.\n1. Participate in the school's coordinated approach to managing food allergies.\n• Help develop a school district's comprehensive approach to managing food allergies that will support the FAMPP used in each school.\n• Promote, disseminate, and communicate food allergy policies to all school staff, families, and the community.\n• Know and inform others about federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure district policies and practices follow these laws and policies.\n• Provide direct assistance to help schools establish procedures and plans for monitoring students with food allergies, including, if appropriate, through Section 504 plans or IEPs.\n• Coordinate with other district staff, including the food service director, curriculum coordinator, and health services director.\n• On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n# Ensure the daily management of food allergies for individual students.\n• Help the school team responsible for implementing the FAMPP write this plan. If a student is eligible to receive services under Section 504 or, if appropiate, IDEA, make sure all provisions of these federal laws are met.\n• Help schools link students with food allergies and their families to community health services and family support services when needed.\n# Prepare for food allergy emergencies.\n• Help develop protocols for responding to food allergy emergencies that can guide practices in district schools.\n• Review school emergency response plans to make sure they include the actions needed to respond to food allergy emergencies.\n• Help schools conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n• Review data and information (e.g., when and where medication was administered) from incident reports of food allergy reactions and assess the effect of the incident on affected students. Provide input to modify policies and practices as needed.\n# Support professional development on food allergies for staff.\n• Help educate district and school staff about food allergies so they are adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n• Help develop district training for all school staff to help them improve their FAMPPs.\n• Know and educate others about federal and state laws, including regulations, and policies relevant to the obligations of schools to students with food allergies and make sure district and school policies and practices follow these laws and policies.\n• Help school building leaders plan and provide food allergy training for staff, parents, and students.\n# Educate students and family members about food allergies.\n• Help school administrators communicate the district's policies and practices for preventing food allergy reactions to parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe school environment.\n• Work collaboratively with district staff to enforce policies that promote healthy physical environments.\n• Work collaboratively with district health services staff, school principals, school counselors, and others to help enforce policies that prohibit discrimination and bullying against all students, including those with food allergies.\n# District Food Service Director\n1. Participate in the school's coordinated approach to managing food allergies.\n• Help develop a school district's comprehensive approach to managing food allergies that will support the FAMPP used in each school.\n• Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n• Access and use resources and guidance from local health departments and the state agency that administers child nutrition programs.\n• Promote, disseminate, and communicate the food allergy policies to school staff, families, and the community.\n• Know and educate others about federal and state laws, including regulations, and policies on food allergies and the need to follow these laws and policies, including those regulations that pertain to the U.S. Department of Agriculture's (USDA's) Child Nutrition Program.\n• Ensure that food service staff understand USDA's required doctor's statement as written and that the statement provides sufficient information to provide a safe meal.\n• Help establish school-level procedures and plans for monitoring students with food allergies, including plans for accommodating the special nutritional needs of individual students when necessary.\n• Coordinate with other district staff, including the student support services director, curriculum coordinator, and health services director.\n• On a regular schedule, review and evaluate the school district's food allergy policies and practices and revise as needed.\n# Ensure the daily management of food allergies for individual students.\n• Develop and implement procedures in each school for identifying students with food allergies in school cafeterias. Make sure that procedures governing access to personally identifiable information from education records are consistent with student rights under the Family Educational Rights and Privacy Act of 1974 (FERPA) and any other federal and state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.)\n• Work with the health services director, principals and other school staff responsible for implementing FAMPPs to set up procedures for handling food allergies in the cafeteria. These plans should be consistent with the student's IHP, Section 504 plan, or, if appropriate, IEP, and USDA regulations on meals and food substitutions, as reflected in the USDA's Accommodating Children with Special Dietary Needs in the School Nutrition Programs. Procedures should be established for children who participate in school meals programs and those who bring food from home.\n• Work with school teams responsible for developing ECPs for students with food allergies. For schools that participate in the USDA's Child Nutrition programs, make sure that documents that list appropriate food substitutions for a student with a food allergy disability are signed by a licensed doctor. The doctor's statement must identify: °°The child's food allergy.\n°°An explanation of why the allergy restricts the child's diet.\n°°The major life activity affected by the allergy.\n°°The food or foods to be omitted from the child's diet and the foods or choices that can be substituted.\n• Establish procedures for obtaining information to clarify food substitutions and other relevant medical information from a student's doctor as needed.\n• Coordinate food substitutions for all schools with students who have food allergies, in consultation as necessary with each child's doctor, and manage the documentation of these activities.\nWhen possible, use foods that are already served in school meals or snacks to make appropriate substitutions.\n• Provide oversight and tracking of each student's dietary plans, including tracking allergic reactions that occur during school meals.\n• Develop and implement policies and procedures to prevent allergic reactions and cross-contact during meal preparation and service. Communicate these policies and procedures to school food service staff.\n• Keep information about ingredients for all foods bought and served by school food service programs and keep labels of foods given to food-allergic children for at least 24 hours so that the labels can be reviewed if needed.\n• Be prepared to share information about ingredients in recipes and foods served by food service programs with parents.\n# Prepare for food allergy emergencies.\n• Help develop protocols for responding to food allergy emergencies that can guide practices in district schools.\n• Help the health services director communicate the appropriate ways to avoid exposure to food allergens and respond to food allergy emergencies to all staff members who are involved in managing a student's food allergy in the cafeteria.\n• Make sure that food service staff are able to respond to a food allergy emergency in the cafeteria and implement an ECP.\n• Review school emergency response plans to make sure they include the actions needed to respond to food allergy emergencies during school meals.\n• Help schools conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n• Review data and information (e.g., when and where medication was administered) from incident reports on any food allergy reactions and assess the effect of the incident on affected students. Provide input to modify policies and practices as needed.\n# Support professional development on food allergies for staff.\n• Help educate district and school staff about food allergies so they are adequately trained, competent, and confident to perform assigned responsibilities to help students with food allergies and respond to an emergency.\n• Provide training opportunities for school food service staff to help them understand how to follow policies and procedures for preparing and serving safe meals and snacks for students with food allergies.\n• Make sure that school food service staff participate in district training on food allergies.\n• Make sure that all school staff understand their role in preventing and responding to emergencies in the school cafeteria.\n• Help school building leaders plan and provide food allergy training for staff, parents, and students.\n# Educate students and family members about food allergies.\n• Help the curriculum coordinator or health education coordinator integrate food allergy lessons, such as how to read food labels, into the district's health education curriculum.\n• Communicate with parents about any foods that might be served as part of school meals programs such as the School Breakfast Program or the Fresh Fruit and Vegetable Program.\n• Share information about options for food substitutions with the parents of students with food allergies. Schools are encouraged to make substitutions with foods that have already been bought, when possible.\n• Work with administrators, classroom teachers, and parent-teacher organizations to offer food allergy education to parents in schools.\n• Help school administrators communicate the policies and procedures used in food service programs to prevent food allergy reactions to parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe school environment.\n• Work collaboratively with district staff to help enforce policies that promote healthy physical environments.\n• Work collaboratively with district health services staff, school principals, school food service staff, and others to help enforce policies that prohibit discrimination and bullying against students with food allergies.\n• Provide guidance to school food service staff that helps them to meet the dietary needs of students with food allergies and protect their health during school meals, while guarding against practices that could result in alienation of or discrimination against these students.\nSee Section 6 for more resources and tools that might assist in managing food allergies and allergy-related emergencies in schools.\n# Section 3. Putting Guidelines into Practice: Actions for School Administrators and Staff\nEffective management of food allergies in schools requires the participation of many people. This section presents the actions that school building administrators and staff can take to implement the recommendations in Section 1. Some actions duplicate responsibilities required under applicable federal and state laws, including regulations, and policies. Although many of the actions presented here are not required by statute, they can contribute to better management of food allergies in schools.\nSome actions are intentionally repeated for different staff positions to ensure that critical actions are addressed even if a particular position does not exist in the district or school (e.g., school doctor). This duplication also reinforces the need for different staff members to work together to manage food allergies effectively. All actions are important, but some will have a greater effect than others. Some actions may be most appropriately carried out by district-level staff members whose roles are to support food allergy management plans and practices across schools or to provide specific services to schools that do not have an on-site staff person to provide these services. Ultimately, each school district or school must determine which actions are most practical and necessary to implement and who should be responsible for those actions.\n# School Administrator\nThe school administrator can be a principal or assistant principal.\n# Lead the school's coordinated approach to managing food allergies.\n• Coordinate planning and implementation of a comprehensive Food Allergy Management and Prevention Plan (FAMPP) for your school. If your school has an on-site registered nurse, work with this person and the members of any relevant team-such as the school wellness team, school health team, or school improvement team-to plan and implement the FAMPP. Designate a qualified person (e.g., the registered nurse) to lead development of the FAMPP and designate responsibilities for implementing the plan as appropriate. If your school does not have an on-site nurse, ask for help from a registered nurse at the district level or from a public health nurse in the community.\n• Make sure staff understand the school's responsibilities under Section 504 of the Rehabilitation Act of 1973, the Americans with Disabilities Act (ADA), the Individuals with Disabilities Education Act (IDEA), and the Richard B. Russell National School Lunch Act to students who are or may be eligible for services under those laws. Make sure they understand the need to comply with the Family Educational Rights and Privacy Act of 1974 (FERPA) and any other federal and state laws that protect the privacy of student information. (See Section 5 for information about applicable federal laws.)\n• Communicate school district policies and the school's practices for managing food allergies to all school staff, substitute teachers, classroom volunteers, and families.\n• Make sure staff implement school district policies for managing food allergies.\n• Help staff implement the school's FAMPP.\n• On a regular basis, review and evaluate your school's FAMPP and revise as needed.\n# Ensure the daily management of food allergies for individual students.\n• Make sure that mechanisms-such as health forms, registration forms, and parent interviewsare in place to identify students with food allergies.\n• If your school does not have an on-site registered nurse, work with the parents of children with food allergies and their doctor to develop a written Emergency Care Plan (ECP) (sometimes called a Food Allergy Action Plan). This plan is needed to manage and monitor students with food allergies on a daily basis, whether they are at school or at school-sponsored events. If a student has been determined to be eligible for services under Section 504 or, if appropriate, IDEA, make sure that all provisions of these federal laws are met.\n• Share information about students with food allergies with all staff members who need to know, provided the exchange of information occurs in accordance with FERPA and any other federal and state laws that protect the confidentiality or privacy of student information. (See section 5 for more information about FERPA.) Make sure these staff members are aware of what actions are needed to manage each student's food allergy on a daily basis.\n# Prepare for and respond to food allergy emergencies.\n• Make sure that responding to life-threatening food allergy reactions is part of the school's \"all-hazards\" approach to emergency planning.\n• Make sure that parents of students with food allergies provide epinephrine auto-injectors to use in food allergy emergencies, if their use is called for in a student's ECP.\n• Set up communication systems that are easy to use for staff who need to respond to food allergy reactions and emergencies.\n• Make sure that staff who are delegated and trained to administer epinephrine auto-injectors can get to them quickly and easily.\n• Make sure that local emergency responders know that epinephrine may be needed when they are called to respond to a school emergency.\n• Prepare for food allergy reactions in students without a prior history of food allergies or anaphylaxis.\n• Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n• Conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n• Contact parents immediately after any suspected allergic reaction and after a child with a food allergy ingests or has contact with a food that may contain an allergen, even if an allergic reaction does not occur. If the child may need treatment, recommend that the parents notify the child's primary health care provider or allergist.\n• Document all responses to food allergy emergencies. Review data and information (e.g., when and where medication was used) from incident reports of food allergy emergencies and assess the effect on affected students. Provide input to modify your school district's emergency response policies and practices as needed.\n# Support professional development on food allergies for staff.\n• Make sure staff receive professional development and training on food allergies.\n• Coordinate training with licensed health care professionals, such as school or district doctors or nurses or local health department staff, and with other essential school or district professionals, such as the district's food service director, if appropriate. Invite parents of students with food allergies to help develop the content for this training.\n# Educate students and family members about food allergies.\n• Make sure that the school's curricular offerings include information about food allergies to raise awareness among students.\n• Communicate the school's responsibilities, expectations, and practices for managing food allergies to all parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe school environment.\n• Increase awareness of food allergies throughout the school environment.\n• Emphasize and support practices that protect and promote the health of students with food allergies across the school environment, during before-and after-school activities, and during transportation of students.\n• Make sure that students with food allergies have an equal opportunity to participate in all school activities and events.\n• Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n• Reinforce the school's rules that prohibit discrimination and bullying as they relate to students with food allergies.\n# Registered School Nurses\n\n# Participate in the school's coordinated approach to managing food allergies.\n• Take the lead in planning and implementing the school's FAMPP or help the school administrator with this task.\n• Support partnerships among school staff and the parents and doctors (e.g., pediatricians or allergists) of students with food allergies.\n• Consult state and local Nurse Practice Acts and guidelines to guide the roles and responsibilities of school nurses.\n# Supervise the daily management of food allergies for individual students.\n• Make sure that students with food allergies are identified. Share information with other staff members as needed, provided the exchange of information occurs in accordance with FERPA and any other federal and state laws that protect the confidentiality or privacy of student information.\n• Obtain or develop an ECP for each student with a food allergy or food allergy disability. Get the medical information needed to care for children with food allergies when they are at school, such as medical records and emergency information. Communicate with parents and health care providers (with parental consent) about known food allergies, signs of allergic reactions, relevant use of medications, complicating conditions, and other relevant health information.\n• Make sure that USDA's required doctor's statement is completed and provides clear information to assist in the preparation of a safe meal accommodation. This statement can be part of an ECP or a separate document.\n• Use a team approach to develop an Individualized Healthcare Plan (IHP) for each student with a food allergy, and, if required by Federal law, a Section 504 plan, or an Individualized Education Program (IEP), if appropriate.\n• Monitor each student's ECP or other relevant plan on a regular basis and modify plans when needed.\n• Refer parents of children who do not have access to health care to services in the community.\n• For students who have permission to carry and use their own epinephrine auto-injectors, regularly assess their ability to perform these tasks.\n# Prepare for and respond to food allergy emergencies.\n• Develop instructions for responding to an emergency if a school nurse is not immediately available. Add these instructions to the school's FAMPP.\n• File ECPs in a place where staff can get to them easily in an emergency. Distribute ECPs to staff on a need-to-know basis.\n• Make sure that the administration of an epinephrine auto-injector follows school policies and state mandates. Make sure that medications are kept in a secure place that staff can get to quickly and easily. Keep back-up epinephrine auto-injectors for students who carry their own. Regularly inspect the expiration date on all stored epinephrine auto-injectors.\n• Train and supervise delegated staff members how to administer an epinephrine auto-injector and recognize the signs and symptoms of food allergy reactions and anaphylaxis.\n• If allowed by state and local laws, work with school leaders to get extra epinephrine auto-injectors or nonpatient-specific prescriptions or standing orders for auto-injectors to keep at school for use by staff delegated and trained to administer epinephrine in an anaphylaxis emergency.\n• Assess whether students can reliably carry and use their own epinephrine auto-injectors and encourage self-directed care when appropriate.\n• Make sure that school emergency plans include procedures for responding to any student who experiences signs of anaphylaxis, whether the student has been identified as having a food allergy or not.\n• Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n• Contact parents immediately after any suspected allergic reaction and after a child with a food allergy ingests or has contact with a food that may contain an allergen, even if an allergic reaction does not occur. If the child may need treatment, recommend that the parents notify the child's primary health care provider or allergist.\n• After each food allergy emergency, review how it was handled with the school administrator, school doctor or nurse (if applicable), parents, staff members involved in the response, emergency medical services (EMS) responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n• Help students with food allergies transition back to school after an emergency.\n• Talk with students who may have witnessed a life-threatening allergic reaction in a way that does not violate the privacy rights of the student with the food allergy.\n# Help provide professional development on food allergies for staff.\n• Stay up-to-date on best practices for managing food allergies. Sources for this information include allergists or other doctors who are treating students with food allergies, local health department staff, national school nursing resources, and the district's food service director or registered dietitian.\n• Educate teachers and other school staff about food allergies and the needs of specific students with food allergies in a manner consistent with FERPA, USDA, and any other federal and state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.)\n• Advise staff to refer students to the school nurse when food allergy symptoms or side effects interfere with school activities so that medical and educational services can be properly coordinated.\n# Provide food allergy education to students and parents.\n• Teach students with food allergies about food allergies and help them develop self-management skills.\n• Make sure that students who are able to manage their own food allergies know how to recognize the signs and symptoms of their own allergic reactions, are capable of using an epinephrine auto-injector, and know how to notify an adult who can respond to a food allergy reaction.\n• Help classroom teachers add food allergy lessons to their health and education curricula.\n• Find ways for the parents of students with food allergies to share their knowledge and experience with other parents.\n• Work with administrators, classroom teachers, and parent-teacher organizations to offer food allergy education for parents at school.\n• Help the school administrator communicate the school's policies and practices for preventing food allergy reactions to parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe school environment.\n• Work with other school staff and parents to create a safe environment for students with food allergies. On a regular basis, assess the school environment, including the cafeteria and classrooms, to identify allergens in the environment that could lead to allergic reactions. Work with appropriate staff to develop strategies to help children avoid identified allergens.\n• Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n• Work with school counselors and other school staff to provide emotional support to students with food allergies.\n• Promote an environment that encourages students with food allergies to tell a staff member if they are bullied because of their allergy.\n# School Doctors\nA school doctor works full-time or part-time to provide consultation and a wide range of health services to the school population.\n# Participate in the school's coordinated approach to managing food allergies.\n• Lead or help plan and implement the school's FAMPP.\n• Support partnerships among school staff and the parents and doctors (e.g., allergists, pediatricians) of students with food allergies.\n• Keep current on federal, state, and local guidance on food allergy management.\n• Consult state and local Nurse Practice Acts to make sure the roles and responsibilities of school nurses are appropriate.\n• Guide and support the food allergy management practices of school nursing staff.\n• Help evaluate school FAMPPs.\n# Ensure the daily management of food allergies for individual students.\n• Help the school nurse perform the actions necessary to manage students with food allergies on a daily basis. (See the items under Action 2 for Registered School Nurses.)\n# 62\n3. Prepare for and respond to food allergy emergencies.\n• Help the school nurse make sure that all students with food allergies have an ECP.\n• If allowed by state and local laws, write prescriptions or standing orders for nonpatient-specific epinephrine auto-injectors so the school can stock back-up medication for use in food allergy emergencies.\n• Help the school nurse assess whether students can reliably carry and use their own epinephrine auto-injector and encourage self-directed care when appropriate.\n• Help the school nurse train staff how to use epinephrine auto-injectors and recognize the signs and symptoms of food allergy reactions and anaphylaxis.\n• Help the school nurse and health assistants regularly inspect the expiration date on all stored epinephrine auto-injectors.\n• Make sure that school emergency plans include procedures for responding to any student who experiences signs of anaphylaxis, whether diagnosed with a food allergy or not.\n• Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n• Contact parents immediately after any suspected allergic reaction and after a child with a food allergy ingests or has contact with a food that may contain an allergen, even if an allergic reaction does not occur. If the child may need treatment, recommend that the parents notify the child's primary health care provider or allergist.\n• After each food allergy emergency, review how it was handled with the school administrator, school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n# Help provide professional development on food allergies for staff.\n• Share current and relevant knowledge of best practices for managing food allergies with school leaders (e.g., school administrator, school nurse).\n• Help educate teachers and other school staff about food allergies and the needs of specific students with food allergies, in a manner consistent with FERPA, USDA, and any other federal and state laws that protect the privacy or confidentiality of student information. (See Section 5 for more information about FERPA.)\n• Advise staff to refer students to the school doctor or nurse when symptoms or side effects of a food allergy interfere with school activities so that medical and educational services can be coordinated.\n# Provide food allergy education to students and parents.\n• Help teach students with food allergies about food allergies and help them develop selfmanagement skills.\n• Help the school nurse make sure that students who are able to manage their food allergies know how to recognize the signs and symptoms of their own allergic reactions, are capable of using an epinephrine auto-injector, and know how to notify an adult who can respond to a food allergy reaction.\n• Help classroom teachers add food allergy lessons to their health and education curricula.\n• Help find ways for parents of students with food allergies to share their knowledge and experience with other parents.\n• Work with administrators, the school nurse, classroom teachers, and parent-teacher organizations to offer food allergy education for parents at school.\n• Help the school administrator communicate the school's policies and practices for preventing food allergy reactions to parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe school environment.\n• Work with other school staff and parents to create a safe environment for students with food allergies.\n• On a regular basis, assess the school environment, including the cafeteria and classrooms, to identify allergens in the environment that could lead to allergic reactions. Work with appropriate staff to manage identified allergens.\n• Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n• Work with school counselors, the school nurse, and other school staff to provide emotional support to students with food allergies.\n• Promote an environment that encourages students with food allergies to tell a staff member if they are bullied or harassed because of their allergy.\n# Health Assistants, Health Aides, or Other Unlicensed Personnel\nThese staff members work with the school or district nurse or doctor.\n# Help with the daily management of food allergies for individual students.\n• Help the school nurse identify students with food allergies. Review the medical records and emergency information of all students.\n• Talk with the school nurse about any allergic reactions and changes in a student's health status.\n# Prepare for and respond to food allergy emergencies.\n• Get a copy of the ECP for every student with food allergies. Make sure the plan includes information about signs and symptoms of an allergic reaction, how to respond, and whether medications should be given.\n• File ECPs in a place where staff can get to them easily in an emergency.\n• Be ready to respond to a food allergy emergency if a nurse is not immediately available. If school policies and state mandates allow you to give medication and you are delegated to perform this task, complete training on how to administer epinephrine, regularly review instructions, and practice this task. Make sure that medications are kept in a secure place that you or other delegated staff members can get to quickly and easily. Regularly inspect the expiration date on all stored epinephrine auto-injectors.\n• After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n# Participate in professional development on food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of allergic reactions and how they are communicated by students.\n°°How to read food labels and identify allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in the school in ways that are consistent with a student's ECP.\n°°Your role in implementing a student's ECP.\n°°When and how to call EMS and parents.\n°°How FERPA, USDA, and other federal and state laws that protect the privacy and confidentiality of student information apply to students with food allergies and food allergy disabilities.\n°°General strategies for reducing or preventing exposure to food allergens in the classroom, such as cleaning surfaces, using nonfood items for celebrations, and getting rid of nonfood items that contain food allergens (e.g., clay, paste).\n°°Policies on bullying and discrimination against all students, including those with food allergies.\n# Provide food allergy education to students and parents.\n• Get help from the school counselor or other mental health professionals to teach students about bullying of and discrimination against students with food allergies.\n• Help communicate policies on bullying and discrimination to parents.\n# Create and maintain a healthy and safe school environment.\n• Work with other school staff and parents to create a safe environment for students with food allergies.\n• Promote an environment that encourages support for students with food allergies and promotes positive interactions between students.\n• Report all cases of bullying against students, including those with food allergies, to the school administrator, school nurse, or school counselor.\n# Classroom Teachers\nThis category includes classroom teachers in all basic subjects, as well as physical education teachers, instructional specialists such as music or art teachers, paraeducators, student teachers, long-term substitute teachers, classroom aides, and classroom volunteers.\n# Participate in the school's coordinated approach to managing food allergies.\n• Ask the school nurse or school administrator for information on current policies and practices for managing students with food allergies, including how to manage medications and respond to a food allergy reaction.\n• Help plan and implement the school's FAMPP.\n# Help with the daily management of food allergies for individual students.\n• Make sure you understand the essential actions that you need to take to help manage food allergies when students with food allergies are under your supervision, including when meals or snacks are served in the classroom, on field trips, or during extracurricular activities. Seek guidance and help from the school administrator, school nurse, or school food service director as needed.\n• Be available and willing to help students who manage their own food allergies.\n• Work with parents and the school nurse and other appropriate school personnel to determine if any classroom modifications are needed to make sure that students with food allergies can participate fully in class activities.\n• With parental consent, share information and responsibilities with substitute teachers and other adults who regularly help in the classroom (e.g., paraeducators, volunteers, instructional specialists).\n(Depending on a school district's FERPA notice as to which individuals would constitute school officials with legitimate educational interests, FERPA may not require parental consent in these circumstances. FERPA also includes an emergency exception to the prior consent requirement if there is an articulable and significant threat to the health or safety of the student or others. See Section 5 for more information about FERPA.)\n• Refer students with undiagnosed but suspected food allergies to the school nurse for follow-up. f f. See footnote e. infra.\n• If your school does not have a nurse on-site, talk with parents about the signs and symptoms you have seen and recommend that they discuss them with their primary health care provider.\n• If you suspect a severe food allergy reaction or anaphylaxis, take immediate action, consistent with your school's FAMPP or \"all-hazards\" emergency response protocol.\n# Prepare for and respond to food allergy emergencies.\n• Read and regularly review each student's ECP. Never hesitate to activate the plan in an emergency.\nIf you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n• Keep copies of ECPs for your students in a secure place that you can get to easily in an emergency.\nWith parental consent, share information from the ECP with substitute teachers and other adults who regularly help in the classroom to help them know how to respond to a food allergy emergency.\n(Depending on a school district's FERPA notice as to which individuals would constitute school officials with legitimate educational interests, FERPA may not require parental consent in these circumstances. FERPA also includes an emergency exception to the prior consent requirement if there is an articulable and significant threat to the health or safety of the student or others. See Section 5 for more information about FERPA.)\n• Support and help students who have permission to carry and use their own epinephrine in cases of an allergic reaction.\n• Make sure that the needs of students with food allergies are met during class field trips and during other extracurricular activities.\n• Immediately contact the school administrator and if available, the school nurse after any suspected allergic reaction.\n• After each food allergy emergency, review how it was handled with the school administrator, school nurse, parents, other staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n• Help students with food allergies transition back to school after an emergency.\n• Address concerns with students who witness a life-threatening allergic reaction in a way that does not compromise the confidentiality rights of the student with the allergy.\n# Participate in professional development on food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are manifested in and communicated by students.\n°°How to read food labels and identify allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to respond to food allergy emergencies in ways that are consistent with a student's ECP, if appropriate, a Section 504 Plan, or IEP, if appropriate.\n°°When and how to call EMS and parents.\n°°Your role in implementing a student's ECP.\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information, and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°General strategies for reducing or preventing exposure to food allergens in the classroom, such as cleaning surfaces, using nonfood items for celebrations, getting rid of nonfood materials that contain food allergens (e.g., clay, paste), and preventing cross contact of allergens when meals or snacks are served in the classroom.\n°°Policies that prohibit discrimination and bullying against all students, including those with food allergies.\n# Provide food allergy education to students and parents.\n• Look for ways to add information about food allergies to your curriculum. Work with other teachers to plan lessons and activities to teach students how they can prevent allergic reactions.\n• Work with the school nurse to educate parents about the presence and needs of students with food allergies in the classroom. Raise awareness and educate the parents of children without food allergies about \"food rules\" for the classroom. Ask parents to help you keep certain foods out of the classroom during meals, celebrations, and other activities that might include food.\n• Ask the school counselor or other mental health professionals for help or resources to teach students about policies that prohibit discrimination and bullying against all students, including those with food allergies.\n• Communicate policies on bullying and discrimination to all parents.\n# Create and maintain a healthy and safe school environment.\n• Promote a safe physical environment through the following actions:\n°°Create classroom rules and practices for dealing with food allergies. Tell parents about these rules and practices at the beginning of the school year or when you find out that a student with a food allergy will be in your class.\n°°Create ways for students with food allergies to participate in all class activities.\n°°Avoid using known allergens in classroom activities, such as arts and crafts, counting, science projects, parties, holidays and celebrations, or cooking.\n°°Enforce hand washing before and after eating, particularly for younger students.\n°°Use nonfood items for rewards or incentives.\n°°Encourage the use of allergen-safe foods or nonfood items for birthday parties or other celebrations in the classroom. Support parents of students with food allergies who wish to send allergen-safe snacks for their children.\n°°Discourage trading or sharing of food with a student with a food allergy in the classroom, particularly for younger students.\n°°Enforce food allergy prevention practices while supervising students in the cafeteria.\n• Manage food allergies on field trips through the following actions:\n°°Determine if the intended location is safe for students with food allergies. If it is not safe, the field trip might have to be changed or cancelled if accommodations cannot be made.\nStudents cannot be excluded from field trips because of food allergies.\n°°Invite the parents of students with food allergies to chaperone or go with their child on the field trip. Many parents may want to go, but they cannot be required to go.\n°°Work with school food service staff to plan meals and snacks.\n°°Make sure you include someone who is delegated and trained to administer epinephrine, that you have quick access to an epinephrine auto-injector, and that you know where the nearest medical facilities are located. If a food allergy emergency occurs, activate the student's ECP and notify the parents.\n°°Make sure there are appropriate emergency protocols and mechanisms in place to respond to a food allergy emergency when away from the school.\n°°Make sure that communication devices are working so you can respond quickly during an emergency.\n• Promote a positive psychosocial climate through the following actions:\n°°Be a role model by respecting the needs of students with food allergies.\n°°Help students make decisions about and manage their own food allergies.\n°°Encourage supportive and positive interactions between students.\n°°Reinforce the school's rules against discrimination and bullying.\n°°Take action to address all reports of bullying or harassment of a student with a food allergy.\n°°Tell parents if their child has been bullied, and report all cases of bullying to the school administrator.\n°°Tell parents and the school nurse if you see negative changes in a student's academic performance or behavior.\n# School Food Service Managers and Staff\n1. Participate in the school's coordinated approach to managing food allergies.\n• Use resources and guidance from the district food service director, local board of health, USDA, and dietitians to reduce exposure to food allergens.\n• Help plan and implement the school's FAMPP. Make sure that it includes specific practices for managing food allergens in school meals served inside and outside of the cafeteria.\n# Help with the daily management of food allergies for individual students.\n• Identify students with food allergies in a way that does not compromise students' privacy or confidentiality rights.\n• Make sure you have and understand dietary orders, or the doctor's statement, and other relevant medical information that you need to make meal accommodations for students with food allergies and food allergy disabilities.\n• Consult with the district foodservice director to help develop individual dietary and cafeteria management plans for each student with a food allergy and food allergy disability. These plans should be consistent with the student's IHP, and if the student has a food allergy, the student's Section 504 plan, or, if appropriate, IEP, and USDA regulations on meals and food substitutions, as reflected in the USDA's Accommodating Children with Special Dietary Needs in the School Nutrition Programs.\n• Help communicate appropriate actions to avoid allergic reactions and respond to food allergy emergencies to all staff members and food service staff who are expected to help manage a student's food allergy in the cafeteria.\n• Follow policies and procedures to prevent allergic reactions and cross-contact of potential food allergens during food preparation and service.\n• Understand how to read labels to identify allergens in foods and beverages served in school meals. Work with the school foodservice director, the district food service director, or the food manufacturer if additional information or clarification is needed on the product's ingredients.\n• Manage food substitutions for students with food allergies and food allergy disabilities and manage the documentation of these activities. Work with the school administrator or school nurse and the district food service director to make sure that the information needed to meet USDA and state regulations for food service is documented as required.\n• Be prepared to share information about ingredients in recipes and foods served by the school food service program with parents.\n# Prepare for and respond to food allergy emergencies.\n• Be familiar with student's ECPs and the doctor's statement required by USDA, what actions must be taken if a food allergy emergency occurs in the cafeteria. Make sure that food service staff are able to respond to a food allergy emergency in the cafeteria and implement an ECP.\n• If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n• If appropriate and allowed by state laws, including regulations, school policy, and the school's FAMPP, keep an epinephrine auto-injector in a secure place in the cafeteria that you can get to quickly and easily.\n• Provide support and help to students who carry and use their own medication.\n• After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future emergencies and improve emergency response.\n# Participate in professional development on food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by student.\n°°How to read food labels and identify allergens.\n°°How to plan meals for students with food allergies and allergy disabilities and how to prevent cross-contact of allergens. Consult with the district school food service director when necessary.\n°°How to deal with emergencies in the school in ways that are consistent with a student's ECP.\n°°The role of the food service manager and staff in implementing a child's doctor statement under USDA requirements and ECP, if applicable.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°General strategies for reducing or preventing allergic reactions in the cafeteria.\n°°Policies on bullying and discrimination against all students, including those with food allergies.\n# Provide food allergy education to students and parents.\n• Help classroom teachers add food allergy lessons into their health and education curriculum, including teaching students how to read food labels.\n• Share menu ideas with parents of students with food allergies to identify potential allergens and improve healthy eating.\n• Find ways for parents of students with food allergies to share their knowledge and experience with other parents.\n• Help the school administrator communicate the policies and practices used by the food service staff to prevent food allergy reactions to parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe school environment.\n• Reduce the potential for allergic reactions through the following actions:\n°°Be able to recognize students with food allergies and food allergy disabilities in the cafeteria.\n°°Follow procedures for handling food allergies in the cafeteria, even if a student is not participating in the Child Nutrition Program school meals program.\n°°Read food labels to identify allergens.\n°°Follow policies and procedures to prevent cross-contact of potential food allergens during food preparation and service.\n°°Make sure that food allergy policies and practices address competitive foods, such as those available in vending machines, in school stores, fundraisers, during class parties, at athletic events, and during after-school programs.\n• Promote a positive psychosocial climate in the cafeteria through the following actions:\n°°Encourage supportive and positive interactions between students.\n°°Reinforce the school's rules against bullying and discrimination.\n°°Take action to address all reports of bullying or harassment of a student with a food allergy.\n°°Report all cases of bullying and harassment against students, including those with food allergies, to the school administrator, school nurse, or school counselor.\n# School Counselors and Other Mental Health Services Staff\nThis category includes school psychologists and school social workers.\n1. Participate in the school's coordinated approach to managing food allergies.\n• Help plan and implement the school's FAMPP.\n# Help with the daily management of food allergies for individual students.\n• Address immediate and long-term mental health problems, such as anxiety, depression, low self-esteem, negative behavior, or eating disorders, among students with food allergies.\n• Address adolescent oppositional behavior, such as noncompliance with IHPs.\n• Make referrals to mental health services and professionals outside the school for students who need them, consistent with applicable requirements of Section 504 and IDEA, if appropriate.\n• Work with school health service staff (e.g., school doctor, school nurse) to develop consistent protocols for referrals.\n• Read and regularly review each student's ECP. Never hesitate to activate the plan in an emergency.\nIf you are the person delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector if needed.\n• After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future allergic reactions and to improve emergency response.\n• Help students with food allergies transition back to school after an emergency.\n• Be prepared to respond to the emotional needs of students who witness a life-threatening allergic reaction in a way that does not compromise the students' privacy or confidentiality rights.\n# Participate in professional development on food allergies.\n• Work with the school or district nurse and other health professionals to support training and education for staff on the mental and emotional health issues faced by a student with food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by students.\n°°How to read food labels and identify allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in the school in ways that are consistent with a student's ECP.\n°°Your role in implementing a child's ECP.\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°Policies that prohibit discrimination and bullying against students with food allergies.\n# Provide food allergy education to students and parents.\n• Work with classroom teachers and other school staff to educate parents and students about bullying and discrimination against students with food allergies.\n# Create and maintain a healthy and safe school environment.\n• Encourage staff to support a broad range of school-based mental health promotion efforts to support all students that promote positive interactions between students, build a positive school climate, encourage diversity and acceptance, discourage bullying, and promote student independence.\n• Reinforce the school's rules against bullying and discrimination.\n• Take action to address all reports of bullying or harassment of a student with a food allergy.\n• Tell parents if their child has been bullied, and report all cases of bullying to school administrators.\n# Bus Drivers and School Transportation Staff\n1. Participate in the school's coordinated approach to managing food allergies.\n• Ask the school nurse or school administrator for information on current policies and practices for managing students with food allergies, including how to manage medications and respond to a food allergy reaction.\n• Support school's FAMPPs.\n# Help with the daily management of food allergies for individual students.\n• Be aware of students with food allergies and know how to respond to an allergic reaction if it occurs while the student is being transported to or from school.\n• Enforce district food policies for all students riding a school bus.\n# Prepare for and respond to food allergy emergencies.\n• Read and regularly review the ECP for any student riding to and from school on a bus. Never hesitate to activate the plan in an emergency. If you are the person delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector if needed.\n• Know procedures for communicating an emergency during the transporting of children to and from school. Make sure that other adults on the bus are aware of emergency communication protocol.\n• Make sure communication devices are working so you can reach school officials, EMS, and others during a food allergy emergency.\n• Call 911 or EMS to ask for emergency transportation of any student exhibiting signs of anaphylaxis. Notify the school administrator of your actions and the need for someone to contact the student's parents.\n• After any food allergy emergency that occurs while a student is being transported to or from school, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future allergic reactions and improve emergency response.\n# Participate in professional development on food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by students.\n°°How to respond to a food allergy emergency while transporting children to and from school. How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in a way that is consistent with a student's ECP or transportation emergency protocol.\n°°Your role in implementing a child's ECP.\n°°FERPA, USDA, and other federal and state laws that protect the privacy or confidentiality of student information and other legal rights of students with food allergies. (See Section 5 for more information about federal laws.)\n°°Policies that prohibit discrimination and bullying against all students, including those with food allergies.\n# Create a healthy and safe environment.\n• Advocate for two-way communication systems between schools and transportation vehicles that are kept in working order.\n• Enforce district food policies for all students riding a school bus.\n• Encourage supportive and positive interactions between students.\n• Reinforce the school's rules against discrimination and bullying.\n• Report all cases of bullying or harassment of students, including those with food allergies, to the school administrator.\n# Facilities and Maintenance Staff\nThis category includes custodial staff.\n# Participate in the school's coordinated approach to managing food allergies.\n• Help plan and implement the school's FAMPP.\n# Help with the daily management of food allergies for individual students.\n• Be aware of students with food allergies and know how to respond to an allergic reaction if it occurs while the student is at school.\n• Help create a safe and healthy environment to prevent allergic reactions.\n# Prepare for and respond to food allergy emergencies.\n• Activate your school's \"all-hazard\" emergency response practices if a student displays signs or symptoms of an allergic reaction.\n• Know and understand your school's communication protocols for an emergency.\n• Make sure communication devices are working.\n• After each food allergy emergency, participate in a review of how it was handled with the school administrator, school doctor (if applicable), school nurse, parents, staff members involved in the response, EMS responders, and the student to identify ways to prevent future allergic reactions and improve emergency response.\n# Participate in professional development on food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by students.\n°°How to respond to emergencies at the school.\n°°Your role in supporting a child's ECP.\n°°Policies that prohibit discrimination and bullying against all students, including those with food allergies.\n°°Policies and standards for washing hands and cleaning surfaces to reduce food allergens on surfaces.\n# Create and maintain a healthy and safe environment.\n• Promote a safe and healthy physical environment through the following actions:\n°°Advocate for two-way communication systems throughout school buildings that are kept in working order.\n°°Enforce district food policies.\n°°Clean floors, surfaces, and food-handling areas with approved soap and water or all-purpose cleaning products.\n• Promote a positive psychosocial climate through the following actions:\n°°Encourage supportive and positive interactions between students.\n°°Reinforce the school's rules against discrimination and bullying.\n°°Report all cases of bullying or harassment of students, including those with food allergies, to the school administrator.\nSee Section 6 for more resources and tools that might assist in managing food allergies and allergy-related emergencies in schools.\n# Section 4. Putting Guidelines into Practice: Actions for Early Care and Education Administrators and Staff\nEffective management of food allergies in early care and education (ECE) programs requires the participation of many people. This section presents the actions that ECE program staff can take to implement the recommendations in Section 1. Some actions duplicate responsibilities required under applicable federal and state laws, including regulations, and policies. Although many responsibilities presented here are not required by statute, they can contribute to better management of food allergies in ECE programs.\nIf the ECE program participates in USDA's Child Nutrition Programs, the ECE program must follow USDA statutes, regulations, and guidance for providing meal accommodations for children with food allergy disabilities.\nSome actions are intentionally repeated for different staff positions to ensure that critical actions are addressed even if a particular position does not exist in the ECE program. This duplication also reinforces the need for different staff members to work together to manage food allergies effectively. All actions are important, but some will have a greater effect than others. Ultimately, each ECE program must determine which actions are most practical and necessary to implement and who should be responsible for those actions.\nAlthough these guidelines are specifically for licensed ECE programs, many of the recommendations can be used in unlicensed child care settings.\n# Program Directors and Family Child Care Providers\n\n# Lead the ECE program's coordinated approach to managing food allergies.\n• Coordinate planning and implementation of a comprehensive Food Allergy Management and Prevention Plan (FAMPP). Work with staff, parents, food services, and the children's health care providers.\n• Designate a qualified person (e.g., health manager, health consultant) to lead development of the program's FAMPP and designate responsibilities for implementing the plan as appropriate.\n• \n# Ensure the daily management of food allergies for individual children.\n• Make sure that mechanisms-such as health forms, registration forms, USDA-required doctor's statement and parent interviews-are in place to identify children with food allergies.\n• Work with the parents of children with food allergies and the child's primary health care provider or allergist to obtain a written Emergency Care Plan (ECP) to manage and monitor children with food allergies on a daily basis.\n• Share information about children with food allergies with all staff who need to know. Make sure they are aware of what actions are needed to manage each child's food allergy on a daily basis.\n# Prepare for and respond to food allergy emergencies.\n• Make sure that all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medications and how they should be used. It should also include specific symptoms that would indicate the need to give one or more medications or take the child to an emergency medical facility.\n• Make sure that parents of children with food allergies provide epinephrine auto-injectors to use in food allergy emergencies if their use is called for in the child's ECP.\n• Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily.\n• Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n• Contact parents immediately after any suspected allergic reaction. You also should contact parents immediately after a child ingests a potential allergen or has contact with a potential allergen, even if an allergic reaction does not occur. If the child needed treatment, recommend that the parents notify the child's primary health care provider or allergist.\n• If epinephrine is given, contact emergency medical services (EMS) and have the child transported to an emergency room by ambulance. Contact the parents to tell them the child's location and condition.\n• Conduct periodic emergency response drills and practice how to handle a food allergy emergency.\n• Be ready to respond to severe allergic reactions in children with no history of diagnosed food allergies or anaphylaxis.\n• Review data and information (e.g., when and where medication was used) from incident reports of food allergy emergencies and assess the effect on affected children. Modify policies and practices as needed.\n# Support professional development on food allergies for staff.\n• Make sure staff receive professional development and training on food allergies.\n• Make sure that training helps your program meet any applicable Head Start Program Performance Standards and Other Regulations.\n• Coordinate training with licensed health care professionals.\n• Invite parents of children with food allergies to participate in training for staff.\n# Educate children and family members about food allergies.\n• Communicate your program's responsibilities, expectations, and practices for managing food allergies to all parents through newsletters, announcements, and other methods.\n# Create and maintain a healthy and safe ECE program environment.\n• Increase awareness of food allergies and food allergy disabilities throughout the program environment.\n• Make sure that children with food allergies have an equal opportunity to participate in all program activities and events.\nChild Care Providers, Preschool Teachers, Teaching Assistants, Volunteers, Aides, and Other Staff\n# Participate in the ECE program's coordinated approach to managing food allergies.\n• Help plan and implement the program's FAMPP.\n# Help with the daily management of food allergies for individual children.\n• Make sure all children with food allergies have an ECP. In programs that participate in USDA's Child Nutrition Programs, include a doctor's statement of disability.\n• Make sure you understand the essential actions that you need to take to help manage food allergies and food allergy disabilities in children when they are under your supervision.\n• Enforce hand washing practices and make sure tables and surfaces are cleaned before and after meals with approved soap and water or all-purpose cleaning products to reduce cross-contact of allergens.\n• Work with parents to determine if any modifications are needed to make sure that children with food allergies can participate fully in all program activities.\n# Prepare for and respond to food allergy emergencies.\n• Make sure that all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medications and how they should be used. It should also include specific symptoms that would indicate the need to give one or more medications or take the child to an emergency medical facility.\n• Make sure that parents of children with food allergies provide epinephrine auto-injectors to use in food allergy emergencies if their use is called for in the child's ECP.\n• Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily.\n• Never hesitate to activate a child's ECP in an emergency. If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n• Keep copies of ECPs for children in your care in a secure place that you can get to quickly and easily in an emergency.\n• Provide feedback on the child's ECP and participate in a debriefing meeting after a food allergy reaction or emergency.\n• Contact parents immediately after any suspected allergic reactions. You also should contact parents immediately after a child ingests a potential allergen or has contact with a potential allergen, even if an allergic reaction does not occur. If the child needed treatment, recommend that the parents notify the child's primary health care provider or allergist.\n• If epinephrine is given, contact EMS, tell them when epinephrine was administered, and have the child transported to an emergency room by ambulance. Contact the parents to tell them the child's location and condition.\n• After each food allergy emergency, review how it was handled with the ECE program administrator, registered nurse, parents, staff members involved in the response, EMS responders, and the child to identify ways to prevent future emergencies and improve emergency response.\n# Participate in professional development on food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of allergic reactions and how they are communicated by young children.\n°°How to read food label and identify allergens.\n°°Your role in implementing a child's ECP.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°General strategies for reducing or preventing exposure to food allergens in the program setting and during field trips or other program-sponsored events.\n°°Policies that prohibit discrimination and bullying against children with food allergies.\n# Create and maintain a healthy and safe ECE program environment.\n• Promote a safe physical environment through the following actions:\n°°Create rules and practices for dealing with food allergies, including preventing exposure to allergens. Tell parents about these rules and practices each year or when you find out that a child with a food allergy will be in your care.\n°°Create ways for children with food allergies to participate in all class activities.\n°°Avoid using known allergens in program activities, such as arts and crafts, counting, science projects, parties, holidays and celebrations, or cooking.\n°°Enforce hand washing before and after eating.\n°°Clean tables and chairs before and after eating with approved soap and water or all-purpose cleaning products.\n°°Use nonfood items for rewards or incentives.\n°°Encourage the use of allergen-safe foods or nonfood items for birthday parties or other celebrations. Support parents of children with food allergies who wish to send allergen-safe snacks for their children.\n°°Discourage trading or sharing of food.\n• Manage food allergies on field trips through the following actions:\n°°Determine if the intended location is safe for children with food allergies.\n°°Make sure that field trips and other events are consistent with the program's food allergy policies.\n°°Plan for meals and snacks.\n°°Make sure you have quick access to an epinephrine auto-injector or other medications and that you know where the nearest medical facilities are located. If a food allergy emergency occurs, activate the child's ECP and notify the parents.\n°°Make sure that a person who is certified in first aid and trained to use an epinephrine auto-injector is available.\n• Promote a positive psychosocial climate through the following actions:\n°°Be a role model by respecting the needs of children with food allergies.\n°°Encourage supportive and positive interactions between children.\n°°Take action to address all reports of bullying or harassment of a child with a food allergy.\n°°Tell parents if you see negative changes in their child's behavior.\n# Nutrition Services Staff\n1. Participate in the ECE program's coordinated approach to managing food allergies.\n• Help plan and implement the program's FAMPP.\n# Help with the daily management of food allergies for individual children.\n• Read and regularly review each child's ECP. Make sure you understand the essential actions that you need to take to help manage food allergies in children during meals.\n• Make sure you get the dietary orders and other relevant medical information that you need to accommodate children with food allergies.\n• Document information about meal substitutions as outlined in each child's ECP. Make sure that the information needed to meet the U.S. Department of Agriculture's (USDA's) Child Nutrition Program regulations and state regulations is documented.\n• Work with the state agency that administers USDA programs, the local health department, and dietitians in the community to get the information and resources you need to make sure your program is following all federal and state regulations and you are responding to a child's dietary requirements.\n• Take the food allergies of the children in your program into account when you buy food and formula.\n• Establish and follow policies and procedures to prevent allergic reactions and cross-contact of potential food allergens during food preparation and service.\n# Prepare for and respond to food allergy emergencies.\n• Make sure all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food. If your program participates in the USDA's Child Nutrition Program, make sure you have the proper documentation to meet USDA and state regulations.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medication and how they should be used.\n• Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily.\n• Never hesitate to activate a child's ECP in an emergency. If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n• Keep copies of ECP for children in your care in a secure place that you can get to quickly and easily in an emergency.\n• Provide feedback on the child's ECP and participate in a debriefing meeting after a food allergy reaction or emergency.\n• Contact parents immediately after any suspected allergic reactions. You also should contact parents immediately after a child ingests a potential allergen or has contact with a potential allergen, even if an allergic reaction does not occur. If the child needed treatment, recommend that the parents notify the child's primary health care provider or allergist.\n• If epinephrine is given, contact EMS, tell them when epinephrine was administered, and have the child transported to an emergency room by ambulance. Contact the parents to tell them the child's location and condition.\n• Make sure that a food service staff member who has been trained to respond to a food allergy reaction is available during all meals and snack times.\n# Participate in professional development on food allergies.\n• Complete training to help you recognize and understand the following:\n°°Signs and symptoms of food allergies and how they are communicated by young children.\n°°How to read food labels and identify food allergens.\n°°How to use an epinephrine auto-injector (if delegated and trained to do so).\n°°How to deal with emergencies in the ECE program setting in ways that are consistent with a child's ECP.\n°°Legal rights of children with food allergies.\n°°USDA's statutes, regulations, and guidance (for ECE programs participating in USDA's Child Nutrition Programs).\n°°State, and local laws and policies for food services and food safety.\n°°General strategies for reducing or preventing exposure to food allergens in the kitchen or area where food is served.\n°°The role of nutrition staff in implementing a child's ECP, including the specific duties outlined in Head Start Program Performance Standards and Other Regulations.\n# Health Services Staff\n\n# Participate in the ECE program's coordinated approach to managing food allergies.\n• Help plan and implement the program's FAMPP.\n# Ensure the daily management of food allergies for individual children.\n• Make sure children with food allergies are identified in a way that complies with Head Start Program Performance Standards and Other Regulations and established enrollment practices but does not compromise their confidentiality rights.\n• Read and regularly review medical records and emergency information for all children with food allergies.\n• Communicate with parents and health care providers (with parental consent) about any allergic reactions, changes in a child's health, and exposures to allergens.\n• Read and regularly review each child's ECP. Make sure that all ECPs include the following: °°A doctor's statement addressing the meal accommodation needs of particular child with a food allergy disability as required for USDA's Child Nutrition Programs.\n°°Written instructions about food(s) to which the child is allergic and steps that should be taken to avoid that food.\n°°A detailed treatment plan to be implemented if an allergic reaction occurs. This plan should include the names and doses of medications and how they should be used. It should also include specific symptoms that would indicate the need to give one or more medications or take the child to an emergency medical facility.\n• Work with parents and health care providers to make sure that the medical needs of children with food allergies are met and that all necessary accommodations are made.\n• Refer parents of children who do not have access to health care to State Children's Health Insurance Program providers.\n# Prepare for and respond to food allergy emergencies.\n• Keep copies of ECPs for children in your care in a secure place that you can get to quickly and easily in an emergency.\n• Make sure that parents of children with food allergies provide epinephrine auto-injectors to use in food allergy emergencies if their use is called for in the child's ECP.\n• Make sure that medications are kept in a secure place and that staff who are delegated and trained to use epinephrine auto-injectors can get to them quickly and easily. Regularly inspect the expiration date of epinephrine auto-injectors.\n• Make sure that staff plan for the needs of students with food allergies during class field trips and during other extracurricular activities.\n• If allowed by state and local laws, work with the program director to get extra epinephrine autoinjectors or nonpatient-specific prescriptions or standing orders for auto-injectors that can be used by a registered nurse and those delegated and trained to administer epinephrine during allergy emergencies.\n• Never hesitate to activate a child's ECP in an emergency. If you are delegated and trained according to state laws, including regulations, be ready to use an epinephrine auto-injector.\n• After each food allergy emergency, review how it was handled with the ECE program administrator, parents, staff members involved in the response, EMS responders, and the child to identify ways to prevent future emergencies and improve emergency response. Make revisions to the child's ECP as appropriate.\n# Help provide professional development on food allergies for staff.\n• Stay up-to-date on best practices for managing food allergies. Sources for this information include allergists who are treating children with food allergies and local health departments.\n• Educate other staff about food allergies and the needs of children with food allergies in a way that does not compromise their confidentiality rights.\n• Use each child's ECP to train other staff members how to recognize the specific signs of an allergic reaction in each child and how to respond to a food allergy emergency.\n• Coordinate annual training for all staff on relevant federal and state regulations for managing food allergies in children.\n• Coordinate annual training for all staff on emergency response protocol and practices, including how to respond to food allergy emergencies.\n• Provide or coordinate training for delegated staff on how to use an epinephrine auto-injector.\nSee Section 6 for more resources and tools that might assist in managing food allergies and allergy-related emergencies in ECE programs.\n# Section 5. Federal Laws and Regulations that Govern Food Allergies in Schools and Early Care and Education Programs\nThe federal laws and regulations described in this section address the responsibilities of schools and early care and education (ECE) programs to help children and adolescents manage food allergies that may constitute a disability under federal law and to ensure that children are not subject to discrimination on the basis of their disability. This section also addresses privacy and confidentiality requirements that apply to the education records of students with food allergies, regardless of whether they have been found to have a disability under federal law. Schools and ECE programs are encouraged to copy and distribute relevant laws to appropriate staff and to reinforce relevant laws and regulations in all training provided to staff. For information on how to get copies of relevant federal laws and regulations, see Section 6. g\nThe federal laws described in this section are enforced or administered by the U.S. Department of Education (ED), the U.S. Department of Justice (DOJ), and the U.S. Department of Agriculture (USDA).\n# Section 504 of the Rehabilitation Act of 1973 (Section 504) and the Americans with Disabilities Act of 1990 (ADA) h\nSection 504 is a federal law that prohibits discrimination on the basis of disability in programs and activities that receive federal financial assistance. Recipients of federal financial assistance from ED include public school districts, other state and local educational agencies, and postsecondary educational institutions. The Department of Education's Office for Civil Rights (OCR) enforces Section 504 as it applies to these recipients. The USDA enforces Section 504 as it applies to recipients of federal financial assistance from USDA.\nTitle II of the ADA prohibits discrimination on the basis of disability by public entities, including public elementary, secondary, and postsecondary educational institutions, whether or not they receive federal financial assistance. For public schools, OCR shares Title II enforcement responsibilities with the U.S. Department of Justice (DOJ).\nSection 504 and Title II of the ADA require that qualified individuals with disabilities, including students, parents, and other program participants, not be excluded from or denied the benefits of services, programs, or activities or otherwise subjected to discrimination by reason of a disability. Public school districts that receive federal financial assistance are covered by both Section 504 and Title II. As a general rule, because Title II does not provide less protection than Section 504, violations of Section 504 also constitute violations of Title II. To the extent that Title II provides greater protections, schools must also comply with Title II and provide those additional protections.\ng. In addition to becoming familiar with these relevant federal laws, schools and ECE programs should determine which applicable state statutes, policies, and regulations and local statues and policies should be considered when developing management plans for children with food allergies. If a student's food allergy is a disability, that student is entitled to the protections of Section 504 and the ADA. Both laws define a disability as a physical or mental impairment that substantially limits a major life activity. Children with food allergies may be substantially limited in major life activities such as eating, breathing, or the operation of major bodily functions such as the respiratory or gastrointestinal system. The U.S. Congress has made clear that the definition of disability under Section 504 and the ADA is to be construed broadly. i\nUnder both Section 504 and Title II, students with disabilities in public schools must be given an equal opportunity to participate in academic, nonacademic, and extracurricular activities. ED's Section 504 regulation outlines a process for schools to use to determine whether a student has a disability and to determine what services a student with a disability needs. j This evaluation process must be tailored individually because each student is different, and his or her needs will vary. The Section 504 regulations specify that school districts must identify all students with disabilities and provide them with a free appropriate public education (FAPE).\nUnder ED's Section 504 regulation, FAPE is the provision of regular or special education and related aids and services designed to meet the individual educational needs of students with disabilities as adequately as the needs of students who do not have disabilities are met. A student does not have to receive special education services, however, in order to receive related aids and services under Section 504. The most common practice is to include these related aids and services, as well as any needed special education services, in a written document, sometimes called a Section 504 plan. Even if a school district does not believe that a student needs special education or related aids and services, Section 504 and Title II require the district to consider whether it can reasonably modify policies, practices, or procedures to ensure that a student with a disability has an equal opportunity to participate in and benefit from the school's services and programs. ED's Section 504 regulation also states that public preschool and day care programs operated by recipients of federal funds may not, on the basis of disability, exclude students with disabilities and must take their needs into account when determining the aid, benefits, or services to be provided. k Under ED's Section 504 regulation, private schools that receive federal financial assistance may not exclude an individual student with a disability if the school can, with minor adjustments; provide an appropriate education to that student. Private, nonreligious schools and ECE programs are covered by Title III of the ADA. Title III prohibits public accommodations such as these from discriminating against individuals with disabilities in the full and equal enjoyment of the entity's services and activities. Under Title III, private schools and ECE programs must make reasonable modifications to policies, practices, and procedures when necessary to give children with disabilities, including those with food allergies, full and equal access to and participation in programs and services unless the entity can show that the modification would result in a fundamental alteration of those programs and services.\nUnder Section 504 and the ADA, children with food allergy disabilities in schools and ECE programs must be provided with the services and modifications they need in order to attend. Examples of these services and modifications might include implementing allergen-safe food plans, administering epinephrine according to a doctor's orders (even if the school or ECE program has a no-medication policy), allowing students to carry their own medication, and providing an allergen-safe environment in which the student can eat meals. Disability harassment is a form of discrimination prohibited by Section 504 and Titles II and III of the ADA.\nHarassment creates a hostile environment when the conduct is sufficiently serious so as to interfere with or limit a student's ability to participate in or benefit from the services, activities, or opportunities offered by a school. When student-on-student disability harassment occurs and the school knows or reasonably should know about the harassment, a school must take prompt and effective steps reasonably calculated to end the harassment, prevent its recurrence, and eliminate any hostile environment created by the harassment. Section 504 and Title II require schools to take such steps and prohibit schools from encouraging, tolerating, or ignoring peer harassment based on disability that creates a hostile environment. Bullying, teasing, or harassment about an allergy can lead to psychological distress for children with food allergies which could lead to a more severe reaction when the allergen is present. And exposing an allergic child to the allergen (e.g., putting the allergen in the child's food or forcing the child to ingest the allergen) can have very serious-even fatal-consequences. School districts, in developing and implementing policies on bullying and harassment, should instruct staff and students as to how such policies apply to children with food allergies, including the possible disciplinary consequences for bullying and harassment that target or place food-allergic children at risk. Additional consequences could be to separate the harasser from the target and to provide counseling for the target or the harasser. Finally, a school should take steps to stop further harassment and prevent any retaliation against the person who made the complaint (or was the subject of the harassment) or against those who provided information as witnesses. The ADA, as amended, Section 504 of the Rehabilitation Act, The Richard B. Russell National School Lunch Act 42 USC 1758(a), the Child Nutrition Act, CNP regulations, and USDA's Non-discrimination regulations at 7 CFR 15b, govern meal accommodations for children with food related disabilities in schools and ECE programs that participate in the CNPs. USDA has oversight for providing meals in these programs. Program operators in the CNPs must make meal accommodations to regular program meals for children identified by a licensed doctor as having a food allergy disability that prevents them from consuming a meal as prepared. For purposes of discussion in these guidelines, if a child has a food allergy that is identified as a disability by a licensed doctor, meal accommodations must be provided.\nAdditionally, a school, institution, and site participating in USDA's Child Nutrition Programs, is not required to establish a Section 504 plan, IEP, IHP, ICP (or any plan that may be used by a child with special dietary needs) to make an accommodation to a program meal for a child with a food related disability. Instead, the CNPs require a written statement from a licensed doctor which identifies the following requirements:\n• The child's disability (according to pertinent statutes).\n• An explanation of why the disability restricts the child's diet.\n• The major life activity affected by the disability.\n• The food or foods to be omitted from the child's diet.\n• The food or choice of foods that must be substituted. 62 A statement signed by a licensed doctor addressing the points above is sufficient. However, the written statement from a licensed doctor may be incorporated in any of the plans discussed above.\n# Individuals with Disabilities Education Act (IDEA)\nIDEA Part B l provides federal funds to help states make FAPE available to eligible children with disabilities in the least restrictive environment. The obligation to make FAPE available in the least restrictive environment begins at the child's third birthday and could last until the child's twenty-second birthday, depending on state law or practice. m FAPE under IDEA Part B refers to the provision of special education and related services at no cost to the parents that include an appropriate preschool, elementary school, or secondary school education at the state level. Eligibility determinations under IDEA Part B are made at the state and local school district level on an individual, case-by-case basis in light of applicable IDEA Part B requirements and state education standards. At the federal level, IDEA is administered by the Office of Special Education Programs in the Office of Special Education and Rehabilitative Services in the ED.\nA child could be found eligible for services under IDEA Part B because of a food allergy only if it adversely affects the child's educational performance, and the child needs special education and related services because of the food allergy. If determined eligible, the school district must develop an Individualized Education Program (IEP) for the child, or if appropriate, an Individualized Family Service Plan (IFSP) for a child age three through five. n An IEP is a written document developed by a team that includes the child's parents and school officials. It sets out, among other elements, the special education and related services and supplementary aids and services to be provided to the child. If parents place their disabled child at a private school at their own expense, IDEA Part B generally would not require the school district to develop an IEP for the child at the private school. In general, if a child with a food allergy only needs a related service and does not need special education, that child would not be eligible for services under IDEA Part B. Such a child might still be eligible for services or modifications under Section 504 or Title II.\nIn addition, IDEA Part C provides federal funds to assist states in identifying and providing early intervention services to children with disabilities from birth to age three and, at the state's discretion, through five or when the child enters kindergarten. Under IDEA Part C, a child is eligible based on a developmental delay, diagnosed condition, or, at the state's discretion, at-risk status. An IFSP is a document written by a team that includes the child's parents that identifies the specific early intervention services needed by the child. o\n# Family Educational Rights and Privacy Act (FERPA) of 1974\nFERPA applies to educational agencies or institutions that receive federal funds under a program administered by ED. p FERPA generally prohibits schools and school districts from disclosing personally identifiable information from a student's education record unless the student's parent or the eligible student (a student who is aged 18 years or older or who attends an institution of postsecondary education) provides prior, written consent for the disclosure. This requirement has several exceptions. q One exception permits schools to disclose personally identifiable information from a student's education record without obtaining prior written consent to school officials, including teachers, who have legitimate educational interests in the information, including the educational interests of the child. Schools must use reasonable methods, such as physical, technological, or administrative access controls, to ensure that school officials obtain access only to those education records in which they have legitimate educational interests. To use this exception, schools must include in their annual notification of FERPA rights to parents and eligible students the criteria for determining who constitutes a school official and what constitutes a legitimate educational interest.\nThis exception for school officials also applies to a contractor, consultant, volunteer, or other party to whom a school has outsourced institutional services or functions provided that the outside party:\n• Performs an institutional service or function for which the school would otherwise use employees.\n• Is under the direct control of the school with respect to the use and maintenance of education records.\n• Is subject to the requirements in FERPA that govern the use and redisclosure of personally identifiable information from education records.\nAnother exception to the requirement of prior written consent permits schools to disclose personally identifiable information from an education record to appropriate parties, including the parent of an eligible student, in connection with an emergency if knowledge of the information is necessary to protect the health or safety of the student or other individuals. Under this exception, a school may take into account the totality of the circumstances pertaining to a threat to the health or safety of a student or other individuals. If a school determines that there is an articulable and significant threat to the health or safety of a student or other individuals, it may disclose information from education records to any person whose knowledge of the information is necessary to protect the health or safety of the student or other individuals. If the information available at the time of the incident forms a rational basis for the decision to disclose information, ED will not substitute its judgment for that of the school in evaluating the circumstances and making its determination. When disclosures are made under this exception, a school must record the articulable and significant threat to the health or safety of a student or other individual that formed the basis for the disclosure and the parties to whom the information was disclosed.\nIn addition, under FERPA, the parent or eligible student must be given the opportunity to inspect and review the student's education records. A school must comply with a request for access to the student's education records within a reasonable period of time, but not more than 45 days after it has received the request.\nAdditional information and resources, including how to access copies of federal laws, are provided in Section 6.\n# Acknowledgements\nFood Allergies: What School Employees Need to Know http://neahin.org/foodallergies Developed by the NEA (National Education Association) Health Information Network, with support from the U.S. Department of Agriculture, this booklet is designed to educate school employees about food allergies and how they can help to prevent and respond to allergic reactions in schools. Booklets are available in print and online in both English and Spanish. \n# National Food Service Management Institute Resources\n\n# Federal Resources\nFood Allergy Overview www.niaid.nih.gov/topics/foodAllergy/understanding/Pages/default.aspx U.S. Department of Health and Human Services (HHS), National Institute of Allergies and Infectious Diseases. These resources are designed to improve understanding of food allergies, share information about food allergy research, and present current guidelines for clinical diagnosis and management of food allergies in the United States. General information about food allergies is also available in PDF format at www.niaid.nih.gov/topics/foodallergy/documents/foodallergy.pdf.\n# Food Allergies: What You Need to Know\nwww.fda.gov/Food/ResourcesForYou/Consumers/ucm079311.htm U.S. Department of Health and Human Services (HHS), Food and Drug Administration. These resources are designed to improve understanding of food allergies and labeling of food products that contain proteins derived from the eight most common food allergens. Information also includes food allergy updates for consumers.\n# Readiness and Emergency Management for Schools (REMS) Technical Assistance (TA) Center\nhttp://rems.ed.gov Sponsored by the U.S. Department of Education (ED) the REMS TA Center's primary goal is to support schools, school districts, and institutions of higher education in school emergency management, including the development and implementation of comprehensive all-hazards emergency management plans. The TA Center disseminates information about school emergency management to help individual schools, school districts, and institutions of higher education learn more about developing, implementing, and evaluating comprehensive, all-hazards school emergency management plans. In addition, the TA Center helps ED coordinate technical assistance meetings and share school emergency management information, and responds to direct requests for technical assistance and training.\n# The National Center on Safe Supportive Learning Environments\nhttp://safesupportiveschools.ed.gov Supported by the U.S. Department of Education, (ED) the National Center on Safe Supportive Learning Environments (NCSSLE) provides information and technical assistance to states, districts, schools, institutions of higher education, communities, and other federal grantees programs on how to improve conditions for learning.\nTo improve conditions for learning, the Center assists others in measuring school climate and conditions for learning and implementing appropriate programmatic interventions, so that all students have the opportunity to realize academic success in safe and supportive environments. The Center also specifically addresses issues related to bullying, violence and substance abuse prevention that often negatively impact learning environments. \n# Guidance Related to Federal Laws\n\n# Federal Statutes and Regulations\nThe following statutes are in the U.S. Code (U.S.C. April 1, 2008), the Food Code is a model that assists food control jurisdictions at all levels of government by providing them with a scientifically sound technical and legal basis for regulating the retail and food service segment of the industry. It serves as a reference document for state, city, county and tribal agencies that regulate restaurants, retail food stores, vending operations and food service operations in institutions such as schools, hospitals, nursing homes and child care centers.\n# Food Allergy and Anaphylaxis: An NASN Tool Kit\nwww.nasn.org/ToolsResources/FoodAllergyandAnaphylaxis Sponsored by the National School Nurses Association, this site provides a variety of tools and templates to educate and help people who are responsible for managing students with food allergies as an integral part of the delivery of health care services in schools.\n# National Nongovernmental Resources: School Policy\n\n# Safe at School and Ready to Learn: A Comprehensive Policy Guide for Protecting Students with Life-Threatening Food Allergies\nwww.nsba.org/foodallergyguide.pdf Developed by the National School Boards Association, this guide is designed to help school leaders, especially school boards, make sure that policies at the district and school level support the safety, well-being, and success of students with life-threatening food allergies. It includes a checklist that school can use to assess the extent to which the guide's components are included in their food allergy policies and used in practice. It also has examples of state and local education policies.\n# Statewide Guidelines for Schools\nhttp://www.foodallergy.org/laws-and-regulations/statewide-guidelines-for-schools Hosted by Food Allergy Research & Education (FARE), this site provides state guidelines for managing food allergies in schools.\n# National Nongovernmental Resources: Food Allergy Training\nHow to CARE for Students with Food Allergies: What Every Educator Should Know http://allergyready.com This free online course, developed by Food Allergy Research & Education (F.A.R.E.), is designed to help teachers, administrators, and other school staff members prevent and manage potentially life-threatening allergic reactions. Educational materials include guidance for people who might be training staff how to use an epinephrine auto-injector.\nManaging Food Allergies in Schools: Food Allergy Education for the School Community www.allergyhome.org/schools This resource was developed in partnership with Kids with Food Allergies, the Asthma and Allergy Foundation of America New England Chapter, the Association of Camp Nurses, and the American Camping Association. It was modified for and approved by the Massachusetts Department of Public Health's School Health Services. It provides practical teaching tools, including presentations with audio to assist in nurse, staff, parent and student education. This resource provides school nurses with tools to assist in the training their school community, including students and parents without food allergies, and includes guidance for school nurses who will train staff on administration of epinephrine by auto-injector. It includes links to other allergy education sites, materials for families of children with food allergies, and materials for others working in child care and camp programs. \n# National Nongovernmental Resources: Parent Education\n\n# Glossary of Abbreviations and Acronyms\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":277,"cells":{"id":{"kind":"string","value":"2231652beaa28e66ae989dbe5b5cea95095b5125"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"This report provides recommendations for use of a newly developed recombinant outer-surface protein A (rOspA) Lyme disease vaccine (LYMErix,™ SmithKline Beecham Pharmaceuticals) for persons aged 15-70 years in the United States. The purpose of these recommendations is to provide health-care providers, public health authorities, and the public with guidance regarding the risk for acquiring Lyme disease and the role of vaccination as an adjunct to preventing Lyme disease. The Advisory Committee on Immunization Practices recommends that decisions regarding vaccine use be made on the basis of assessment of individual risk, taking into account both geographic risk and a person's activities and behaviors relating to tick exposure. *sensu lato: including all subordinate taxa of a taxon that would otherwise be considered separately. † sensu stricto: excluding similar taxa that otherwise would be considered together.# INTRODUCTION\nLyme disease is a tickborne zoonosis caused by infection with the spirochete Borrelia burgdorferi. The number of annually reported cases of Lyme disease in the United States has increased approximately 25-fold since national surveillance began in 1982; during 1993-1997, a mean of 12,451 cases annually were reported by states to CDC (1,2, CDC, unpublished data, 1998). In the United States, the disease is primarily localized to states in the northeastern, mid-Atlantic, and upper north-central regions, and to several areas in northwestern California (1 ).\nLyme disease is a multisystem, multistage, inflammatory illness. In its early stages, Lyme disease can be treated successfully with oral antibiotics; however, untreated or inadequately treated infection can progress to late-stage complications requiring more intensive therapy. The first line of defense against Lyme disease and other tickborne illnesses is avoidance of tick-infested habitats, use of personal protective measures (e.g., repellents and protective clothing), and checking for and removing attached ticks. Early diagnosis and treatment are effective in preventing late-stage complications.\nRecently, two Lyme disease vaccines have been developed that use recombinant B. burgdorferi lipidated outer-surface protein A (rOspA) as immunogen -LYMErix,™ SmithKline Beecham Pharmaceuticals, and ImuLyme,™ Pasteur Mérieux Connaught. As of publication of this report, only LYMErix has been licensed by the U.S. Food and Drug Administration for use in the United States; therefore, these recommendations apply only to the use of that vaccine. Additional statements will be provided as other Lyme disease vaccines are licensed.\nResults of a large-scale, randomized, controlled (Phase III) trial of safety and efficacy of LYMErix in persons aged 15-70 years residing in disease-endemic areas of the northeastern and north-central United States indicate that the vaccine is safe and efficacious when administered on a three-dose schedule of 0, 1, and 12 months (3,4 ). Information regarding vaccine safety and efficacy beyond the transmission season immediately after the third dose is not available. Thus, the duration of protective immunity and need for booster doses beyond the third dose are unknown.\n\n# CLINICAL FEATURES OF LYME DISEASE Clinical Description\nMost often, Lyme disease is evidenced by a characteristic rash (erythema migrans) accompanied by nonspecific symptoms (e.g., fever, malaise, fatigue, headache, myalgia, and arthralgia) (5)(6)(7). The incubation period from infection to onset of erythema migrans is typically 7-14 days but can be as short as 3 days or as long as 30 days. Some infected persons have no recognized illness (i.e., asymptomatic infection determined by serologic testing), or they manifest only nonspecific symptoms (e.g., fever, headache, fatigue, and myalgia).\nLyme disease spirochetes disseminate from the site of inoculation by cutaneous, lymphatic, and bloodborne routes. The signs of early disseminated infection usually occur from days to weeks after the appearance of a solitary erythema migrans lesion. In addition to multiple or secondary erythema migrans lesions, early disseminated infection can be manifested as disease of the nervous system, the musculoskeletal system, or the heart (5)(6)(7). Early neurologic manifestations include lymphocytic meningitis; cranial neuropathy, especially facial nerve palsy; and radiculoneuritis. Musculoskeletal manifestations can include migratory joint and muscle pains with or without objective signs of joint swelling. Cardiac manifestations are rare but can include myocarditis and transient atrioventricular block of varying degree.\nB. burgdorferi infection in the untreated or inadequately treated patient can progress to late-disseminated disease from weeks to months after infection (5)(6)(7). The most common objective manifestation of late-disseminated Lyme disease is intermittent swelling and pain of one or some joints, usually large, weight-bearing joints (e.g., the knee). Some patients experience chronic axonal polyneuropathy, or encephalopathy, the latter usually manifested by cognitive disorders, sleep disturbance, fatigue, and personality changes. Infrequently, Lyme disease morbidity can be severe, chronic, and disabling (8,9 ). An ill-defined post-Lyme disease syndrome occurs in some persons after treatment for Lyme disease (10)(11)(12). Lyme disease is rarely, if ever, fatal.\n\n# Diagnosis\nThe diagnosis of Lyme disease is based primarily on clinical findings, and treating patients with early disease solely on the basis of objective signs and a known exposure is often appropriate (13 ). Serologic testing can, however, provide valuable supportive diagnostic information in patients with endemic exposure and objective clinical findings that indicate later-stage disseminated Lyme disease (13 ).\nWhen serologic testing is indicated, CDC recommends testing initially with a sensitive first test, either an enzyme-linked immunosorbent assay (ELISA) or an indirect fluorescent antibody test, followed by testing with the more specific Western immunoblot (WB) test to corroborate equivocal or positive results obtained with the first test (14 ). Although antibiotic treatment in early localized disease can blunt or abrogate the antibody response, patients with early disseminated or late-stage disease usually have strong serologic reactivity and demonstrate expanded WB immunoglobulin G (IgG) banding patterns to diagnostic B. burgdorferi antigens (15,16 ).\nAntibodies often persist for months or years after successfully treated or untreated infection. Thus, seroreactivity alone cannot be used as a marker of active disease. Neither positive serologic test results nor a history of previous Lyme disease ensures that a person has protective immunity. Repeated infection with B. burgdorferi has been reported (17 ).\nB. burgdorferi can be cultured from 80% or more of biopsy specimens taken from early erythema migrans lesions (18 ). However, the diagnostic usefulness of this procedure is limited because of the need for a special bacteriologic medium (i.e., modified Barbour-Stoenner-Kelly medium) and protracted observation of cultures. Polymerase chain reaction (PCR) has been used to amplify genomic DNA of B. burgdorferi in skin, blood, cerebrospinal fluid, and synovial fluid (19,20 ), but PCR has not been standardized for routine diagnosis of Lyme disease.\n\n# Treatment\nLyme disease can usually be treated successfully with standard antibiotic regimens (5,6 ). Early and uncomplicated infection, including infection with isolated cranial nerve palsy, usually responds satisfactorily to treatment with orally administered antibiotics (21 ). Parenteral antibiotics are generally recommended for treating meningitis, carditis, later-stage neurologic Lyme disease, and complicated Lyme disease arthritis. Late, complicated Lyme disease might respond slowly or incompletely, and more than one antibiotic treatment course can be required to eliminate active infection (8,9 ). Refractory Lyme disease arthritis is associated with expression of certain Class II major histocompatibility complex (MHC II) molecules (22 ), and can require anti-inflammatory agents and surgical synovectomy for relief of symptoms (8 ). In a limited number of patients, persistent or recurrent symptoms after appropriate antibiotic therapy often can be attributed to causes other than persistent infection (22,23 ).\n\n# EPIDEMIOLOGY OF LYME DISEASE Antigenic Variation of B. burgdorferi Sensu Lato*\nIn the United States, a number of genospecies of B. burgdorferi sensu lato have been isolated from animals and ticks, but only OspA expressing B. burgdorferi sensu stricto † has been isolated from humans (24 ). Existing evidence also demonstrates that rOspA vaccines will be protective against most if not all human infections in the United States (25 ). B. burgdorferi sensu stricto also occurs in Europe, but the dominant European and Asian genospecies are B. garinii and B. afzelii, both of which are antigenically distinct from B. burgdorferi sensu stricto (26 ) and vary in their expression of OspA. Vaccines using combinations of immunogenic proteins might be necessary to provide protection against multiple genospecies (27 ).\n\n# Routes of Transmission\nHumans acquire B. burgdorferi infection from infected ticks at the time the tick takes a blood meal (28 ); Lyme disease is not spread by person-to-person contact or by direct contact with infected animals. Transplacental transmission of B. burgdorferi has been reported (29,30 ), but the effects of such transmission on the fetus remain unclear. The results of two epidemiologic studies document that congenital Lyme disease must be rare, if it occurs at all (31,32 ). Transmission in breast milk has not been described. B. burgdorferi can be cultured from the blood in some patients with early acute infection, and it is able to survive for several weeks in stored blood. However, at least one study has found that the risk for transfusion-acquired infection is minimal (33 ).\n\n# Tick Vectors of Lyme Disease\nB. burgdorferi is transmitted to humans by ticks of the Ixodes ricinus complex (34 ). I. scapularis, the black-legged or deer tick, is the vector in the eastern United States; I. pacificus, the western black-legged tick, transmits B. burgdorferi in the western United States (35,36 ). I. scapularis is also a vector for human granulocytic ehrlichiosis and babesiosis (34,37 ). In their nymphal stage, these ticks feed predominantly in the late spring and early summer. The majority of Lyme disease cases result from bites by infected nymphs. In highly enzootic areas of the United States, approximately 15%-30% of questing I. scapularis nymphs and up to 14% of I. pacificus nymphs are infected with B. burgdorferi (38)(39)(40)(41). However, in the southern United States, the prevalence of infection in I. scapularis ticks is generally 0%-3% (36 ). The risk for acquiring Lyme disease in the United States varies with the distribution, density, and prevalence of infection in vector ticks (Appendix).\nDuring the past several decades, the distribution of I. scapularis has spread slowly in the northeastern and upper north-central regions of the United States (42 ). Although deer are not competent reservoirs of B. burgdorferi, they are the principal maintenance hosts for adult black-legged ticks, and the presence of deer appears to be a prerequisite for the establishment of I. scapularis in any area (43 ). The explosive repopulation in the eastern United States by white-tailed deer during recent decades has been linked to the spread of I. scapularis ticks and of Lyme disease in this region. The future limits of this spread are not known (42 ).\n\n# Distribution of Human Cases of Lyme Disease\nLyme disease is endemic in several regions in the United States, Canada, and temperate Eurasia (1,44 ). The disease accounts for more than 95% of all reported cases of vectorborne illness in the United States. Using a national surveillance case definition (45 ), state health officials reported >62,000 cases to CDC during 1993-1997, and the national mean annual rate during this 5-year period was 5.5 cases/100,000 population (1,2, CDC, unpublished data, 1998). Persons of all ages are equally susceptible to infection, although the highest reported rates of Lyme disease occur in children aged <15 years and in adults aged 30-59 years (1 ). Both underreporting and overdiagnosis are common (46)(47)(48). Approximately 90% of cases are reported by approximately 140 counties located along the northeastern and mid-Atlantic seaboard and in the upper north-central region of the United States (Appendix).\nA rash similar to erythema migrans of Lyme disease, but not caused by B. burgdorferi infection, has been described in patients who have been bitten by ticks in the southern United States (49,50 ). This rash is suspected of being associated with the bite of Amblyomma americanum ticks (51 ).\n\n# Populations at Risk for Lyme Disease\nMost B. burgdorferi infections result from periresidential exposure to infected ticks (38,(52)(53)(54)(55) during property maintenance, recreation, and leisure activities. Thus, persons who live or work in residential areas surrrounded by woods or overgrown brush infested by vector ticks are at risk for acquiring Lyme disease. In addition, persons who participate in recreational activities away from home (e.g., hiking, camping, fishing, and hunting) in tick habitat and persons who engage in outdoor occupations (e.g., landscaping, brush clearing, forestry, and wildlife and parks management) in endemic areas might also be at elevated risk for acquiring Lyme disease (56)(57)(58).\n\n# PREVENTION AND CONTROL OF LYME DISEASE\n\n# Avoidance of Tick Habitat\nWhenever possible, persons should avoid entering areas that are likely to be infested with ticks, particularly in spring and summer when nymphal ticks feed. Ticks favor a moist, shaded environment, especially that provided by leaf litter and lowlying vegetation in wooded, brushy, or overgrown grassy habitat. Both deer and rodent hosts must be abundant to maintain the enzootic cycle of B. burgdorferi. Sources of information regarding the distribution of ticks in an area include state and local health departments, park personnel, and agricultural extension services.\n\n# Personal Protection\nPersons who are exposed to tick-infested areas should wear light-colored clothing so that ticks can be spotted more easily and removed before becoming attached. Wearing long-sleeved shirts and tucking pants into socks or boot tops can help keep ticks from reaching the skin. Ticks are usually located close to the ground, so wearing high rubber boots can provide additional protection. Applying insect repellents containing DEET (n,n-diethyl-m-toluamide) to clothes and exposed skin and applying permethrin, which kills ticks on contact, to clothes, should also help reduce the risk of tick attachment. DEET can be used safely on children and adults but should be applied according to the U.S. Environmental Protection Agency guidelines to reduce the possibility of toxicity (59 ). Because transmission of B. burgdorferi from an infected tick is unlikely to occur before 36 hours of tick attachment (28,60 ), daily checks for ticks and their prompt removal will help prevent infection.\n\n# Strategies for Reducing Tick Abundance\nThe number of ticks in endemic residential areas can be reduced by removing leaf litter, brush, and woodpiles around houses and at the edges of yards and by clearing trees and brush to admit more sunlight, thus reducing deer, rodent, and tick habitat (61 ). Tick populations have also been effectively suppressed by applying pesticides to residential properties (62,63 ). Community-based interventions to reduce deer populations or to kill ticks on deer and rodents have not been extensively implemented, but might be effective in reducing communitywide risk for Lyme disease (64 ). The effectiveness of deer feeding stations equipped with pesticide applicators to kill ticks on deer and other baited devices to kill ticks on rodents is currently under evaluation.\n\n# Prophylaxis After Tick Bite\nThe relative cost-effectiveness of postexposure treatment of tick bites to avoid Lyme disease in endemic areas is dependent on the probability of B. burgdorferi infection after a tick bite (65 ). In most circumstances, treating persons for tick bite alone is not recommended (6,66 ). Persons who are bitten by a deer tick should remove the tick and seek medical attention if any signs and symptoms of early Lyme disease, ehrlichiosis, or babesiosis develop during the ensuing days or weeks.\n\n# Early Diagnosis and Treatment\nLyme disease is readily treatable in its early stages (5,6 ). The early diagnosis and proper antibiotic treatment of Lyme disease are important strategies for avoiding the morbidity and costs of complicated and late-stage illness.\n\n# LYME DISEASE VACCINE Description\nLYMErix is made from lipidated rOspA of B. burgdorferi sensu stricto. The rOspA protein is expressed in Escherichia coli and purified. Each 0.5-mL dose of LYMErix contains 30 µg of purified rOspA lipidated protein adsorbed onto aluminum hydroxide adjuvant.\n\n# Mechanism of Action\nSeveral studies in animals have provided evidence that B. burgdorferi in a vector tick undergoes substantial antigenic change between the time of tick attachment on a mammalian host and subsequent transmission of the bacterium to the host. The spirochetes residing in the tick gut at the initiation of tick feeding express primarily OspA. As tick feeding begins, the expression of outer-surface protein C (OspC) is increased and the expression of OspA is decreased, so that spirochetes that reach the mammalian host after passing through the tick salivary glands express primarily OspC (67 ).\nThus, the rOspA vaccine might exert its principal protective effect by eliciting antibodies that kill Lyme disease spirochetes within the tick gut (68,69 ).\n\n# Route of Administration, Vaccination Schedule, and Dosage\nLYMErix is administered by intramuscular injection, 0.5 mL (30 µg), into the deltoid muscle. Three doses are required for optimal protection. The first dose is followed by a second dose 1 month later and a third dose administered 12 months after the first dose. Vaccine administration should be timed so that the second dose of the vaccine (year 1) and the third dose (year 2) are administered several weeks before the beginning of the B. burgdorferi transmission season, which usually begins in April. The safety and immunogenicity of alternate dosing schedules are currently being evaluated.\n\n# VACCINE PERFORMANCE\n\n# Safety\n\n# Randomized, Controlled Clinical (Phase III) Trial of LYMErix\nA total of 10,936 subjects aged 15-70 years living in Lyme disease-endemic areas were recruited at 31 sites and randomized to receive three doses of vaccine or placebo (3 ); 5,469 subjects received at least one 30-µg dose of rOspA vaccine, and 5,467 subjects received at least one injection of placebo. The subjects were then followed for 20 months. Information regarding adverse events that were believed to be related or possibly related to injection were available from 4,999 subjects in each group. Soreness at the injection site was the most frequently reported adverse event, which was reported without solicitation by 24.1% of vaccine recipients and 7.6% of placebo recipients (p < 0.001). Redness and swelling at the injection site were reported by <2% of either group but were reported more frequently among vaccine recipients than among those who received placebo (p < 0.001). Myalgia, influenza-like illness, fever, and chills were more common among vaccine recipients than placebo recipients (p < 0.001), but none of these was reported by more than 3.2% of subjects (3 ). Reports of arthritis were not significantly different between vaccine and placebo recipients, but vaccine recipients were significantly (p < 0.05) more likely to report arthralgia or myalgia within 30 days after each dose (70 ). No statistically significant differences existed between vaccine and placebo groups in the incidence of adverse events more than 30 days after receiving a dose, and no episodes of immediate hypersensitivity among vaccine recipients were noted (3 ).\n\n# Safety in Patients with Previously Diagnosed Lyme Disease\nThe safety of three different dosage strengths of rOspA vaccine with adjuvant in 30 adults with previous Lyme disease was evaluated in an uncontrolled safety and immunogenicity trial (71 ). Doses were administered at 0, 1, and 2 months. Follow-up of subjects was conducted 1 month after the third dose. No serious adverse events were recorded during the study period.\nIn the randomized controlled Phase III trial of LYMErix, the incidence of adverse events among vaccinees who were seropositive at baseline was similar to the incidence among those who were seronegative (70 ). The incidence of musculoskeletal symptoms within the first 30 days after vaccination was higher among vaccinees with a self-reported previous history of Lyme disease compared with vaccinees with no such history. This difference was not statistically significant at the p = 0.05 level in the placebo group. No statistically significant difference existed in the incidence of late musculoskeletal adverse events between vaccine and placebo recipients with a selfreported previous history of Lyme disease (70 ).\n\n# Risk for Possible Immunopathogenicity of rOspA Vaccine\nAfter infection with B. burgdorferi, persons who express certain MHC II molecules are more likely than others to develop chronic, poorly responsive Lyme arthritis associated with high levels of antibody to OspA in serum and synovial fluid (22 ). In chronic Lyme arthritis patients, the levels of antibody to OspA, and especially to the C-terminal epitope of OspA, have been found to correlate directly with the severity and duration of the arthritis (72 ). Researchers have proposed that an autoimmune reaction might develop within the joints of some Lyme arthritis patients as a result of molecular mimicry between the dominant T-cell epitope of OspA and human leukocyte function associated antigen 1 (hLFA-1) (73 ). The Phase III trial did not detect differences in the incidence of neurologic or rheumatologic disorders between vaccine recipients and their placebo controls during the 20 months after the initial dose (3 ). However, because the association between immune reactivity to OspA and treatment-resistant Lyme arthritis is poorly understood, the vaccine should not be administered to persons with a history of treatment-resistant Lyme arthritis.\n\n# Efficacy Randomized, Controlled Trial (Phase III) of LYMErix\nUsing an intention-to-treat analysis, the vaccine efficacy in protecting against \"definite\" Lyme disease after two doses was 49% (95% confidence interval = 15%-69%) and after three doses was 76% (95% CI = 58%-86%) (3 ). (In this study, \"definite\" Lyme disease was defined as the presence of erythema migrans or objective neurologic, musculoskeletal, or cardiovascular manifestations of Lyme disease, plus laboratory confirmation of infection by cultural isolation, PCR positivity, or WB seroconversion.) Efficacy in protecting against asymptomatic infection (no recognized symptoms, but with WB seroconversions recorded in year 1 or year 2) was 83% (95% CI = 32%-97%) in year 1 and 100% (95% CI = 26%-100%) in year 2.\n\n# Immunogenicity\nA subset of adult subjects enrolled in the Phase III clinical trial of LYMErix was studied for the development of OspA antibodies at months 2, 12, 13, and 20 (3 ). At month 2, one month after the second injection, the geometric mean antibody titer (GMT) of IgG anti-OspA antibodies was 1,227 ELISA units/mL. Ten months later, the GMT had declined to 116 ELISA units/mL. At month 13, one month after the third injection, a marked anamnestic response resulted in a GMT of 6,006 ELISA units/mL. At month 20, the mean response had decreased to 1,991 ELISA units/mL (70 ). An analysis of antibody titers and the risk for developing Lyme disease for a subset of subjects enrolled in the Phase III clinical trial concluded that a titer >1,200 ELISA units/mL correlated with protection (SmithKline Beecham poster at Infectious Disease Society of America Conference, Denver, Colorado, November 1998).\n\n# Effect of Vaccination on the Serologic Diagnosis of Lyme Disease\nCare providers and laboratorians should be advised that vaccine-induced anti-rOspA antibodies routinely cause false-positive ELISA results for Lyme disease (74 ). Experienced laboratory workers, through careful interpretation of the results of WB, can usually discriminate between B. burgdorferi infection and previous rOspA immunization, because anti-OspA antibodies do not develop after natural infection.\n\n# COST-EFFECTIVENESS OF LYME DISEASE VACCINATION\nThe cost of Lyme disease has been evaluated from both a societal and a thirdparty-payer perspective (75 ). The cost-effectiveness of vaccinating against Lyme disease has also been analyzed from a societal perspective (76 ). At an assumed cost of vaccination of $100/person/year, a vaccine effectiveness of 0.85, a probability of 0.85 of correctly identifying and treating early Lyme disease, and an assumed incidence of Lyme disease of 1,000/100,000 persons/year, the net cost of vaccination to society was $5,692/case averted and $35,375/complicated neurologic or arthritic case avoided (Figure 1). Using these same baseline assumptions, the societal cost of vaccination exceeds the cost of not vaccinating, unless the incidence of Lyme disease is >1,973/100,000 persons/year. Of the variables examined, the incidence of Lyme disease had the greatest impact on cost-effectiveness of vaccination. The likelihood of early diagnosis and treatment also has a substantial impact on vaccine costeffectiveness because of the reduced incidence of sequelae when Lyme disease is diagnosed and patients are treated early in the disease.\nMost disease-endemic states and counties report Lyme disease incidence that are substantially below 1,000/100,000 persons/year. For example, in 1997, the highest reported state incidence was 70/100,000 persons in Connecticut, and the highest reported county incidence was 600/100,000 population in Nantucket County, Massachusetts. However, some studies document that approximately 10%-15% of physician-diagnosed cases of Lyme disease are reported to state authorities in highly endemic areas (46,47 ). Epidemiologic studies of populations at high risk in the northeastern United States have estimated annual incidence of >1,000/100,000 persons/ year in several communities (77)(78)(79)(80).\n\n# ASSESSING THE RISK FOR LYME DISEASE\nThe decision to administer Lyme disease vaccine should be made on the basis of an assessment of individual risk, which depends on a person's likelihood of being bitten by tick vectors infected with B. burgdorferi. This likelihood is primarily determined by the following:\n- density of vector ticks in the environment, which varies by place and season;\n- the prevalence of B. burgdorferi infection in vector ticks; and - the extent of person-tick contact, which is related to the type, frequency, and duration of a person's activities in a tick-infested environment.\nAssessing risk should include considering the geographic distribution of Lyme disease. The areas of highest Lyme disease risk in the United States are concentrated within some northeastern and north-central states. The risk for Lyme disease differs not only between regions and states and counties within states (Appendix), but even within counties and townships. Detailed information regarding the distribution of Lyme disease risk within specific areas is best obtained from state and local public health authorities.\nThe second step in determining Lyme disease risk is to assess a person's activities. Activities that place persons at high risk are those that involve frequent or prolonged exposure to the habitat of infected ticks at times of the year when the nymphal stages of these ticks are actively seeking hosts, which in most endemic areas is April-July. Typical habitat of Ixodes ticks are wooded, brushy, or overgrown grassy areas that are favorable for deer and the ticks' rodent hosts. Several recreational, property\n\n# FIGURE 1. Cost-effectiveness of Lyme disease vaccination OBJECTIVE\nThis MMWR provides recommendations regarding prevention and control of Lyme disease. These recommendations were developed by CDC staff members and the ACIP members. This report is intended to guide clinical practice and policy development related to administration of the Lyme disease vaccine. Upon completion of this educational activity, the reader should be able to describe the epidemiology of Lyme disease in the United States; list effective methods of Lyme disease prevention; describe the characteristics and use of the currently licensed Lyme disease vaccine; and recognize the most common adverse reactions following administration of Lyme disease vaccine.\n\n# EXPIRATION -June 4, 2000\nThe response form must be completed and returned electronically, by fax, or by mail, postmarked no later than 1 year from the publication date of this report, for eligibility to receive continuing education credit.\n\n# INSTRUCTIONS\n1. Read this MMWR (Vol. 48, RR-7 ), which contains the correct answers to the questions beginning on the next page. 2. Complete all registration information on the response form, including your name, mailing address, phone number, and e-mail address, if available.\n\n# Indicate whether you are registering for Continuing Medical Education (CME) credit, Continuing\nEducation Unit (CEU) credit, or Continuing Nursing Education (CNE) credit. 4. Select your answers to the questions, and mark the corresponding letters on the response form. To receive continuing education credit, you must answer all of the questions. Questions with more than one correct answer will instruct you to \"indicate all that are true.\" 5. Sign and date the response form.\n\n# MMWR Response Form for Continuing Education Credit\nJune 4, 1999 / Vol. 48 / No. RR-7\n\n# Recommendations for the Use of Lyme Disease Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP)\nFill in the appropriate block(s) to indicate your answer(s). To receive continuing education credit, you must answer all of the questions.\n. A B C D E 2. A B C D E 3. A B C D E 4. A B C D E 5. A B C D E 6. A B C D E 7. A B C D E 8. A B C D E 9. A B C D E 10. A B C D E F 11. A B C D E F 12. A B C D E 13. A B C D E 14. A B C 15. A B C D E 16. A B C D E 17. A B C D E 18. A B C D E\nDetach or photocopy. 1.2 hours of CNE credit maintenance, occupational, or leisure pursuits that are carried out in tick habitat can be risky activities.\nWhen in highly endemic areas, persons can reduce their risk for Lyme disease and other tickborne illnesses by avoiding tick-infested habitats. If exposure to a tick-infested habitat cannot be avoided, persons should use repellents, wear protective clothing, and regularly check themselves for ticks.\nPersons who are unlikely to seek medical care for early manifestations of Lyme disease can be at increased risk for Lyme disease complications. Morbidity from Lyme disease can be substantially reduced by detecting and treating the infection in its early stages, because early and correct treatment usually results in a prompt and uncomplicated cure.\n\n# RECOMMENDATIONS FOR USE OF LYME DISEASE VACCINE\nLyme disease vaccine does not protect all recipients against infection with B. burgdorferi and offers no protection against other tickborne diseases. Vaccinated persons should continue to practice personal protective measures against ticks and should seek early diagnosis and treatment of suspected tickborne infections. Because Lyme disease is not transmitted person-to-person, use of the vaccine will not reduce risk among unvaccinated persons. Decisions regarding the use of vaccine should be based on individual assessment of the risk for exposure to infected ticks and on careful consideration of the relative risks and benefits of vaccination compared with other protective measures, including early diagnosis and treatment of Lyme disease. The risk for Lyme disease is focally distributed in the United States (Appendix). Detailed information regarding the distribution of Lyme disease risk within specific areas is best obtained from state and local public health authorities.\nThe following recommendations are made regarding use of Lyme disease vaccine: -Lyme disease vaccination may be considered for persons aged 15-70 years who are exposed to tick-infested habitat but whose exposure is neither frequent nor prolonged. The benefit of vaccination beyond that provided by basic personal protection and early diagnosis and treatment of infection is uncertain.\n-Lyme disease vaccination is not recommended for persons who have minimal or no exposure to tick-infested habitat.\n- Travelers can obtain some protection from two doses of vaccine but will not achieve optimal protection until the full series of three doses has been administered. All travelers to high-or moderate-risk areas during Lyme disease transmission season should practice personal protection measures as described earlier and seek prompt diagnosis and treatment if signs or symptoms of Lyme disease develop. Lyme disease is endemic in some temperate areas of Europe and Asia; however, considerable heterogeneity of expression exists in the Eurasian strains of B. burgdorferi sensu lato that infect humans, and whether the rOspA vaccine licensed for use in the United States would protect against infection with Eurasian strains is uncertain. - Pregnant Women -Because the safety of rOspA vaccines administered during pregnancy has not been established, vaccination of women who are known to be pregnant is not recommended.\nNo evidence exists that pregnancy increases the risk for Lyme disease or its severity. Acute Lyme disease during pregnancy responds well to antibiotic therapy, and adverse fetal outcomes have not been reported in pregnant women receiving standard courses of treatment. A vaccine pregnancy registry has been established by SmithKline Beecham Pharmaceuticals. In the event that a pregnant women is vaccinated, health-care providers are encouraged to register this vaccination by calling, toll-free, (800) 366-8900, ext. 5231.\n- Persons with Immunodeficiency -Persons with immunodeficiency were excluded from the Phase III safety and efficacy trial, and no data are available regarding Lyme disease vaccine use in this group.\n\n# Persons with Musculoskeletal Disease\n-Persons with diseases associated with joint swelling (including rheumatoid arthritis) or diffuse musculoskeletal pain were excluded from the Phase III safety and efficacy trial, and only limited data are available regarding Lyme disease vaccine use in such patients.\n- Persons with a Previous History of Lyme Disease -Vaccination should be considered for persons with a history of previous uncomplicated Lyme disease who are at continued high risk.\n-Persons who have treatment-resistant Lyme arthritis should not be vaccinated because of the association between this condition and immune reactivity to OspA.\n-Persons with chronic joint or neurologic illness related to Lyme disease, as well as second-or third-degree atrioventricular block, were excluded from the Phase III safety and efficacy trial, and thus, the safety and efficacy of Lyme disease vaccine in such persons are unknown.\n- Vaccine Schedule, Including Spacing and Timing of Administration -Three doses of the vaccine should be administered by intramuscular injection.\nThe initial dose should be followed by a second dose 1 month later and a third dose 12 months after the first dose. Vaccine administration should be timed so that the second dose of the vaccine (year 1) and the third dose (year 2) are administered several weeks before the beginning of the B. burgdorferi transmission season, which usually begins in April.\n- Boosters -Whether protective immunity will last longer than 1 year beyond the month-12 dose is unknown. Data regarding antibody levels during a 20-month period after the first injection of LYMErix indicate that boosters beyond the month-12 booster might be necessary (see Immunogenicity). Additional data are needed before recommendations regarding vaccination with more than three doses of rOspA vaccine can be made.\n\n# Simultaneous Administration with Other Vaccines\n-The safety and efficacy of the simultaneous administration of rOspA vaccine with other vaccines have not been established. If LYMErix must be administered concurrently with other vaccines, each vaccine should be administered in a separate syringe at a separate injection site.\n\n# FUTURE CONSIDERATIONS\n\n# Recommendations for Surveillance, Research, Education, and Program Evaluation Activities\n- Determine safety, immunogenicity, and efficacy of Lyme disease vaccine in children.\n- Determine optimal vaccine dosage schedules and timing of administration.\n- Determine the need for and spacing of booster doses.\n- Determine safety and efficacy of the vaccine in persons aged >70 years.\n- Develop additional serodiagnostic tests that discriminate between infection and vaccine-induced antibody production.\n- Develop a program of Lyme disease vaccine education for care providers and prospective vaccine clients.\n- Develop an information sheet to be distributed to prospective vaccine recipients or to persons at the time of vaccine administration.\n- Conduct surveillance for rare or late-developing adverse effects of vaccination.\n- Establish postlicensure epidemiologic studies of safety, efficacy, prevention effectiveness, cost-effectiveness, and patterns of use.\n- Develop a program to monitor vaccine use at the local, state, and national levels and to measure its public health and economic impact.\n- Develop population-based studies to assess the impact of vaccine use on incidence of Lyme disease in communities.\n- Continue to develop maps of geographic distribution of Lyme disease with improved accuracy and predictive power.\nexposure were compiled on a county-unit scale for the United States. Then geographic information systems (GIS) technology was used to combine these data and categorize each of the 3,140 counties into four risk classes.\n\n# ENTOMOLOGIC RISK Vector Distribution\nVector data were obtained from a national distribution map of Ixodes scapularis and I. pacificus, which was previously published by CDC (2 ). These data delineate three classes of tick distribution based on all published and unpublished county collection records available to CDC before 1998. The three classes are as follows:\n- established populations (≥6 ticks reported or more than one life stage); - reported occurrence (<6 ticks reported and only one life stage); and - absence of ticks or missing data.\nAlthough these data are currently the best source of vector distribution available, many gaps exist because of uneven sampling efforts among the counties. Therefore, a neighborhood analysis GIS procedure was used to modify the original tick distribution to smooth absent data and minimize the impact of reporting gaps. In this process, the original tick coverage map was rasterized to 1 km, and each cell was given a numeric value corresponding to the county tick class (0 = absent; 1 = reported; and 2 = established). A neighborhood analysis was performed using ERDAS IMAGINE- image-processing software. This function employed a moving filter (25 by 25 km), which summed the values of the area surrounding each 1-km pixel and created a new focally smoothed image. An outline of counties was overlaid to define boundaries on the smoothed map, and new values were summed from the total pixel values for each county. The three original vector classes were maintained with the new classification. The revised map employed a threshold reclassification based on mean summary statistics generated from the neighborhood analysis. This procedure resulted in a weighted value for each county that was determined by the classes of surrounding counties, thus smoothing the map to minimize rough edges and isolated holes in the data. The modified vector distribution increased the number of counties containing I. scapularis and I. pacificus from 1,058 counties (34% of total counties) in the original data set to 1,404 (45% of total) in the modified version. This modification resulted in greater continuity among adjacent counties, as well as a less-conservative description of vector distribution.\n\n# Infection Prevalence in Vectors\nThe prevalence of infection with B. burgdorferi is low throughout the distribution of I. pacificus (3 ) with the exception of one California county (4 ). Within the entire southern distribution of I. scapularis, prevalence of infection with B. burgdorferi is low compared with the Northeast and upper Midwest (3 ). One possible reason for these *ERDAS IMAGINE map production computer software, a product of ERDAS, Inc., 2801 Buford Highway, Atlanta, GA 30329-2137, (404) 248-9000, . The national map illustrates a clear focal pattern of Lyme disease risk with the greatest risk occurring in the Northeast and upper Midwest regions. Overall, 115 (4%) counties were classified as high risk, followed by 146 (5%) moderate risk, 1,143 (36%) low risk, and 1,736 (55%) as minimal or no-risk counties.\nLyme disease risk is measurable as a function of two epidemiologic parametersentomologic risk and human exposure. Entomologic risk for Lyme disease is defined as the density per unit area of host-seeking nymphal ticks infected with Borrelia burgdorferi (1 ). Field studies needed for determination of entomologic risk require trained entomologists, and such studies are limited to a narrow seasonal window within the life-cycle of vector ticks. Limited resources preclude the direct measurement of entomologic risk over large geographic areas; therefore, indirect measures were used to estimate risk to develop this national Lyme disease risk map. First, data on vector distribution, abundance, B. burgdorferi infection prevalence, and human\n\n# High risk\n\n# Moderate risk\n\n# Low risk\n\n# Minimal or no risk\n\n# Areas of predicted Lyme disease transmission\nNote: This map demonstrates an approximate distribution of predicted Lyme disease risk in the United States. The true relative risk in any given county compared with other counties might differ from that shown here and might change from year to year. Risk categories are defined in the accompanying text. Information on risk distribution within states and counties is best obtained from state and local public health authorities. differences is the geographic variations in abundance of hosts that are competent reservoirs of infection for immature ticks. The white-footed mouse (Peromyscus leucopus) is the principal host for ticks in the Northeast and upper Midwest and is a competent reservoir for the spirochete. But in the Southeast and West Coast regions, reptiles appear to serve as major hosts for immature ticks, and reptiles are either inefficient or incompetent reservoir hosts for spirochetes. This pattern of tick-host association might result from the greater population density of lizards relative to rodents ( 5), resulting in reduced transmission rates in regions where lizards dominate. An index was created to map the effect of host-species composition on infection prevalence in I. scapularis ticks.\n\n# National Lyme disease risk map with four categories of risk\nA literature survey was conducted to identify a complete list of hosts for I. scapularis (6 ). A total of 38 nondomestic host species was identified, including 32 mammal species and 6 reptile species. Birds were excluded because of their migratory nature and their uncertain role as natural reservoir hosts. Species range maps were obtained from the literature (7,8 ), then digitized by county into ArcView GIS- software for presence or absence of reservoir hosts. The county data were then summed to determine the total host species composition available for I. scapularis.\nA ratio of total reptiles divided by the total hosts multiplied by 100 was calculated for each county and mapped. The reptile ratio index delineates those areas having a high reptile-to-total-hosts ratio (>10) and forms a linear boundary, below which reptiles are more likely to serve as hosts for ticks. The geographic boundary runs roughly on the 38º north latitude from Virginia to Missouri. This reptile ratio illustrates that although total hosts in the northern states can be equal to those of the southern states, reptiles dilute the force of transmission, thus lowering the prevalence of infection in ticks and creating less of a risk to humans in the South.\n\n# HUMAN EXPOSURE TO RISK\nCDC case reports were used as a measure of human exposure to entomologic risk. County-specific data were compiled for the years 1994-1997. Counties comprising the ninetieth percentile of all human cases reported during this 4-year period were selected to represent counties with high human exposure. These 137 counties reported a minimum total of 23 cases. Heuristic, or procedure-based decision rule, was employed to construct the national Lyme disease risk map. Expert decision rule was applied to construct the risk classification as follows:\n\n# Risk Classes\n- High Risk. Counties where I. scapularis or I. pacificus populations are established and where prevalence of infection is predicted to be high, and which are in the top tenth percentile of counties reporting human cases during the 4-year period, 1994-1997."},"raw_text":{"kind":"string","value":"This report provides recommendations for use of a newly developed recombinant outer-surface protein A (rOspA) Lyme disease vaccine (LYMErix,™ SmithKline Beecham Pharmaceuticals) for persons aged 15-70 years in the United States. The purpose of these recommendations is to provide health-care providers, public health authorities, and the public with guidance regarding the risk for acquiring Lyme disease and the role of vaccination as an adjunct to preventing Lyme disease. The Advisory Committee on Immunization Practices recommends that decisions regarding vaccine use be made on the basis of assessment of individual risk, taking into account both geographic risk and a person's activities and behaviors relating to tick exposure. *sensu lato: including all subordinate taxa of a taxon that would otherwise be considered separately. † sensu stricto: excluding similar taxa that otherwise would be considered together.# INTRODUCTION\nLyme disease is a tickborne zoonosis caused by infection with the spirochete Borrelia burgdorferi. The number of annually reported cases of Lyme disease in the United States has increased approximately 25-fold since national surveillance began in 1982; during 1993-1997, a mean of 12,451 cases annually were reported by states to CDC (1,2, CDC, unpublished data, 1998). In the United States, the disease is primarily localized to states in the northeastern, mid-Atlantic, and upper north-central regions, and to several areas in northwestern California (1 ).\nLyme disease is a multisystem, multistage, inflammatory illness. In its early stages, Lyme disease can be treated successfully with oral antibiotics; however, untreated or inadequately treated infection can progress to late-stage complications requiring more intensive therapy. The first line of defense against Lyme disease and other tickborne illnesses is avoidance of tick-infested habitats, use of personal protective measures (e.g., repellents and protective clothing), and checking for and removing attached ticks. Early diagnosis and treatment are effective in preventing late-stage complications.\nRecently, two Lyme disease vaccines have been developed that use recombinant B. burgdorferi lipidated outer-surface protein A (rOspA) as immunogen -LYMErix,™ SmithKline Beecham Pharmaceuticals, and ImuLyme,™ Pasteur Mérieux Connaught. As of publication of this report, only LYMErix has been licensed by the U.S. Food and Drug Administration for use in the United States; therefore, these recommendations apply only to the use of that vaccine. Additional statements will be provided as other Lyme disease vaccines are licensed.\nResults of a large-scale, randomized, controlled (Phase III) trial of safety and efficacy of LYMErix in persons aged 15-70 years residing in disease-endemic areas of the northeastern and north-central United States indicate that the vaccine is safe and efficacious when administered on a three-dose schedule of 0, 1, and 12 months (3,4 ). Information regarding vaccine safety and efficacy beyond the transmission season immediately after the third dose is not available. Thus, the duration of protective immunity and need for booster doses beyond the third dose are unknown.\n# CLINICAL FEATURES OF LYME DISEASE Clinical Description\nMost often, Lyme disease is evidenced by a characteristic rash (erythema migrans) accompanied by nonspecific symptoms (e.g., fever, malaise, fatigue, headache, myalgia, and arthralgia) (5)(6)(7). The incubation period from infection to onset of erythema migrans is typically 7-14 days but can be as short as 3 days or as long as 30 days. Some infected persons have no recognized illness (i.e., asymptomatic infection determined by serologic testing), or they manifest only nonspecific symptoms (e.g., fever, headache, fatigue, and myalgia).\nLyme disease spirochetes disseminate from the site of inoculation by cutaneous, lymphatic, and bloodborne routes. The signs of early disseminated infection usually occur from days to weeks after the appearance of a solitary erythema migrans lesion. In addition to multiple or secondary erythema migrans lesions, early disseminated infection can be manifested as disease of the nervous system, the musculoskeletal system, or the heart (5)(6)(7). Early neurologic manifestations include lymphocytic meningitis; cranial neuropathy, especially facial nerve palsy; and radiculoneuritis. Musculoskeletal manifestations can include migratory joint and muscle pains with or without objective signs of joint swelling. Cardiac manifestations are rare but can include myocarditis and transient atrioventricular block of varying degree.\nB. burgdorferi infection in the untreated or inadequately treated patient can progress to late-disseminated disease from weeks to months after infection (5)(6)(7). The most common objective manifestation of late-disseminated Lyme disease is intermittent swelling and pain of one or some joints, usually large, weight-bearing joints (e.g., the knee). Some patients experience chronic axonal polyneuropathy, or encephalopathy, the latter usually manifested by cognitive disorders, sleep disturbance, fatigue, and personality changes. Infrequently, Lyme disease morbidity can be severe, chronic, and disabling (8,9 ). An ill-defined post-Lyme disease syndrome occurs in some persons after treatment for Lyme disease (10)(11)(12). Lyme disease is rarely, if ever, fatal.\n# Diagnosis\nThe diagnosis of Lyme disease is based primarily on clinical findings, and treating patients with early disease solely on the basis of objective signs and a known exposure is often appropriate (13 ). Serologic testing can, however, provide valuable supportive diagnostic information in patients with endemic exposure and objective clinical findings that indicate later-stage disseminated Lyme disease (13 ).\nWhen serologic testing is indicated, CDC recommends testing initially with a sensitive first test, either an enzyme-linked immunosorbent assay (ELISA) or an indirect fluorescent antibody test, followed by testing with the more specific Western immunoblot (WB) test to corroborate equivocal or positive results obtained with the first test (14 ). Although antibiotic treatment in early localized disease can blunt or abrogate the antibody response, patients with early disseminated or late-stage disease usually have strong serologic reactivity and demonstrate expanded WB immunoglobulin G (IgG) banding patterns to diagnostic B. burgdorferi antigens (15,16 ).\nAntibodies often persist for months or years after successfully treated or untreated infection. Thus, seroreactivity alone cannot be used as a marker of active disease. Neither positive serologic test results nor a history of previous Lyme disease ensures that a person has protective immunity. Repeated infection with B. burgdorferi has been reported (17 ).\nB. burgdorferi can be cultured from 80% or more of biopsy specimens taken from early erythema migrans lesions (18 ). However, the diagnostic usefulness of this procedure is limited because of the need for a special bacteriologic medium (i.e., modified Barbour-Stoenner-Kelly medium) and protracted observation of cultures. Polymerase chain reaction (PCR) has been used to amplify genomic DNA of B. burgdorferi in skin, blood, cerebrospinal fluid, and synovial fluid (19,20 ), but PCR has not been standardized for routine diagnosis of Lyme disease.\n# Treatment\nLyme disease can usually be treated successfully with standard antibiotic regimens (5,6 ). Early and uncomplicated infection, including infection with isolated cranial nerve palsy, usually responds satisfactorily to treatment with orally administered antibiotics (21 ). Parenteral antibiotics are generally recommended for treating meningitis, carditis, later-stage neurologic Lyme disease, and complicated Lyme disease arthritis. Late, complicated Lyme disease might respond slowly or incompletely, and more than one antibiotic treatment course can be required to eliminate active infection (8,9 ). Refractory Lyme disease arthritis is associated with expression of certain Class II major histocompatibility complex (MHC II) molecules (22 ), and can require anti-inflammatory agents and surgical synovectomy for relief of symptoms (8 ). In a limited number of patients, persistent or recurrent symptoms after appropriate antibiotic therapy often can be attributed to causes other than persistent infection (22,23 ).\n# EPIDEMIOLOGY OF LYME DISEASE Antigenic Variation of B. burgdorferi Sensu Lato*\nIn the United States, a number of genospecies of B. burgdorferi sensu lato have been isolated from animals and ticks, but only OspA expressing B. burgdorferi sensu stricto † has been isolated from humans (24 ). Existing evidence also demonstrates that rOspA vaccines will be protective against most if not all human infections in the United States (25 ). B. burgdorferi sensu stricto also occurs in Europe, but the dominant European and Asian genospecies are B. garinii and B. afzelii, both of which are antigenically distinct from B. burgdorferi sensu stricto (26 ) and vary in their expression of OspA. Vaccines using combinations of immunogenic proteins might be necessary to provide protection against multiple genospecies (27 ).\n# Routes of Transmission\nHumans acquire B. burgdorferi infection from infected ticks at the time the tick takes a blood meal (28 ); Lyme disease is not spread by person-to-person contact or by direct contact with infected animals. Transplacental transmission of B. burgdorferi has been reported (29,30 ), but the effects of such transmission on the fetus remain unclear. The results of two epidemiologic studies document that congenital Lyme disease must be rare, if it occurs at all (31,32 ). Transmission in breast milk has not been described. B. burgdorferi can be cultured from the blood in some patients with early acute infection, and it is able to survive for several weeks in stored blood. However, at least one study has found that the risk for transfusion-acquired infection is minimal (33 ).\n# Tick Vectors of Lyme Disease\nB. burgdorferi is transmitted to humans by ticks of the Ixodes ricinus complex (34 ). I. scapularis, the black-legged or deer tick, is the vector in the eastern United States; I. pacificus, the western black-legged tick, transmits B. burgdorferi in the western United States (35,36 ). I. scapularis is also a vector for human granulocytic ehrlichiosis and babesiosis (34,37 ). In their nymphal stage, these ticks feed predominantly in the late spring and early summer. The majority of Lyme disease cases result from bites by infected nymphs. In highly enzootic areas of the United States, approximately 15%-30% of questing I. scapularis nymphs and up to 14% of I. pacificus nymphs are infected with B. burgdorferi (38)(39)(40)(41). However, in the southern United States, the prevalence of infection in I. scapularis ticks is generally 0%-3% (36 ). The risk for acquiring Lyme disease in the United States varies with the distribution, density, and prevalence of infection in vector ticks (Appendix).\nDuring the past several decades, the distribution of I. scapularis has spread slowly in the northeastern and upper north-central regions of the United States (42 ). Although deer are not competent reservoirs of B. burgdorferi, they are the principal maintenance hosts for adult black-legged ticks, and the presence of deer appears to be a prerequisite for the establishment of I. scapularis in any area (43 ). The explosive repopulation in the eastern United States by white-tailed deer during recent decades has been linked to the spread of I. scapularis ticks and of Lyme disease in this region. The future limits of this spread are not known (42 ).\n# Distribution of Human Cases of Lyme Disease\nLyme disease is endemic in several regions in the United States, Canada, and temperate Eurasia (1,44 ). The disease accounts for more than 95% of all reported cases of vectorborne illness in the United States. Using a national surveillance case definition (45 ), state health officials reported >62,000 cases to CDC during 1993-1997, and the national mean annual rate during this 5-year period was 5.5 cases/100,000 population (1,2, CDC, unpublished data, 1998). Persons of all ages are equally susceptible to infection, although the highest reported rates of Lyme disease occur in children aged <15 years and in adults aged 30-59 years (1 ). Both underreporting and overdiagnosis are common (46)(47)(48). Approximately 90% of cases are reported by approximately 140 counties located along the northeastern and mid-Atlantic seaboard and in the upper north-central region of the United States (Appendix).\nA rash similar to erythema migrans of Lyme disease, but not caused by B. burgdorferi infection, has been described in patients who have been bitten by ticks in the southern United States (49,50 ). This rash is suspected of being associated with the bite of Amblyomma americanum ticks (51 ).\n# Populations at Risk for Lyme Disease\nMost B. burgdorferi infections result from periresidential exposure to infected ticks (38,(52)(53)(54)(55) during property maintenance, recreation, and leisure activities. Thus, persons who live or work in residential areas surrrounded by woods or overgrown brush infested by vector ticks are at risk for acquiring Lyme disease. In addition, persons who participate in recreational activities away from home (e.g., hiking, camping, fishing, and hunting) in tick habitat and persons who engage in outdoor occupations (e.g., landscaping, brush clearing, forestry, and wildlife and parks management) in endemic areas might also be at elevated risk for acquiring Lyme disease (56)(57)(58).\n# PREVENTION AND CONTROL OF LYME DISEASE\n\n# Avoidance of Tick Habitat\nWhenever possible, persons should avoid entering areas that are likely to be infested with ticks, particularly in spring and summer when nymphal ticks feed. Ticks favor a moist, shaded environment, especially that provided by leaf litter and lowlying vegetation in wooded, brushy, or overgrown grassy habitat. Both deer and rodent hosts must be abundant to maintain the enzootic cycle of B. burgdorferi. Sources of information regarding the distribution of ticks in an area include state and local health departments, park personnel, and agricultural extension services.\n# Personal Protection\nPersons who are exposed to tick-infested areas should wear light-colored clothing so that ticks can be spotted more easily and removed before becoming attached. Wearing long-sleeved shirts and tucking pants into socks or boot tops can help keep ticks from reaching the skin. Ticks are usually located close to the ground, so wearing high rubber boots can provide additional protection. Applying insect repellents containing DEET (n,n-diethyl-m-toluamide) to clothes and exposed skin and applying permethrin, which kills ticks on contact, to clothes, should also help reduce the risk of tick attachment. DEET can be used safely on children and adults but should be applied according to the U.S. Environmental Protection Agency guidelines to reduce the possibility of toxicity (59 ). Because transmission of B. burgdorferi from an infected tick is unlikely to occur before 36 hours of tick attachment (28,60 ), daily checks for ticks and their prompt removal will help prevent infection.\n# Strategies for Reducing Tick Abundance\nThe number of ticks in endemic residential areas can be reduced by removing leaf litter, brush, and woodpiles around houses and at the edges of yards and by clearing trees and brush to admit more sunlight, thus reducing deer, rodent, and tick habitat (61 ). Tick populations have also been effectively suppressed by applying pesticides to residential properties (62,63 ). Community-based interventions to reduce deer populations or to kill ticks on deer and rodents have not been extensively implemented, but might be effective in reducing communitywide risk for Lyme disease (64 ). The effectiveness of deer feeding stations equipped with pesticide applicators to kill ticks on deer and other baited devices to kill ticks on rodents is currently under evaluation.\n# Prophylaxis After Tick Bite\nThe relative cost-effectiveness of postexposure treatment of tick bites to avoid Lyme disease in endemic areas is dependent on the probability of B. burgdorferi infection after a tick bite (65 ). In most circumstances, treating persons for tick bite alone is not recommended (6,66 ). Persons who are bitten by a deer tick should remove the tick and seek medical attention if any signs and symptoms of early Lyme disease, ehrlichiosis, or babesiosis develop during the ensuing days or weeks.\n# Early Diagnosis and Treatment\nLyme disease is readily treatable in its early stages (5,6 ). The early diagnosis and proper antibiotic treatment of Lyme disease are important strategies for avoiding the morbidity and costs of complicated and late-stage illness.\n# LYME DISEASE VACCINE Description\nLYMErix is made from lipidated rOspA of B. burgdorferi sensu stricto. The rOspA protein is expressed in Escherichia coli and purified. Each 0.5-mL dose of LYMErix contains 30 µg of purified rOspA lipidated protein adsorbed onto aluminum hydroxide adjuvant.\n# Mechanism of Action\nSeveral studies in animals have provided evidence that B. burgdorferi in a vector tick undergoes substantial antigenic change between the time of tick attachment on a mammalian host and subsequent transmission of the bacterium to the host. The spirochetes residing in the tick gut at the initiation of tick feeding express primarily OspA. As tick feeding begins, the expression of outer-surface protein C (OspC) is increased and the expression of OspA is decreased, so that spirochetes that reach the mammalian host after passing through the tick salivary glands express primarily OspC (67 ).\nThus, the rOspA vaccine might exert its principal protective effect by eliciting antibodies that kill Lyme disease spirochetes within the tick gut (68,69 ).\n# Route of Administration, Vaccination Schedule, and Dosage\nLYMErix is administered by intramuscular injection, 0.5 mL (30 µg), into the deltoid muscle. Three doses are required for optimal protection. The first dose is followed by a second dose 1 month later and a third dose administered 12 months after the first dose. Vaccine administration should be timed so that the second dose of the vaccine (year 1) and the third dose (year 2) are administered several weeks before the beginning of the B. burgdorferi transmission season, which usually begins in April. The safety and immunogenicity of alternate dosing schedules are currently being evaluated.\n# VACCINE PERFORMANCE\n\n# Safety\n\n# Randomized, Controlled Clinical (Phase III) Trial of LYMErix\nA total of 10,936 subjects aged 15-70 years living in Lyme disease-endemic areas were recruited at 31 sites and randomized to receive three doses of vaccine or placebo (3 ); 5,469 subjects received at least one 30-µg dose of rOspA vaccine, and 5,467 subjects received at least one injection of placebo. The subjects were then followed for 20 months. Information regarding adverse events that were believed to be related or possibly related to injection were available from 4,999 subjects in each group. Soreness at the injection site was the most frequently reported adverse event, which was reported without solicitation by 24.1% of vaccine recipients and 7.6% of placebo recipients (p < 0.001). Redness and swelling at the injection site were reported by <2% of either group but were reported more frequently among vaccine recipients than among those who received placebo (p < 0.001). Myalgia, influenza-like illness, fever, and chills were more common among vaccine recipients than placebo recipients (p < 0.001), but none of these was reported by more than 3.2% of subjects (3 ). Reports of arthritis were not significantly different between vaccine and placebo recipients, but vaccine recipients were significantly (p < 0.05) more likely to report arthralgia or myalgia within 30 days after each dose (70 ). No statistically significant differences existed between vaccine and placebo groups in the incidence of adverse events more than 30 days after receiving a dose, and no episodes of immediate hypersensitivity among vaccine recipients were noted (3 ).\n# Safety in Patients with Previously Diagnosed Lyme Disease\nThe safety of three different dosage strengths of rOspA vaccine with adjuvant in 30 adults with previous Lyme disease was evaluated in an uncontrolled safety and immunogenicity trial (71 ). Doses were administered at 0, 1, and 2 months. Follow-up of subjects was conducted 1 month after the third dose. No serious adverse events were recorded during the study period.\nIn the randomized controlled Phase III trial of LYMErix, the incidence of adverse events among vaccinees who were seropositive at baseline was similar to the incidence among those who were seronegative (70 ). The incidence of musculoskeletal symptoms within the first 30 days after vaccination was higher among vaccinees with a self-reported previous history of Lyme disease compared with vaccinees with no such history. This difference was not statistically significant at the p = 0.05 level in the placebo group. No statistically significant difference existed in the incidence of late musculoskeletal adverse events between vaccine and placebo recipients with a selfreported previous history of Lyme disease (70 ).\n# Risk for Possible Immunopathogenicity of rOspA Vaccine\nAfter infection with B. burgdorferi, persons who express certain MHC II molecules are more likely than others to develop chronic, poorly responsive Lyme arthritis associated with high levels of antibody to OspA in serum and synovial fluid (22 ). In chronic Lyme arthritis patients, the levels of antibody to OspA, and especially to the C-terminal epitope of OspA, have been found to correlate directly with the severity and duration of the arthritis (72 ). Researchers have proposed that an autoimmune reaction might develop within the joints of some Lyme arthritis patients as a result of molecular mimicry between the dominant T-cell epitope of OspA and human leukocyte function associated antigen 1 (hLFA-1) (73 ). The Phase III trial did not detect differences in the incidence of neurologic or rheumatologic disorders between vaccine recipients and their placebo controls during the 20 months after the initial dose (3 ). However, because the association between immune reactivity to OspA and treatment-resistant Lyme arthritis is poorly understood, the vaccine should not be administered to persons with a history of treatment-resistant Lyme arthritis.\n# Efficacy Randomized, Controlled Trial (Phase III) of LYMErix\nUsing an intention-to-treat analysis, the vaccine efficacy in protecting against \"definite\" Lyme disease after two doses was 49% (95% confidence interval [CI] = 15%-69%) and after three doses was 76% (95% CI = 58%-86%) (3 ). (In this study, \"definite\" Lyme disease was defined as the presence of erythema migrans or objective neurologic, musculoskeletal, or cardiovascular manifestations of Lyme disease, plus laboratory confirmation of infection by cultural isolation, PCR positivity, or WB seroconversion.) Efficacy in protecting against asymptomatic infection (no recognized symptoms, but with WB seroconversions recorded in year 1 or year 2) was 83% (95% CI = 32%-97%) in year 1 and 100% (95% CI = 26%-100%) in year 2.\n# Immunogenicity\nA subset of adult subjects enrolled in the Phase III clinical trial of LYMErix was studied for the development of OspA antibodies at months 2, 12, 13, and 20 (3 ). At month 2, one month after the second injection, the geometric mean antibody titer (GMT) of IgG anti-OspA antibodies was 1,227 ELISA units/mL. Ten months later, the GMT had declined to 116 ELISA units/mL. At month 13, one month after the third injection, a marked anamnestic response resulted in a GMT of 6,006 ELISA units/mL. At month 20, the mean response had decreased to 1,991 ELISA units/mL (70 ). An analysis of antibody titers and the risk for developing Lyme disease for a subset of subjects enrolled in the Phase III clinical trial concluded that a titer >1,200 ELISA units/mL correlated with protection (SmithKline Beecham poster at Infectious Disease Society of America Conference, Denver, Colorado, November 1998).\n# Effect of Vaccination on the Serologic Diagnosis of Lyme Disease\nCare providers and laboratorians should be advised that vaccine-induced anti-rOspA antibodies routinely cause false-positive ELISA results for Lyme disease (74 ). Experienced laboratory workers, through careful interpretation of the results of WB, can usually discriminate between B. burgdorferi infection and previous rOspA immunization, because anti-OspA antibodies do not develop after natural infection.\n# COST-EFFECTIVENESS OF LYME DISEASE VACCINATION\nThe cost of Lyme disease has been evaluated from both a societal and a thirdparty-payer perspective (75 ). The cost-effectiveness of vaccinating against Lyme disease has also been analyzed from a societal perspective (76 ). At an assumed cost of vaccination of $100/person/year, a vaccine effectiveness of 0.85, a probability of 0.85 of correctly identifying and treating early Lyme disease, and an assumed incidence of Lyme disease of 1,000/100,000 persons/year, the net cost of vaccination to society was $5,692/case averted and $35,375/complicated neurologic or arthritic case avoided (Figure 1). Using these same baseline assumptions, the societal cost of vaccination exceeds the cost of not vaccinating, unless the incidence of Lyme disease is >1,973/100,000 persons/year. Of the variables examined, the incidence of Lyme disease had the greatest impact on cost-effectiveness of vaccination. The likelihood of early diagnosis and treatment also has a substantial impact on vaccine costeffectiveness because of the reduced incidence of sequelae when Lyme disease is diagnosed and patients are treated early in the disease.\nMost disease-endemic states and counties report Lyme disease incidence that are substantially below 1,000/100,000 persons/year. For example, in 1997, the highest reported state incidence was 70/100,000 persons in Connecticut, and the highest reported county incidence was 600/100,000 population in Nantucket County, Massachusetts. However, some studies document that approximately 10%-15% of physician-diagnosed cases of Lyme disease are reported to state authorities in highly endemic areas (46,47 ). Epidemiologic studies of populations at high risk in the northeastern United States have estimated annual incidence of >1,000/100,000 persons/ year in several communities (77)(78)(79)(80).\n# ASSESSING THE RISK FOR LYME DISEASE\nThe decision to administer Lyme disease vaccine should be made on the basis of an assessment of individual risk, which depends on a person's likelihood of being bitten by tick vectors infected with B. burgdorferi. This likelihood is primarily determined by the following:\n• density of vector ticks in the environment, which varies by place and season;\n• the prevalence of B. burgdorferi infection in vector ticks; and • the extent of person-tick contact, which is related to the type, frequency, and duration of a person's activities in a tick-infested environment.\nAssessing risk should include considering the geographic distribution of Lyme disease. The areas of highest Lyme disease risk in the United States are concentrated within some northeastern and north-central states. The risk for Lyme disease differs not only between regions and states and counties within states (Appendix), but even within counties and townships. Detailed information regarding the distribution of Lyme disease risk within specific areas is best obtained from state and local public health authorities.\nThe second step in determining Lyme disease risk is to assess a person's activities. Activities that place persons at high risk are those that involve frequent or prolonged exposure to the habitat of infected ticks at times of the year when the nymphal stages of these ticks are actively seeking hosts, which in most endemic areas is April-July. Typical habitat of Ixodes ticks are wooded, brushy, or overgrown grassy areas that are favorable for deer and the ticks' rodent hosts. Several recreational, property \n# FIGURE 1. Cost-effectiveness of Lyme disease vaccination OBJECTIVE\nThis MMWR provides recommendations regarding prevention and control of Lyme disease. These recommendations were developed by CDC staff members and the ACIP members. This report is intended to guide clinical practice and policy development related to administration of the Lyme disease vaccine. Upon completion of this educational activity, the reader should be able to describe the epidemiology of Lyme disease in the United States; list effective methods of Lyme disease prevention; describe the characteristics and use of the currently licensed Lyme disease vaccine; and recognize the most common adverse reactions following administration of Lyme disease vaccine. \n# EXPIRATION -June 4, 2000\nThe response form must be completed and returned electronically, by fax, or by mail, postmarked no later than 1 year from the publication date of this report, for eligibility to receive continuing education credit.\n# INSTRUCTIONS\n1. Read this MMWR (Vol. 48, RR-7 ), which contains the correct answers to the questions beginning on the next page. 2. Complete all registration information on the response form, including your name, mailing address, phone number, and e-mail address, if available.\n# Indicate whether you are registering for Continuing Medical Education (CME) credit, Continuing\nEducation Unit (CEU) credit, or Continuing Nursing Education (CNE) credit. 4. Select your answers to the questions, and mark the corresponding letters on the response form. To receive continuing education credit, you must answer all of the questions. Questions with more than one correct answer will instruct you to \"indicate all that are true.\" 5. Sign and date the response form. \n# MMWR Response Form for Continuing Education Credit\nJune 4, 1999 / Vol. 48 / No. RR-7\n# Recommendations for the Use of Lyme Disease Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP)\nFill in the appropriate block(s) to indicate your answer(s). To receive continuing education credit, you must answer all of the questions.\n1\n. [ ] A [ ] B [ ] C [ ] D [ ] E 2. [ ] A [ ] B [ ] C [ ] D [ ] E 3. [ ] A [ ] B [ ] C [ ] D [ ] E 4. [ ] A [ ] B [ ] C [ ] D [ ] E 5. [ ] A [ ] B [ ] C [ ] D [ ] E 6. [ ] A [ ] B [ ] C [ ] D [ ] E 7. [ ] A [ ] B [ ] C [ ] D [ ] E 8. [ ] A [ ] B [ ] C [ ] D [ ] E 9. [ ] A [ ] B [ ] C [ ] D [ ] E 10. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 11. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 12. [ ] A [ ] B [ ] C [ ] D [ ] E 13. [ ] A [ ] B [ ] C [ ] D [ ] E 14. [ ] A [ ] B [ ] C 15. [ ] A [ ] B [ ] C [ ] D [ ] E 16. [ ] A [ ] B [ ] C [ ] D [ ] E 17. [ ] A [ ] B [ ] C [ ] D [ ] E 18. [ ] A [ ] B [ ] C [ ] D [ ] E\nDetach or photocopy. 1.2 hours of CNE credit maintenance, occupational, or leisure pursuits that are carried out in tick habitat can be risky activities.\nWhen in highly endemic areas, persons can reduce their risk for Lyme disease and other tickborne illnesses by avoiding tick-infested habitats. If exposure to a tick-infested habitat cannot be avoided, persons should use repellents, wear protective clothing, and regularly check themselves for ticks.\nPersons who are unlikely to seek medical care for early manifestations of Lyme disease can be at increased risk for Lyme disease complications. Morbidity from Lyme disease can be substantially reduced by detecting and treating the infection in its early stages, because early and correct treatment usually results in a prompt and uncomplicated cure.\n# RECOMMENDATIONS FOR USE OF LYME DISEASE VACCINE\nLyme disease vaccine does not protect all recipients against infection with B. burgdorferi and offers no protection against other tickborne diseases. Vaccinated persons should continue to practice personal protective measures against ticks and should seek early diagnosis and treatment of suspected tickborne infections. Because Lyme disease is not transmitted person-to-person, use of the vaccine will not reduce risk among unvaccinated persons. Decisions regarding the use of vaccine should be based on individual assessment of the risk for exposure to infected ticks and on careful consideration of the relative risks and benefits of vaccination compared with other protective measures, including early diagnosis and treatment of Lyme disease. The risk for Lyme disease is focally distributed in the United States (Appendix). Detailed information regarding the distribution of Lyme disease risk within specific areas is best obtained from state and local public health authorities.\nThe following recommendations are made regarding use of Lyme disease vaccine: -Lyme disease vaccination may be considered for persons aged 15-70 years who are exposed to tick-infested habitat but whose exposure is neither frequent nor prolonged. The benefit of vaccination beyond that provided by basic personal protection and early diagnosis and treatment of infection is uncertain.\n•\n-Lyme disease vaccination is not recommended for persons who have minimal or no exposure to tick-infested habitat.\n• Travelers can obtain some protection from two doses of vaccine but will not achieve optimal protection until the full series of three doses has been administered. All travelers to high-or moderate-risk areas during Lyme disease transmission season should practice personal protection measures as described earlier and seek prompt diagnosis and treatment if signs or symptoms of Lyme disease develop. Lyme disease is endemic in some temperate areas of Europe and Asia; however, considerable heterogeneity of expression exists in the Eurasian strains of B. burgdorferi sensu lato that infect humans, and whether the rOspA vaccine licensed for use in the United States would protect against infection with Eurasian strains is uncertain. • Pregnant Women -Because the safety of rOspA vaccines administered during pregnancy has not been established, vaccination of women who are known to be pregnant is not recommended.\nNo evidence exists that pregnancy increases the risk for Lyme disease or its severity. Acute Lyme disease during pregnancy responds well to antibiotic therapy, and adverse fetal outcomes have not been reported in pregnant women receiving standard courses of treatment. A vaccine pregnancy registry has been established by SmithKline Beecham Pharmaceuticals. In the event that a pregnant women is vaccinated, health-care providers are encouraged to register this vaccination by calling, toll-free, (800) 366-8900, ext. 5231.\n• Persons with Immunodeficiency -Persons with immunodeficiency were excluded from the Phase III safety and efficacy trial, and no data are available regarding Lyme disease vaccine use in this group.\n# • Persons with Musculoskeletal Disease\n-Persons with diseases associated with joint swelling (including rheumatoid arthritis) or diffuse musculoskeletal pain were excluded from the Phase III safety and efficacy trial, and only limited data are available regarding Lyme disease vaccine use in such patients.\n• Persons with a Previous History of Lyme Disease -Vaccination should be considered for persons with a history of previous uncomplicated Lyme disease who are at continued high risk.\n-Persons who have treatment-resistant Lyme arthritis should not be vaccinated because of the association between this condition and immune reactivity to OspA.\n-Persons with chronic joint or neurologic illness related to Lyme disease, as well as second-or third-degree atrioventricular block, were excluded from the Phase III safety and efficacy trial, and thus, the safety and efficacy of Lyme disease vaccine in such persons are unknown.\n• Vaccine Schedule, Including Spacing and Timing of Administration -Three doses of the vaccine should be administered by intramuscular injection.\nThe initial dose should be followed by a second dose 1 month later and a third dose 12 months after the first dose. Vaccine administration should be timed so that the second dose of the vaccine (year 1) and the third dose (year 2) are administered several weeks before the beginning of the B. burgdorferi transmission season, which usually begins in April.\n• Boosters -Whether protective immunity will last longer than 1 year beyond the month-12 dose is unknown. Data regarding antibody levels during a 20-month period after the first injection of LYMErix indicate that boosters beyond the month-12 booster might be necessary (see Immunogenicity). Additional data are needed before recommendations regarding vaccination with more than three doses of rOspA vaccine can be made.\n# • Simultaneous Administration with Other Vaccines\n-The safety and efficacy of the simultaneous administration of rOspA vaccine with other vaccines have not been established. If LYMErix must be administered concurrently with other vaccines, each vaccine should be administered in a separate syringe at a separate injection site.\n# FUTURE CONSIDERATIONS\n\n# Recommendations for Surveillance, Research, Education, and Program Evaluation Activities\n• Determine safety, immunogenicity, and efficacy of Lyme disease vaccine in children.\n• Determine optimal vaccine dosage schedules and timing of administration.\n• Determine the need for and spacing of booster doses.\n• Determine safety and efficacy of the vaccine in persons aged >70 years.\n• Develop additional serodiagnostic tests that discriminate between infection and vaccine-induced antibody production.\n• Develop a program of Lyme disease vaccine education for care providers and prospective vaccine clients.\n• Develop an information sheet to be distributed to prospective vaccine recipients or to persons at the time of vaccine administration.\n• Conduct surveillance for rare or late-developing adverse effects of vaccination.\n• Establish postlicensure epidemiologic studies of safety, efficacy, prevention effectiveness, cost-effectiveness, and patterns of use.\n• Develop a program to monitor vaccine use at the local, state, and national levels and to measure its public health and economic impact.\n• Develop population-based studies to assess the impact of vaccine use on incidence of Lyme disease in communities.\n• Continue to develop maps of geographic distribution of Lyme disease with improved accuracy and predictive power.\nexposure were compiled on a county-unit scale for the United States. Then geographic information systems (GIS) technology was used to combine these data and categorize each of the 3,140 counties into four risk classes.\n# ENTOMOLOGIC RISK Vector Distribution\nVector data were obtained from a national distribution map of Ixodes scapularis and I. pacificus, which was previously published by CDC (2 ). These data delineate three classes of tick distribution based on all published and unpublished county collection records available to CDC before 1998. The three classes are as follows:\n• established populations (≥6 ticks reported or more than one life stage); • reported occurrence (<6 ticks reported and only one life stage); and • absence of ticks or missing data.\nAlthough these data are currently the best source of vector distribution available, many gaps exist because of uneven sampling efforts among the counties. Therefore, a neighborhood analysis GIS procedure was used to modify the original tick distribution to smooth absent data and minimize the impact of reporting gaps. In this process, the original tick coverage map was rasterized to 1 km, and each cell was given a numeric value corresponding to the county tick class (0 = absent; 1 = reported; and 2 = established). A neighborhood analysis was performed using ERDAS IMAGINE* image-processing software. This function employed a moving filter (25 by 25 km), which summed the values of the area surrounding each 1-km pixel and created a new focally smoothed image. An outline of counties was overlaid to define boundaries on the smoothed map, and new values were summed from the total pixel values for each county. The three original vector classes were maintained with the new classification. The revised map employed a threshold reclassification based on mean summary statistics generated from the neighborhood analysis. This procedure resulted in a weighted value for each county that was determined by the classes of surrounding counties, thus smoothing the map to minimize rough edges and isolated holes in the data. The modified vector distribution increased the number of counties containing I. scapularis and I. pacificus from 1,058 counties (34% of total counties) in the original data set to 1,404 (45% of total) in the modified version. This modification resulted in greater continuity among adjacent counties, as well as a less-conservative description of vector distribution.\n# Infection Prevalence in Vectors\nThe prevalence of infection with B. burgdorferi is low throughout the distribution of I. pacificus (3 ) with the exception of one California county (4 ). Within the entire southern distribution of I. scapularis, prevalence of infection with B. burgdorferi is low compared with the Northeast and upper Midwest (3 ). One possible reason for these *ERDAS IMAGINE map production computer software, a product of ERDAS, Inc., 2801 Buford Highway, Atlanta, GA 30329-2137, (404) 248-9000, <http://www.erdas.com>. The national map illustrates a clear focal pattern of Lyme disease risk with the greatest risk occurring in the Northeast and upper Midwest regions. Overall, 115 (4%) counties were classified as high risk, followed by 146 (5%) moderate risk, 1,143 (36%) low risk, and 1,736 (55%) as minimal or no-risk counties.\n# \nLyme disease risk is measurable as a function of two epidemiologic parametersentomologic risk and human exposure. Entomologic risk for Lyme disease is defined as the density per unit area of host-seeking nymphal ticks infected with Borrelia burgdorferi (1 ). Field studies needed for determination of entomologic risk require trained entomologists, and such studies are limited to a narrow seasonal window within the life-cycle of vector ticks. Limited resources preclude the direct measurement of entomologic risk over large geographic areas; therefore, indirect measures were used to estimate risk to develop this national Lyme disease risk map. First, data on vector distribution, abundance, B. burgdorferi infection prevalence, and human\n# High risk\n\n# Moderate risk\n\n# Low risk\n\n# Minimal or no risk\n\n# Areas of predicted Lyme disease transmission\nNote: This map demonstrates an approximate distribution of predicted Lyme disease risk in the United States. The true relative risk in any given county compared with other counties might differ from that shown here and might change from year to year. Risk categories are defined in the accompanying text. Information on risk distribution within states and counties is best obtained from state and local public health authorities. differences is the geographic variations in abundance of hosts that are competent reservoirs of infection for immature ticks. The white-footed mouse (Peromyscus leucopus) is the principal host for ticks in the Northeast and upper Midwest and is a competent reservoir for the spirochete. But in the Southeast and West Coast regions, reptiles appear to serve as major hosts for immature ticks, and reptiles are either inefficient or incompetent reservoir hosts for spirochetes. This pattern of tick-host association might result from the greater population density of lizards relative to rodents ( 5), resulting in reduced transmission rates in regions where lizards dominate. An index was created to map the effect of host-species composition on infection prevalence in I. scapularis ticks.\n# National Lyme disease risk map with four categories of risk\nA literature survey was conducted to identify a complete list of hosts for I. scapularis (6 ). A total of 38 nondomestic host species was identified, including 32 mammal species and 6 reptile species. Birds were excluded because of their migratory nature and their uncertain role as natural reservoir hosts. Species range maps were obtained from the literature (7,8 ), then digitized by county into ArcView GIS* software for presence or absence of reservoir hosts. The county data were then summed to determine the total host species composition available for I. scapularis.\nA ratio of total reptiles divided by the total hosts multiplied by 100 was calculated for each county and mapped. The reptile ratio index delineates those areas having a high reptile-to-total-hosts ratio (>10) and forms a linear boundary, below which reptiles are more likely to serve as hosts for ticks. The geographic boundary runs roughly on the 38º north latitude from Virginia to Missouri. This reptile ratio illustrates that although total hosts in the northern states can be equal to those of the southern states, reptiles dilute the force of transmission, thus lowering the prevalence of infection in ticks and creating less of a risk to humans in the South.\n# HUMAN EXPOSURE TO RISK\nCDC case reports were used as a measure of human exposure to entomologic risk. County-specific data were compiled for the years 1994-1997. Counties comprising the ninetieth percentile of all human cases reported during this 4-year period were selected to represent counties with high human exposure. These 137 counties reported a minimum total of 23 cases. Heuristic, or procedure-based decision rule, was employed to construct the national Lyme disease risk map. Expert decision rule was applied to construct the risk classification as follows:\n# Risk Classes\n• High Risk. Counties where I. scapularis or I. pacificus populations are established and where prevalence of infection is predicted to be high, and which are in the top tenth percentile of counties reporting human cases during the 4-year period, 1994-1997. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":278,"cells":{"id":{"kind":"string","value":"06de1b920cca6d89d0a2e1383657a3f65ba74c9c"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"These recommendations include information on two vaccines recently licensed for use among infants: Haemophilus b Conjugate Vaccine (PRP-T ), manufactured by Pasteur Mérieux Vaccins, and TETRAMUNE TM , manufactured by Lederle Laboratories/Praxis Biologics. This statement also updates recommendations for use of other available Haemophilus b vaccines (PRP-D ; HbOC ; and PRP-OMP ) for infants and children.# INTRODUCTION\nThe incidence of Haemophilus influenzae type b (Hib) disease in the United States has declined since the mid-1980s (1 ). Before the introduction of effective vaccines, Hib was the leading cause of bacterial meningitis and other invasive bacterial disease among children <5 years of age; approximately one in 200 children developed invasive Hib disease before the age of 5 years. Nearly all infections occurred among children <5 years of age, and approximately two thirds of all cases occurred among children <18 months of age. Meningitis occurred in approximately two thirds of children with invasive Hib disease, resulting in hearing impairment or neurologic sequelae in 15%-30%. The case-fatality rate was 2%-5% (2 ).\nIn 1985, the first Hib vaccines were licensed for use in the United States. These vaccines contained purified polyribosylribitol phosphate (PRP) capsular material from type b strains. Antibody against PRP was shown to be the primary component of serum bactericidal activity against the organism. Although the vaccine was highly effective in trials in Finland among children ≥18 months of age (3 ), postmarketing efficacy studies in the United States demonstrated variable efficacy (4,5 ). PRP vaccines were ineffective in children <18 months of age because of the T-cell-independent nature of the immune response to PRP polysaccharide (3 ).\nConjugation of the PRP polysaccharide with protein carriers confers T-celldependent characteristics to the vaccine and substantially enhances the immunologic response to the PRP antigen. By 1989, Hib conjugate vaccines (PRP-D ; HbOC ; and PRP-OMP ) were licensed for use among children ≥15 months of age. In late 1990, following two prospective studies, PRP-OMP (6 ) and HbOC (7 ) were licensed for use among infants. On the basis of findings establishing comparable immunogenicity, a third conjugate vaccine, PRP-T (ActHIB TM , OmniHIB TM ) has now been licensed for use among infants. Specific characteristics of the four conjugate vaccines available for infants and children vary (e.g., the type of protein carrier, the size of the polysaccharide, and the chemical linkage between the polysaccharide and carrier) (Table 1).\nCurrent recommendations for universal vaccination of infants require parenteral administration of three different vaccines (diphtheria-tetanus-pertussis , Hib conjugate, and hepatitis B) during two or three different visits to a health-care provider. Combination vaccines were developed to reduce the number of injections at each visit. TETRAMUNE TM is the first licensed combination vaccine that provides protection against diphtheria, tetanus, pertussis, and Hib disease.\nThis statement a) summarizes current immunogenicity and efficacy data regarding Hib conjugate vaccines, including PRP-T; b) summarizes available information regarding the safety and immunogenicity of TETRAMUNE TM ; and c) provides updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of conjugate Hib vaccines and TETRAMUNE TM for infants and children.\n\n# HIB CONJUGATE VACCINES Immunogenicity\nStudies have been performed with all four Hib conjugate vaccines to determine immunogenicity in infants 2-6 months of age. Direct comparison of studies is complicated by differing vaccination and blood collection regimens and interlaboratory variation in assays for measurement of PRP antibody. Also, the precise level of antibody required for protection against invasive disease is not clearly established. However, a geometric mean titer (GMT) of 1 µg/mL 3 weeks postvaccination correlated with protection in studies following vaccination with unconjugated PRP vaccine and suggests long-term protection from invasive disease (8 ). After three vaccinations at ages 2, 4, and 6 months, each of three Hib conjugate vaccines-HbOC, PRP-OMP, and PRP-T-produced protective levels of anticapsular antibody (9)(10)(11)(12)(13). One study reported comparative immunogenicity with PRP-OMP, HbOC, and PRP-T (12 ), and two other studies compared immunogenicity with all four conjugate vaccines (11,13 ) (Table 2). In this age group, only PRP-OMP vaccine produced a substantial increase in antibody after one dose (12,13 ). Antibody response among infants following a series of three infant vaccinations with PRP-D is limited (only 15%-45% of infants develop a GMT ≥1 µg/mL after 3 doses) (11,13,14 ) and is lower than with HbOC, PRP-OMP, or PRP-T.\nWith each conjugate vaccine, antibody levels decline after administration of the primary series. Regardless of the conjugate vaccine used in the primary series for infants, booster vaccination of children ≥12 months of age with any of the licensed conjugate vaccines will likely elicit an adequate response, as studies indicate that a) unconjugated PRP (administered at 12-14 months of age) elicits a good booster response in infants who are administered PRP-OMP (15 ), HbOC (15,16 ), or PRP-T (15,16, ) during infancy; b) PRP-D administered as a booster at age 15 months induces adequate immunologic response regardless of the Hib conjugate administered in the initial series (17 ); and c) each conjugate vaccine demonstrates adequate immunogenicity when administered as a single vaccination to children ≥15 months of age (18,19 ).\nLimited information is available regarding the interchangeability of different Hib vaccines for the primary series at 2, 4, and 6 months of age (Table 3). Preliminary findings from two studies suggest that the vaccination series consisting of PRP-OMP at 2 months, followed by either PRP-T (20,21 ) or HbOC (20,22 ) at 4 months and 6 months, induces adequate anti-PRP antibody response. The sequence HbOC, PRP-T, PRP-T was also immunogenic (20 ) after the complete primary series was administered. This information suggests that any combination of three doses of Hib conjugate vaccines licensed for use among infants will provide adequate protection.\nThe carrier proteins used in PRP-T, PRP-D, and HbOC (but not PRP-OMP) are derived from the toxoids used in DTP vaccine (Table 1). Limited data have indicated that prior or concurrent administration of DTP vaccine may enhance anti-PRP antibody response following vaccination with these Hib vaccines (23)(24)(25)(26). It has been suggested that priming T-cells to the carrier proteins may be important for optimal antibody response to the conjugated vaccine. For infants, the immunogenicity of PRP-OMP (which has a carrier derived from the meningococcal outer membrane protein) appears to be unaffected by the absence of prior or concurrent DTP vaccination (24 ).\n\n# Efficacy\nEfficacy studies of PRP-D, PRP-OMP, HbOC, and PRP-T vaccines administered to infants 2-6 months of age are summarized in this report (Table 4). Two randomized, double-blind trials evaluating PRP-T vaccine efficacy were discontinued in the United States in October 1990 after licensure was granted to HbOC and PRP-OMP vaccines. A third efficacy trial of PRP-T in England has recently been completed.\nEfficacy of the PRP-D conjugate has varied with the age of the population studied. Postlicensure studies performed in the United States among children aged 15-60 months demonstrated point estimates of efficacy ranging from 74%-96%. Two studies have prospectively evaluated efficacy of PRP-D administered to children <12 months of age. In a trial in Finland involving 114,000 infants vaccinated at 3, 4, and 6 months of age, the point estimate of efficacy was 89% (95% confidence interval = 70-96) (27 ). In comparison, among Alaskan Natives vaccinated at ages 2, 4, and 6 months, the point estimate of efficacy was 35% (95% CI = -57-73) and not significantly different from zero (28 ). PRP-OMP was shown to be 93%-100% efficacious in Navajo infants (a population at particularly high risk of disease) vaccinated at 2 and 4 months of age (6 ). Two studies have indicated a point estimate of efficacy of ≥97% following the administration of two doses of HbOC (in Finland) (29 ) or three doses of vaccine (in the United States) (7 ) to infants.\nAlthough the trials evaluating PRP-T vaccine efficacy among infants in the United States were terminated early, no cases of invasive Hib disease were reported among more than 6,200 vaccinees at the time of termination (30 , J.C. Parke, Carolinas Medical Center, unpublished data). In a trial in Great Britain, PRP-T was protective in infants vaccinated at ages 2, 3, and 4 months (31 ). Efficacy of PRP-T was also suggested in a nationwide immunization program that was implemented in Finland in January 1990. There were no reported cases of invasive Hib disease among more than 97,000 infants who received ≥2 doses of PRP-T. Two children developed disease after one dose of vaccine (32 ).\nIn the United States, 30-50 cases of invasive Hib disease have been reported among children who had received appropriate vaccination with the Hib conjugate vaccine and therefore were expected to have had adequate levels of protective antibody (33)(34)(35). These cases may represent vaccine failure. Results of immunologic evaluation of children who had vaccine failure vary with the age of the child. In a study of children vaccinated with Hib conjugate vaccine at age ≥15 months, subnormal immunoglobulin concentrations were present in approximately 40% of those who developed invasive Hib disease (33 ). However, in a separate study that evaluated fully vaccinated children <12 months of age who developed invasive Hib disease, only 9% had evidence of low immunoglobulin levels (34 ).\n\n# COMBINATION VACCINES TETRAMUNE TM\nOn March 30, 1993, the Food and Drug Administration licensed TETRAMUNE TM , a vaccine manufactured by Lederle Laboratories/Praxis Biologics by combining a licensed DTP vaccine (TRI-IMMUNOL ® ) and HbOC (HibTITER ® ). TETRAMUNE TM contains 12.5 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, an estimated 4 protective units of pertussis vaccine, 10 µg of purified Hib polysaccharide, and approximately 25 µg of CRM197 protein. The single-dose volume is 0.5 mL to be administered intramuscularly.\n\n# Safety and Immunogenicity\nThe safety of TETRAMUNE TM vaccine was evaluated in a study of 6,497 infants in California who received doses at ages 2, 4, and 6 months, compared with 3,935 infants who received DTP (TRI-IMMUNOL ® ) and HbOC vaccines as separate concurrent injections (36, Lederle Laboratories/Praxis Biologics, unpublished data). Based on follow-up of a randomized subset of 1,411 infants (for whom 1,347 parents were interviewed), the risk for local and systemic reactions was similar for infants who received the combination product when compared with those who received two separate injections of DTP and HbOC. The infants who received the combination vaccine, however, experienced a higher likelihood of restless sleep following the second dose and ≥1 inch of swelling at the injection site after administration of the first dose of the combination vaccine (Table 5).\nImmunogenicity studies among infants who received TETRAMUNE TM at ages 2, 4, and 6 months (37, Lederle Laboratories/Praxis Biologics, unpublished data) indicated that antibody responses to Hib PRP, diphtheria, and tetanus toxins were comparable to or higher than those in persons who received separate, but concurrent administration of DTP and HbOC vaccines. Similarly, antibody responses to pertussis toxin, filamentous hemagglutinin, 69-kd outer-membrane protein (pertactin), and pertussis agglutinins were comparable to or higher than those following separate concurrent administration of DTP and HbOC vaccines (Table 6). Comparable immunogenicity results also were reported for children aged 15-18 months (who had received prior doses of DTP, but not Hib vaccine) following a dose of TETRAMUNE TM when compared with separate but concurrent administration of DTP and HbOC vaccines.\n\n# Efficacy\nNo efficacy information is available for TETRAMUNE TM , but the immunogenicity information suggests TETRAMUNE TM will provide similar protection against Hib disease and diphtheria, tetanus, and pertussis as will the separate administration of HbOC or DTP vaccines.\n\n# Other combination vaccines\nPublished studies have evaluated the safety and immunogenicity of other vaccines that combine DTP (or DTaP ) and Hib in the same formulation or the same syringe. However, none of these formulations (PRP-D-DTaP , HbOC-DTaP , or PRP-T-DTP ) have been licensed for use. Two studies have shown a slight reduction in the immune response to pertussis when certain Hib vaccines were combined with DTP (42,43 ), but the magnitude of the effect is unlikely to be clinically relevant.\n\n# Simultaneous vaccination\nLarge prelicensure and postlicensure studies have demonstrated the safety, immunogenicity, and efficacy of each of the licensed Hib conjugate vaccines administered to infants concurrently with DTP vaccine and oral polio vaccine (OPV) (6,7,9,32 ) as well as the safety and immunogenicity of TETRAMUNE TM when administered concurrently with OPV in recommended schedules (36,37 ). More limited data also support the safety and immunogenicity of Hib conjugate vaccines when administered simultaneously with hepatitis B vaccine to infants, and with DTP, OPV, measles, mumps, and rubella (MMR) and/or hepatitis B vaccine when administered at ages 12-18 months.\n\n# Recommendations for Hib Vaccination General\nAll infants should receive a conjugate Hib vaccine (separate or in combination with DTP ), beginning at age 2 months (but not earlier than 6 weeks). If the first vaccination is delayed beyond age 6 months, the schedule of vaccination for previously unimmunized children should be followed (Table 7). When possible, the Hib conjugate vaccine used at the first vaccination should be used for all subsequent vaccinations in the primary series. When either Hib vaccines or TETRAMUNE TM is used, the vaccine should be administered intramuscularly using a separate syringe and administered at a separate site from any other concurrent vaccinations.\n\n# HbOC or PRP-T\nPreviously unvaccinated infants aged 2-6 months should receive three doses of vaccine administered 2 months apart, followed by a booster dose at age 12-15 months, at least 2 months after the last vaccination. Unvaccinated children ages 7-11 months should receive two doses of vaccine, 2 months apart, followed by a booster dose at age 12-18 months, at least 2 months after the last vaccination. Unvaccinated children ages 12-14 months should receive two doses of vaccine, at least 2 months apart. Any previously unvaccinated child aged 15-59 months should receive a single dose of vaccine.\n\n# PRP-OMP\nPreviously unvaccinated infants ages 2-6 months should receive two doses of vaccine administered at least 2 months apart. Although PRP-OMP induces a substantial antibody response after one dose, all children should receive all recommended doses of PRP-OMP. Because of the substantial antibody response after one dose, it may be advantageous to use PRP-OMP vaccine in populations that are known to be at increased risk for disease during early infancy (e.g., Alaskan Natives). A booster dose should be administered to all children at 12-15 months of age at least 2 months after the last vaccination. Unvaccinated children ages 7-11 months should receive two doses of vaccine, 2 months apart, followed by a booster dose at 12-18 months of age, at least 2 months after the last dose. Unvaccinated children ages 12-14 months should receive two doses of vaccine, 2 months apart. Any previously unvaccinated child 15-59 months of age should receive a single dose of vaccine.\n\n# PRP-D\nOne dose of PRP-D may be administered to unvaccinated children aged 15-59 months. This vaccine may be used as a booster dose at 12-18 months of age following a two-or three-dose primary series, regardless of the vaccine used in the primary series. This vaccine is not licensed for use among infants because of its limited immunogenicity and variable protective efficacy in this age group.\n\n# TETRAMUNE TM\nThe combination vaccine TETRAMUNE TM may be used for routine vaccination of infants, beginning at age 2 months, to prevent diphtheria, tetanus, pertussis, and invasive Hib disease. Previously unvaccinated infants aged 2-6 months should receive three doses administered at least 2 months apart. An additional dose should be administered at 12-15 months of age, after at least a 6-month interval following the third dose. Alternatively, acellular DTP and Hib vaccine can be administered as separate injections at 12-15 months of age. Acellular DTP is preferred for doses four and five of the five-dose DTP series. For infants who begin both Hib and DTP vaccinations late (after 2 months of age), TETRAMUNE TM may be used for the first and second doses of the vaccine series. However, because delay in initiation of the DTP series does not reduce the number of required doses of DTP, additional doses of DTP without Hib are necessary to ensure that all four doses are administered. Infants ages 7-11 months who have not previously been vaccinated with DTP or Hib vaccines should receive two doses of TETRAMUNE TM , administered at least 2 months apart, followed by a dose of DTP vaccine 4-8 weeks after the second dose of TETRAMUNE TM . An additional dose of DTP and Hib vaccines should then be administered: DTP vaccine at least 6 months after the third immunizing dose against diphtheria, tetanus, and pertussis; and Hib vaccine at 12-18 months of age, at least 2 months after the last Hib dose.\nTETRAMUNE TM may be used to complete an infant immunization series started with any Hib vaccine (licensed for use in this age group) and with any DTP vaccine if both vaccines are to be administered simultaneously. Completion of the primary series using the same Hib vaccine, however, is preferable. Conversely, any DTP vaccine may be used to complete a series initiated with TETRAMUNE TM (see the general ACIP statement on Diphtheria, Tetanus and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures for further information).\n\n# Other considerations for Hib vaccination\nOther considerations for Hib vaccination are discussed in the following section:\n1) Although an interval of 2 months between doses of Hib vaccine in the primary series is recommended, an interval of 1 month is acceptable, if necessary.\n\n# Adverse reactions\nAdverse reactions to each of the four Hib conjugate vaccines are generally uncommon. Swelling, redness, and/or pain have been reported in 5%-30% of recipients and usually resolve within 12-24 hours. Systemic reactions such as fever and irritability are infrequent. Available information on side effects and adverse reactions suggests that the risks for local and systemic events following TETRAMUNE TM administration are similar to those following concurrent administration of its individual component vaccines (i.e., DTP and Hib vaccines), and may be due largely to the pertussis component of the DTP vaccine (52 ).\nSurveillance regarding the safety of TETRAMUNE TM , PRP-T, and other Hib vaccines in large-scale use aids in the assessment of vaccine safety by identifying potential events that may warrant further study. The Vaccine Adverse Event Reporting System (VAERS) of the U.S. Department of Health and Human Services encourages reports of all serious adverse events that occur after receipt of any vaccine.- Invasive Hib disease is a reportable condition in 43 states. All health-care workers should report any case of invasive Hib disease to local and state health departments.\n\n# Contraindications and Precautions\nVaccination with a specific Hib conjugate vaccine is contraindicated in persons known to have experienced anaphylaxis following a prior dose of that vaccine. Vaccination should be delayed in children with moderate or severe illnesses. Minor illnesses (e.g., mild upper-respiratory infection) are not contraindications to vaccination.\nContraindications and precautions of the use of TETRAMUNE TM are the same as those for its individual component vaccines (i.e., DTP or Hib) (see the general ACIP statement on Diphtheria, Tetanus, and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures for more details on the use of vaccines containing DTP).\nThe following CDC staff members prepared this report:\n\n# Advisory Committee on Immunization Practices\nMembership List, October 1993 -Continued"},"raw_text":{"kind":"string","value":"These recommendations include information on two vaccines recently licensed for use among infants: Haemophilus b Conjugate Vaccine (PRP-T [ActHIB TM , OmniHIB TM ]), manufactured by Pasteur Mérieux Vaccins, and TETRAMUNE TM , manufactured by Lederle Laboratories/Praxis Biologics. This statement also updates recommendations for use of other available Haemophilus b vaccines (PRP-D [ProHIBiT ® ]; HbOC [HibTITER ® ]; and PRP-OMP [PedvaxHIB ® ]) for infants and children.# INTRODUCTION\nThe incidence of Haemophilus influenzae type b (Hib) disease in the United States has declined since the mid-1980s (1 ). Before the introduction of effective vaccines, Hib was the leading cause of bacterial meningitis and other invasive bacterial disease among children <5 years of age; approximately one in 200 children developed invasive Hib disease before the age of 5 years. Nearly all infections occurred among children <5 years of age, and approximately two thirds of all cases occurred among children <18 months of age. Meningitis occurred in approximately two thirds of children with invasive Hib disease, resulting in hearing impairment or neurologic sequelae in 15%-30%. The case-fatality rate was 2%-5% (2 ).\nIn 1985, the first Hib vaccines were licensed for use in the United States. These vaccines contained purified polyribosylribitol phosphate (PRP) capsular material from type b strains. Antibody against PRP was shown to be the primary component of serum bactericidal activity against the organism. Although the vaccine was highly effective in trials in Finland among children ≥18 months of age (3 ), postmarketing efficacy studies in the United States demonstrated variable efficacy (4,5 ). PRP vaccines were ineffective in children <18 months of age because of the T-cell-independent nature of the immune response to PRP polysaccharide (3 ).\nConjugation of the PRP polysaccharide with protein carriers confers T-celldependent characteristics to the vaccine and substantially enhances the immunologic response to the PRP antigen. By 1989, Hib conjugate vaccines (PRP-D [ProHIBiT ® ]; HbOC [HibTITER ® ]; and PRP-OMP [PedvaxHIB ® ]) were licensed for use among children ≥15 months of age. In late 1990, following two prospective studies, PRP-OMP (6 ) and HbOC (7 ) were licensed for use among infants. On the basis of findings establishing comparable immunogenicity, a third conjugate vaccine, PRP-T (ActHIB TM , OmniHIB TM ) has now been licensed for use among infants. Specific characteristics of the four conjugate vaccines available for infants and children vary (e.g., the type of protein carrier, the size of the polysaccharide, and the chemical linkage between the polysaccharide and carrier) (Table 1).\nCurrent recommendations for universal vaccination of infants require parenteral administration of three different vaccines (diphtheria-tetanus-pertussis [DTP], Hib conjugate, and hepatitis B) during two or three different visits to a health-care provider. Combination vaccines were developed to reduce the number of injections at each visit. TETRAMUNE TM is the first licensed combination vaccine that provides protection against diphtheria, tetanus, pertussis, and Hib disease.\nThis statement a) summarizes current immunogenicity and efficacy data regarding Hib conjugate vaccines, including PRP-T; b) summarizes available information regarding the safety and immunogenicity of TETRAMUNE TM ; and c) provides updated recommendations from the Advisory Committee on Immunization Practices (ACIP) for use of conjugate Hib vaccines and TETRAMUNE TM for infants and children.\n# HIB CONJUGATE VACCINES Immunogenicity\nStudies have been performed with all four Hib conjugate vaccines to determine immunogenicity in infants 2-6 months of age. Direct comparison of studies is complicated by differing vaccination and blood collection regimens and interlaboratory variation in assays for measurement of PRP antibody. Also, the precise level of antibody required for protection against invasive disease is not clearly established. However, a geometric mean titer (GMT) of 1 µg/mL 3 weeks postvaccination correlated with protection in studies following vaccination with unconjugated PRP vaccine and suggests long-term protection from invasive disease (8 ). After three vaccinations at ages 2, 4, and 6 months, each of three Hib conjugate vaccines-HbOC, PRP-OMP, and PRP-T-produced protective levels of anticapsular antibody (9)(10)(11)(12)(13). One study reported comparative immunogenicity with PRP-OMP, HbOC, and PRP-T (12 ), and two other studies compared immunogenicity with all four conjugate vaccines (11,13 ) (Table 2). In this age group, only PRP-OMP vaccine produced a substantial increase in antibody after one dose (12,13 ). Antibody response among infants following a series of three infant vaccinations with PRP-D is limited (only 15%-45% of infants develop a GMT ≥1 µg/mL after 3 doses) (11,13,14 ) and is lower than with HbOC, PRP-OMP, or PRP-T.\nWith each conjugate vaccine, antibody levels decline after administration of the primary series. Regardless of the conjugate vaccine used in the primary series for infants, booster vaccination of children ≥12 months of age with any of the licensed conjugate vaccines will likely elicit an adequate response, as studies indicate that a) unconjugated PRP (administered at 12-14 months of age) elicits a good booster response in infants who are administered PRP-OMP (15 ), HbOC (15,16 ), or PRP-T (15,16, ) during infancy; b) PRP-D administered as a booster at age 15 months induces adequate immunologic response regardless of the Hib conjugate administered in the initial series (17 ); and c) each conjugate vaccine demonstrates adequate immunogenicity when administered as a single vaccination to children ≥15 months of age (18,19 ).\nLimited information is available regarding the interchangeability of different Hib vaccines for the primary series at 2, 4, and 6 months of age (Table 3). Preliminary findings from two studies suggest that the vaccination series consisting of PRP-OMP at 2 months, followed by either PRP-T (20,21 ) or HbOC (20,22 ) at 4 months and 6 months, induces adequate anti-PRP antibody response. The sequence HbOC, PRP-T, PRP-T was also immunogenic (20 ) after the complete primary series was administered. This information suggests that any combination of three doses of Hib conjugate vaccines licensed for use among infants will provide adequate protection.\nThe carrier proteins used in PRP-T, PRP-D, and HbOC (but not PRP-OMP) are derived from the toxoids used in DTP vaccine (Table 1). Limited data have indicated that prior or concurrent administration of DTP vaccine may enhance anti-PRP antibody response following vaccination with these Hib vaccines (23)(24)(25)(26). It has been suggested that priming T-cells to the carrier proteins may be important for optimal antibody response to the conjugated vaccine. For infants, the immunogenicity of PRP-OMP (which has a carrier derived from the meningococcal outer membrane protein) appears to be unaffected by the absence of prior or concurrent DTP vaccination (24 ).\n# Efficacy\nEfficacy studies of PRP-D, PRP-OMP, HbOC, and PRP-T vaccines administered to infants 2-6 months of age are summarized in this report (Table 4). Two randomized, double-blind trials evaluating PRP-T vaccine efficacy were discontinued in the United States in October 1990 after licensure was granted to HbOC and PRP-OMP vaccines. A third efficacy trial of PRP-T in England has recently been completed.\nEfficacy of the PRP-D conjugate has varied with the age of the population studied. Postlicensure studies performed in the United States among children aged 15-60 months demonstrated point estimates of efficacy ranging from 74%-96%. Two studies have prospectively evaluated efficacy of PRP-D administered to children <12 months of age. In a trial in Finland involving 114,000 infants vaccinated at 3, 4, and 6 months of age, the point estimate of efficacy was 89% (95% confidence interval [CI] = 70-96) (27 ). In comparison, among Alaskan Natives vaccinated at ages 2, 4, and 6 months, the point estimate of efficacy was 35% (95% CI = -57-73) and not significantly different from zero (28 ). PRP-OMP was shown to be 93%-100% efficacious in Navajo infants (a population at particularly high risk of disease) vaccinated at 2 and 4 months of age (6 ). Two studies have indicated a point estimate of efficacy of ≥97% following the administration of two doses of HbOC (in Finland) (29 ) or three doses of vaccine (in the United States) (7 ) to infants.\nAlthough the trials evaluating PRP-T vaccine efficacy among infants in the United States were terminated early, no cases of invasive Hib disease were reported among more than 6,200 vaccinees at the time of termination (30 , J.C. Parke, Carolinas Medical Center, unpublished data). In a trial in Great Britain, PRP-T was protective in infants vaccinated at ages 2, 3, and 4 months (31 ). Efficacy of PRP-T was also suggested in a nationwide immunization program that was implemented in Finland in January 1990. There were no reported cases of invasive Hib disease among more than 97,000 infants who received ≥2 doses of PRP-T. Two children developed disease after one dose of vaccine (32 ).\nIn the United States, 30-50 cases of invasive Hib disease have been reported among children who had received appropriate vaccination with the Hib conjugate vaccine and therefore were expected to have had adequate levels of protective antibody (33)(34)(35). These cases may represent vaccine failure. Results of immunologic evaluation of children who had vaccine failure vary with the age of the child. In a study of children vaccinated with Hib conjugate vaccine at age ≥15 months, subnormal immunoglobulin concentrations were present in approximately 40% of those who developed invasive Hib disease (33 ). However, in a separate study that evaluated fully vaccinated children <12 months of age who developed invasive Hib disease, only 9% had evidence of low immunoglobulin levels (34 ).\n# COMBINATION VACCINES TETRAMUNE TM\nOn March 30, 1993, the Food and Drug Administration licensed TETRAMUNE TM , a vaccine manufactured by Lederle Laboratories/Praxis Biologics by combining a licensed DTP vaccine (TRI-IMMUNOL ® ) and HbOC (HibTITER ® ). TETRAMUNE TM contains 12.5 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, an estimated 4 protective units of pertussis vaccine, 10 µg of purified Hib polysaccharide, and approximately 25 µg of CRM197 protein. The single-dose volume is 0.5 mL to be administered intramuscularly.\n# Safety and Immunogenicity\nThe safety of TETRAMUNE TM vaccine was evaluated in a study of 6,497 infants in California who received doses at ages 2, 4, and 6 months, compared with 3,935 infants who received DTP (TRI-IMMUNOL ® ) and HbOC vaccines as separate concurrent injections (36, Lederle Laboratories/Praxis Biologics, unpublished data). Based on follow-up of a randomized subset of 1,411 infants (for whom 1,347 parents were interviewed), the risk for local and systemic reactions was similar for infants who received the combination product when compared with those who received two separate injections of DTP and HbOC. The infants who received the combination vaccine, however, experienced a higher likelihood of restless sleep following the second dose and ≥1 inch of swelling at the injection site after administration of the first dose of the combination vaccine (Table 5).\nImmunogenicity studies among infants who received TETRAMUNE TM at ages 2, 4, and 6 months (37, Lederle Laboratories/Praxis Biologics, unpublished data) indicated that antibody responses to Hib PRP, diphtheria, and tetanus toxins were comparable to or higher than those in persons who received separate, but concurrent administration of DTP and HbOC vaccines. Similarly, antibody responses to pertussis toxin, filamentous hemagglutinin, 69-kd outer-membrane protein (pertactin), and pertussis agglutinins were comparable to or higher than those following separate concurrent administration of DTP and HbOC vaccines (Table 6). Comparable immunogenicity results also were reported for children aged 15-18 months (who had received prior doses of DTP, but not Hib vaccine) following a dose of TETRAMUNE TM when compared with separate but concurrent administration of DTP and HbOC vaccines.\n# Efficacy\nNo efficacy information is available for TETRAMUNE TM , but the immunogenicity information suggests TETRAMUNE TM will provide similar protection against Hib disease and diphtheria, tetanus, and pertussis as will the separate administration of HbOC or DTP vaccines.\n# Other combination vaccines\nPublished studies have evaluated the safety and immunogenicity of other vaccines that combine DTP (or DTaP [acellular pertussis component]) and Hib in the same formulation or the same syringe. However, none of these formulations (PRP-D-DTaP [38 ], HbOC-DTaP [39,40 ], or PRP-T-DTP [41 ]) have been licensed for use. Two studies have shown a slight reduction in the immune response to pertussis when certain Hib vaccines were combined with DTP (42,43 ), but the magnitude of the effect is unlikely to be clinically relevant.\n# Simultaneous vaccination\nLarge prelicensure and postlicensure studies have demonstrated the safety, immunogenicity, and efficacy of each of the licensed Hib conjugate vaccines administered to infants concurrently with DTP vaccine and oral polio vaccine (OPV) (6,7,9,32 ) as well as the safety and immunogenicity of TETRAMUNE TM when administered concurrently with OPV in recommended schedules (36,37 ). More limited data also support the safety and immunogenicity of Hib conjugate vaccines when administered simultaneously with hepatitis B vaccine to infants, and with DTP, OPV, measles, mumps, and rubella (MMR) and/or hepatitis B vaccine when administered at ages 12-18 months. \n# Recommendations for Hib Vaccination General\nAll infants should receive a conjugate Hib vaccine (separate or in combination with DTP [TETRAMUNE TM ]), beginning at age 2 months (but not earlier than 6 weeks). If the first vaccination is delayed beyond age 6 months, the schedule of vaccination for previously unimmunized children should be followed (Table 7). When possible, the Hib conjugate vaccine used at the first vaccination should be used for all subsequent vaccinations in the primary series. When either Hib vaccines or TETRAMUNE TM is used, the vaccine should be administered intramuscularly using a separate syringe and administered at a separate site from any other concurrent vaccinations. \n# HbOC or PRP-T\nPreviously unvaccinated infants aged 2-6 months should receive three doses of vaccine administered 2 months apart, followed by a booster dose at age 12-15 months, at least 2 months after the last vaccination. Unvaccinated children ages 7-11 months should receive two doses of vaccine, 2 months apart, followed by a booster dose at age 12-18 months, at least 2 months after the last vaccination. Unvaccinated children ages 12-14 months should receive two doses of vaccine, at least 2 months apart. Any previously unvaccinated child aged 15-59 months should receive a single dose of vaccine.\n# PRP-OMP\nPreviously unvaccinated infants ages 2-6 months should receive two doses of vaccine administered at least 2 months apart. Although PRP-OMP induces a substantial antibody response after one dose, all children should receive all recommended doses of PRP-OMP. Because of the substantial antibody response after one dose, it may be advantageous to use PRP-OMP vaccine in populations that are known to be at increased risk for disease during early infancy (e.g., Alaskan Natives). A booster dose should be administered to all children at 12-15 months of age at least 2 months after the last vaccination. Unvaccinated children ages 7-11 months should receive two doses of vaccine, 2 months apart, followed by a booster dose at 12-18 months of age, at least 2 months after the last dose. Unvaccinated children ages 12-14 months should receive two doses of vaccine, 2 months apart. Any previously unvaccinated child 15-59 months of age should receive a single dose of vaccine. \n# PRP-D\nOne dose of PRP-D may be administered to unvaccinated children aged 15-59 months. This vaccine may be used as a booster dose at 12-18 months of age following a two-or three-dose primary series, regardless of the vaccine used in the primary series. This vaccine is not licensed for use among infants because of its limited immunogenicity and variable protective efficacy in this age group.\n# TETRAMUNE TM\nThe combination vaccine TETRAMUNE TM may be used for routine vaccination of infants, beginning at age 2 months, to prevent diphtheria, tetanus, pertussis, and invasive Hib disease. Previously unvaccinated infants aged 2-6 months should receive three doses administered at least 2 months apart. An additional dose should be administered at 12-15 months of age, after at least a 6-month interval following the third dose. Alternatively, acellular DTP and Hib vaccine can be administered as separate injections at 12-15 months of age. Acellular DTP is preferred for doses four and five of the five-dose DTP series. For infants who begin both Hib and DTP vaccinations late (after 2 months of age), TETRAMUNE TM may be used for the first and second doses of the vaccine series. However, because delay in initiation of the DTP series does not reduce the number of required doses of DTP, additional doses of DTP without Hib are necessary to ensure that all four doses are administered. Infants ages 7-11 months who have not previously been vaccinated with DTP or Hib vaccines should receive two doses of TETRAMUNE TM , administered at least 2 months apart, followed by a dose of DTP vaccine 4-8 weeks after the second dose of TETRAMUNE TM . An additional dose of DTP and Hib vaccines should then be administered: DTP vaccine at least 6 months after the third immunizing dose against diphtheria, tetanus, and pertussis; and Hib vaccine at 12-18 months of age, at least 2 months after the last Hib dose.\nTETRAMUNE TM may be used to complete an infant immunization series started with any Hib vaccine (licensed for use in this age group) and with any DTP vaccine if both vaccines are to be administered simultaneously. Completion of the primary series using the same Hib vaccine, however, is preferable. Conversely, any DTP vaccine may be used to complete a series initiated with TETRAMUNE TM (see the general ACIP statement on Diphtheria, Tetanus and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures [44 ] for further information).\n# Other considerations for Hib vaccination\nOther considerations for Hib vaccination are discussed in the following section:\n1) Although an interval of 2 months between doses of Hib vaccine in the primary series is recommended, an interval of 1 month is acceptable, if necessary. \n# Adverse reactions\nAdverse reactions to each of the four Hib conjugate vaccines are generally uncommon. Swelling, redness, and/or pain have been reported in 5%-30% of recipients and usually resolve within 12-24 hours. Systemic reactions such as fever and irritability are infrequent. Available information on side effects and adverse reactions suggests that the risks for local and systemic events following TETRAMUNE TM administration are similar to those following concurrent administration of its individual component vaccines (i.e., DTP and Hib vaccines), and may be due largely to the pertussis component of the DTP vaccine (52 ).\nSurveillance regarding the safety of TETRAMUNE TM , PRP-T, and other Hib vaccines in large-scale use aids in the assessment of vaccine safety by identifying potential events that may warrant further study. The Vaccine Adverse Event Reporting System (VAERS) of the U.S. Department of Health and Human Services encourages reports of all serious adverse events that occur after receipt of any vaccine.* Invasive Hib disease is a reportable condition in 43 states. All health-care workers should report any case of invasive Hib disease to local and state health departments.\n# Contraindications and Precautions\nVaccination with a specific Hib conjugate vaccine is contraindicated in persons known to have experienced anaphylaxis following a prior dose of that vaccine. Vaccination should be delayed in children with moderate or severe illnesses. Minor illnesses (e.g., mild upper-respiratory infection) are not contraindications to vaccination.\nContraindications and precautions of the use of TETRAMUNE TM are the same as those for its individual component vaccines (i.e., DTP or Hib) (see the general ACIP statement on Diphtheria, Tetanus, and Pertussis: Recommendations for Vaccine Use and Other Preventive Measures [44 ] for more details on the use of vaccines containing DTP). \n# \nThe following CDC staff members prepared this report: \n# Advisory Committee on Immunization Practices\nMembership List, October 1993 -Continued"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":279,"cells":{"id":{"kind":"string","value":"db29efcc9b1369cc37601a2af1d1842df9202278"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"the nation's, the proportion of total homicide-attributable YPLL in Michigan involving blacks is 68% compared with 44% in the nation. These differences largely reflect the higher homicide rate for blacks in Michigan than for the U.S. black population. Black homicide victims are also slightly younger than white victims in Michigan; in 1985, they had an average of 33 YPLL per homicide death, compared with 31 for whites.\nExamining descriptive data such as those presented here is important for public health agencies addressing homicide. In addition, analytic studies of potentially modifiable risk factors are needed. Because 67% of Michigan's homicides in 1985 occurred in the Detroit area, these data highlight the importance of implementing and evaluating prevention measures, such as the recently implemented handgun ordi nance, in Detroit. At the state level, excess homicide has led to plans to integrate health department and police data bases for surveillance of homicide. These data may help define factors associated with excess homicide in Michigan.\n\n# INTRODUCTION\nSince measles vaccine was introduced in the United States in 1963, the reported incidence of measles has decreased 99%, and indigenous measles transmission has been eliminated from most of the country. However, the goal to eliminate measles by October 1982 has not been met. Between 1981 and 1987, a low of 1497 (1983) to a high of 6282 (1986) cases were reported annually (7).\nTwo major types of outbreaks have occurred recently in the United States: those among unvaccinated preschool-aged children, including children younger than the recommended age for routine vaccination (i.e., 15 months), and those among vac cinated school-aged children (2). Large outbreaks among unvaccinated preschoolaged children have occurred in several inner-city areas. In these outbreaks, up to 88% of cases in vaccine-eligible children 16 months to 4 years of age were unvaccinated; as many as 40% of all cases occurred in children <16 months of age. Surveys of immunization levels in areas where these outbreaks occurred indicate that only 49%-65% of 2-year-olds had received measles vaccine (3).\nMany outbreaks have occurred among school-aged children in schools with vaccination levels above 98%. These outbreaks have occurred in all parts of the country. Attack rates in individual schools have been low (1%-5%), and the calculated vaccine efficacy has been high. Primary vaccine failures (i.e., the approximately January 13,1989 ACIP: Measles -Continued 2%-10% of vaccinees who fail to seroconvert after measles vaccination) have played a substantial role in transmission. In many of these outbreaks, children vaccinated at 12-14 months of age have had higher attack rates than those vaccinated at older ages (4).\nIn a few outbreaks (5,6), persons vaccinated in the more distant past, independent of age at vaccination, have been at increased risk for disease. However, no conclusive data indicate that waning vaccine-induced immunity itself has been a major problem.\n\n# EVALUATION OF THE CURRENT MEASLES ELIMINATION STRATEGY\nThe current measles elimination strategy calls for administration of one dose of measles vaccine at 15 months of age (7). A documented history of vaccination at or after 12 months of age, however, is considered appropriate vaccination. High immunization levels, along with careful surveillance and aggressive outbreak control, are the three essential elements of this strategy. The Immunization Practices Advisory Committee (ACIP) has periodically reviewed the current strategy and progress toward measles elimination (7). At a recent meeting, the ACIP again reviewed the epidemi ology of measles in the United States as well as recommendations, made by a group of consultants convened by CDC in February 1988, for modification of the measles elimination strategy.\nTo increase vaccine coverage among preschool-aged children in inner-city areas, the ACIP considered it essential that research be conducted to determine ways to increase vaccine delivery. A variety of additions and/or changes in the current strategy were considered, including a routine two-dose measles vaccination schedule and a one-time mass revaccination for school-aged children. Two new strategies were recommended and are described below (Table 1).\n\n# NEW RECOMMENDATIONS Changes in vaccination schedule in areas with recurrent measles transmission among preschool-aged children\nTo improve immunity levels in high-risk children <15 months of age, the ACIP recommends that a routine two-dose vaccination schedule for preschoolers be implemented in areas with recurrent measles transmission (i.e., counties with more than five reported cases among preschool-aged children during each of the last 5 years). If recurrent measles transmission is occurring in defined parts of a county, local officials may elect to implement the routine two-dose schedule selectively in those parts. Health authorities in other urban areas that have experienced recent outbreaks among unvaccinated preschool-aged children may also consider imple menting this policy. The first dose of measles vaccine should be administered at age 9 months or at the first health-care contact thereafter. Infants vaccinated before their first birthday should receive a second dose at or about 15 months of age. Single antigen (monovalent) measles vaccine should be used for infants <1 year of age, and measles, mumps, and rubella vaccine (MMR), for persons vaccinated on or after the first birthday. Although some data suggest that children who do not respond to the first dose administered at a young age may have an altered immune response when revaccinated at an older age (8), there are no data to suggest that such children are not protected from measles (9 ). If resource constraints do not permit a routine two-dose schedule, an acceptable alternative is to lower the age for routine vaccination to 12 months in those areas using one dose of MMR. If children also need diphtheria and tetanus toxoids and pertussis vaccine (DTP) and oral polio vaccine (OPV), these vaccines can be admin istered simultaneously with measles vaccine or MMR.\n\n# Changes in outbreak-control strategies for school-based outbreaks\nBecause of the prominent role that persons with primary vaccine failure are playing in measles transmission, the ACIP recommends the institution of some form of revaccination in outbreaks that occur in junior or senior high schools, colleges, universities, or other secondary institutions. In an outbreak, the ACIP recommends that, in affected schools as well as unaffected schools at risk of measles transmission from students in affected schools, all students and their siblings who received their most recent dose of measles vaccine before 1980 should be revaccinated. This date was selected for several reasons: 1) this strategy will capture almost all students vaccinated between 12 and 14 months of age, a group known to be at increased risk of primary vaccine failure, since the recommended age for routine vaccination was changed from 12 to 15 months in 1976; 2) it may be easier to identify students by year of vaccination than by age at vaccination; and 3) in some outbreak investigations, students vaccinated before 1978-1980 have been found to be at increased risk for measles. This is not felt to be due to waning immunity but rather to a higher rate o primary vaccine failure in persons vaccinated before that time. This higher rate may be due to different reasons, including less than optimal vaccine storage and handling or to the greater lability of the measles vaccine manufactured before a new stabilizer was used in 1979. While the exact date has not been determined, 1980 is a conservative cutoff. If all students vaccinated before 1980 cannot be revaccinated, then persons vaccinated before 15 months of age should be targeted.\n\n# Notices to Readers\n\n# Epidemiology in Action Course\nCDC and Emory University will cosponsor a course designed for practicing state and local health department professionals. This course, \" Epidemiology in Action/' will be held at CDC May 15-26, 1989. It emphasizes the practical application of epidemiology to public health problems and will consist of lectures, workshops, classroom exercises (including actual epidemiologic problems), roundtable discus sions, and an on-site community survey."},"raw_text":{"kind":"string","value":"# \nthe nation's, the proportion of total homicide-attributable YPLL in Michigan involving blacks is 68% compared with 44% in the nation. These differences largely reflect the higher homicide rate for blacks in Michigan than for the U.S. black population. Black homicide victims are also slightly younger than white victims in Michigan; in 1985, they had an average of 33 YPLL per homicide death, compared with 31 for whites.\nExamining descriptive data such as those presented here is important for public health agencies addressing homicide. In addition, analytic studies of potentially modifiable risk factors are needed. Because 67% of Michigan's homicides in 1985 occurred in the Detroit area, these data highlight the importance of implementing and evaluating prevention measures, such as the recently implemented handgun ordi nance, in Detroit. At the state level, excess homicide has led to plans to integrate health department and police data bases for surveillance of homicide. These data may help define factors associated with excess homicide in Michigan.\n# INTRODUCTION\nSince measles vaccine was introduced in the United States in 1963, the reported incidence of measles has decreased 99%, and indigenous measles transmission has been eliminated from most of the country. However, the goal to eliminate measles by October 1982 has not been met. Between 1981 and 1987, a low of 1497 (1983) to a high of 6282 (1986) cases were reported annually (7).\nTwo major types of outbreaks have occurred recently in the United States: those among unvaccinated preschool-aged children, including children younger than the recommended age for routine vaccination (i.e., 15 months), and those among vac cinated school-aged children (2). Large outbreaks among unvaccinated preschoolaged children have occurred in several inner-city areas. In these outbreaks, up to 88% of cases in vaccine-eligible children 16 months to 4 years of age were unvaccinated; as many as 40% of all cases occurred in children <16 months of age. Surveys of immunization levels in areas where these outbreaks occurred indicate that only 49%-65% of 2-year-olds had received measles vaccine (3).\nMany outbreaks have occurred among school-aged children in schools with vaccination levels above 98%. These outbreaks have occurred in all parts of the country. Attack rates in individual schools have been low (1%-5%), and the calculated vaccine efficacy has been high. Primary vaccine failures (i.e., the approximately January 13,1989 ACIP: Measles -Continued 2%-10% of vaccinees who fail to seroconvert after measles vaccination) have played a substantial role in transmission. In many of these outbreaks, children vaccinated at 12-14 months of age have had higher attack rates than those vaccinated at older ages (4).\nIn a few outbreaks (5,6), persons vaccinated in the more distant past, independent of age at vaccination, have been at increased risk for disease. However, no conclusive data indicate that waning vaccine-induced immunity itself has been a major problem.\n# EVALUATION OF THE CURRENT MEASLES ELIMINATION STRATEGY\nThe current measles elimination strategy calls for administration of one dose of measles vaccine at 15 months of age (7). A documented history of vaccination at or after 12 months of age, however, is considered appropriate vaccination. High immunization levels, along with careful surveillance and aggressive outbreak control, are the three essential elements of this strategy. The Immunization Practices Advisory Committee (ACIP) has periodically reviewed the current strategy and progress toward measles elimination (7). At a recent meeting, the ACIP again reviewed the epidemi ology of measles in the United States as well as recommendations, made by a group of consultants convened by CDC in February 1988, for modification of the measles elimination strategy.\nTo increase vaccine coverage among preschool-aged children in inner-city areas, the ACIP considered it essential that research be conducted to determine ways to increase vaccine delivery. A variety of additions and/or changes in the current strategy were considered, including a routine two-dose measles vaccination schedule and a one-time mass revaccination for school-aged children. Two new strategies were recommended and are described below (Table 1).\n# NEW RECOMMENDATIONS Changes in vaccination schedule in areas with recurrent measles transmission among preschool-aged children\nTo improve immunity levels in high-risk children <15 months of age, the ACIP recommends that a routine two-dose vaccination schedule for preschoolers be implemented in areas with recurrent measles transmission (i.e., counties with more than five reported cases among preschool-aged children during each of the last 5 years). If recurrent measles transmission is occurring in defined parts of a county, local officials may elect to implement the routine two-dose schedule selectively in those parts. Health authorities in other urban areas that have experienced recent outbreaks among unvaccinated preschool-aged children may also consider imple menting this policy. The first dose of measles vaccine should be administered at age 9 months or at the first health-care contact thereafter. Infants vaccinated before their first birthday should receive a second dose at or about 15 months of age. Single antigen (monovalent) measles vaccine should be used for infants <1 year of age, and measles, mumps, and rubella vaccine (MMR), for persons vaccinated on or after the first birthday. Although some data suggest that children who do not respond to the first dose administered at a young age may have an altered immune response when revaccinated at an older age (8), there are no data to suggest that such children are not protected from measles (9 ). If resource constraints do not permit a routine two-dose schedule, an acceptable alternative is to lower the age for routine vaccination to 12 months in those areas using one dose of MMR. If children also need diphtheria and tetanus toxoids and pertussis vaccine (DTP) and oral polio vaccine (OPV), these vaccines can be admin istered simultaneously with measles vaccine or MMR.\n# Changes in outbreak-control strategies for school-based outbreaks\nBecause of the prominent role that persons with primary vaccine failure are playing in measles transmission, the ACIP recommends the institution of some form of revaccination in outbreaks that occur in junior or senior high schools, colleges, universities, or other secondary institutions. In an outbreak, the ACIP recommends that, in affected schools as well as unaffected schools at risk of measles transmission from students in affected schools, all students and their siblings who received their most recent dose of measles vaccine before 1980 should be revaccinated. This date was selected for several reasons: 1) this strategy will capture almost all students vaccinated between 12 and 14 months of age, a group known to be at increased risk of primary vaccine failure, since the recommended age for routine vaccination was changed from 12 to 15 months in 1976; 2) it may be easier to identify students by year of vaccination than by age at vaccination; and 3) in some outbreak investigations, students vaccinated before 1978-1980 have been found to be at increased risk for measles. This is not felt to be due to waning immunity but rather to a higher rate o primary vaccine failure in persons vaccinated before that time. This higher rate may be due to different reasons, including less than optimal vaccine storage and handling or to the greater lability of the measles vaccine manufactured before a new stabilizer was used in 1979. While the exact date has not been determined, 1980 is a conservative cutoff. If all students vaccinated before 1980 cannot be revaccinated, then persons vaccinated before 15 months of age should be targeted. \n# Notices to Readers\n\n# Epidemiology in Action Course\nCDC and Emory University will cosponsor a course designed for practicing state and local health department professionals. This course, \" Epidemiology in Action/' will be held at CDC May 15-26, 1989. It emphasizes the practical application of epidemiology to public health problems and will consist of lectures, workshops, classroom exercises (including actual epidemiologic problems), roundtable discus sions, and an on-site community survey. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":280,"cells":{"id":{"kind":"string","value":"616b92a2fa71d500b78c7cf8a3c4001ab569216a"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"# Prevention and Control of Influenza:\nPart II, Antiviral Agents Recommendations of the Advisory Committee on Immunization Practices (ACIP) Summary These recommendations provide information about two antiviral agents: amantadine hydrochloride and rimantadine hydrochloride. These recommendations supersede MMWR 1992;41(No. RR-9). The primary changes include information about the recently licensed drug rimantadine, expanded information on the potential for adverse reactions to amantadine and rimantadine, and guidelines for the use of these drugs among certain persons.\n\n# INTRODUCTION\nThe two antiviral agents with specific activity against influenza A viruses are amantadine hydrochloride and rimantadine hydrochloride. These chemically related drugs interfere with the replication cycle of type A (but not type B) influenza viruses. When administered prophylactically to healthy adults or children before and throughout the epidemic period, both drugs are approximately 70%-90% effective in preventing illness caused by naturally occurring strains of type A influenza viruses. Because antiviral agents taken prophylactically may prevent illness but not subclinical infection, some persons who take these drugs may still develop immune responses that will protect them when they are exposed to antigenically related viruses in later years.\nIn otherwise healthy adults, amantadine and rimantadine can reduce the severity and duration of signs and symptoms of influenza A illness when administered within 48 hours of illness onset. Studies evaluating the efficacy of treatment for children with either amantadine or rimantadine are limited. Amantadine was approved for treatment and prophylaxis of all influenza type A virus infections in 1976. Although few placebo-controlled studies were conducted to determine the efficacy of amantadine treatment among children prior to approval, amantadine is indicated for treatment and prophylaxis of adults and children ≥1 year of age. Rimantadine was approved in 1993 for treatment and prophylaxis in adults but was approved only for prophylaxis in children. Further studies may provide the data needed to support future approval of rimantadine treatment in this age group.\nAs with all drugs, amantadine and rimantadine may cause adverse reactions in some persons. Such adverse reactions are rarely severe; however, for some categories of patients, severe adverse reactions are more likely to occur. Amantadine has been associated with a higher incidence of adverse central nervous system (CNS) reactions than rimantadine (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment).\n\n# RECOMMENDATIONS FOR THE USE OF AMANTADINE AND RIMANTADINE\n\n# Use as Prophylaxis\nChemoprophylaxis is not a substitute for vaccination. Recommendations for chemoprophylaxis are provided primarily to help health-care providers make decisions regarding persons who are at greatest risk of severe illness and complications if infected with influenza A virus (i.e., persons at high risk). Groups at high risk for influenza-related complications include:\n- persons ≥65 years of age;\n- residents of nursing homes and other chronic-care facilities that house persons of any age with chronic medical conditions;\n- adults and children with chronic disorders of the pulmonary or cardiovascular systems, including children with asthma;\n- adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications); and - children and teenagers (6 months-18 years of age) who are receiving long-term aspirin therapy and therefore may be at risk for developing Reye syndrome after influenza.\nWhen amantadine or rimantadine is administered as prophylaxis, factors such as cost, compliance, and potential side effects should be considered when determining the period of prophylaxis. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost effective, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community.\n\n# Persons at High Risk Vaccinated After Influenza A Activity Has Begun\nPersons at high risk can still be vaccinated after an outbreak of influenza A has begun in a community. However, the development of antibodies in adults after vaccination can take as long as 2 weeks, during which time chemoprophylaxis should be considered. Children who receive influenza vaccine for the first time may require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 2 weeks after the second dose of vaccine has been received). Amantadine and rimantadine do not interfere with the antibody response to the vaccine.\n\n# Persons Providing Care to Those at High Risk\nTo reduce the spread of virus to persons at high risk, chemoprophylaxis may be considered during community outbreaks for a) unvaccinated persons who have frequent contact with persons at high risk (e.g., household members, visiting nurses, and volunteer workers) and b) unvaccinated employees of hospitals, clinics, and chroniccare facilities. For those persons who cannot be vaccinated, chemoprophylaxis during the period of peak influenza activity may be considered. For those persons who receive vaccine at a time when influenza A is present in the community, chemoprophylaxis can be administered for 2 weeks after vaccination. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that may not be controlled by the vaccine.\n\n# Persons Who Have Immune Deficiency\nChemoprophylaxis may be indicated for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons with human immunodeficiency virus (HIV) infection, especially those with advanced HIV disease. No data are available on possible interactions with other drugs used in the management of patients with HIV infection. Such patients should be monitored closely if amantadine or rimantadine chemoprophylaxis is administered.\n\n# Persons for Whom Influenza Vaccine Is Contraindicated\nChemoprophylaxis throughout the influenza season or during peak influenza activity may be appropriate for persons at high risk who should not be vaccinated. Influenza vaccine may be contraindicated in persons with severe anaphylactic hypersensitivity to egg protein or other vaccine components.\n\n# Other Persons\nAmantadine or rimantadine also can be administered prophylactically to anyone who wishes to avoid influenza A illness. The health-care provider and patient should make this decision on an individual basis.\n\n# Use of Antivirals as Therapy\nAmantadine and rimantadine can reduce the severity and shorten the duration of influenza A illness among healthy adults when administered within 48 hours of illness onset. Whether antiviral therapy will prevent complications of influenza type A among high-risk persons is unknown. Insufficient data exist to determine the efficacy of rimantadine treatment in children. Thus, rimantadine is currently approved only for prophylaxis in children, but it is not approved for treatment in this age group. Amantadine-and rimantadine-resistant influenza A viruses can emerge when either of these drugs is administered for treatment; amantadine-resistant strains are cross-resistant to rimantadine and vice versa. Both the frequency with which resistant viruses emerge and the extent of their transmission are unknown, but data indicate that amantadine-and rimantadine-resistant viruses are no more virulent or transmissible than amantadine-and rimantadine-sensitive viruses.\nThe screening of naturally occurring epidemic strains of influenza type A has rarely detected amantadine-and rimantadine-resistant viruses. Resistant viruses have most frequently been isolated from persons taking one of these drugs as therapy for influenza A infection. Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy. Persons who have influenza-like illness should avoid contact with uninfected persons as much as possible, regardless of whether they are being treated with amantadine or rimantadine. Persons who have influenza type A infection and who are treated with either drug may shed amantadine-or rimantadine-sensitive viruses early in the course of treatment, but may later shed drug-resistant viruses, especially after 5-7 days of therapy. Such persons can benefit from therapy even when resistant viruses emerge; however, they also can transmit infection to other persons with whom they come in contact. Because of possible induction of amantadine or rimantadine resistance, treatment of persons who have influenza-like illness should be discontinued as soon as clinically warranted, generally after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. Laboratory isolation of influenza viruses obtained from persons who are receiving amantadine or rimantadine should be reported to CDC through state health departments, and the isolates should be saved for antiviral sensitivity testing.\n\n# Outbreak Control in Institutions\nWhen confirmed or suspected outbreaks of influenza A occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. Contingency planning is needed to ensure rapid administration of amantadine or rimantadine to residents. This planning should include preapproved medication orders or plans to obtain physicians' orders on short notice. When amantadine or rimantadine is used for outbreak control, the drug should be administered to all residents of the institution-regardless of whether they received influenza vaccine the previous fall. The drug should be continued for at least 2 weeks or until approximately 1 week after the end of the outbreak. The dose for each resident should be determined after consulting the dosage recommendations and precautions (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment) and the manufacturer's package insert. To reduce the spread of virus and to minimize disruption of patient care, chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that is not controlled by the vaccine.\nChemoprophylaxis also may be considered for controlling influenza A outbreaks in other closed or semi-closed settings (e.g., dormitories or other settings where persons live in close proximity). To reduce the spread of infection and the chances of prophylaxis failure due to transmission of drug-resistant virus, measures should be taken to reduce contact as much as possible between persons on chemoprophylaxis and those taking drug for treatment.\n\n# CONSIDERATIONS FOR SELECTING AMANTADINE OR RIMANTADINE FOR CHEMOPROPHYLAXIS OR TREATMENT Side Effects/Toxicity\nDespite the similarities between the two drugs, amantadine and rimantadine differ in their pharmacokinetic properties. More than 90% of amantadine is excreted unchanged, whereas approximately 75% of rimantadine is metabolized by the liver. However, both drugs and their metabolites are excreted by the kidney. The pharmacokinetic differences between amantadine and rimantadine may partially explain differences in side effects. Although both drugs can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine compared with those taking rimantadine. In a 6-week study of prophylaxis in healthy adults, approximately 6% of participants taking rimantadine at a dose of 200 mg/day experienced at least one CNS symptom, compared with approximately 14% of those taking the same dose of amantadine and 4% of those taking placebo. The incidence of gastrointestinal side effects (e.g., nausea and anorexia) is approximately 3% in persons taking either drug, compared with 1%-2% of persons receiving the placebo. Side effects associated with both drugs are usually mild and cease soon after discontinuing the drug. Side effects may diminish or disappear after the first week despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects, and recommendations for reduced dosages for these groups of patients have been made. Because rimantadine has only recently been approved for marketing, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently. Clinical trials of rimantadine have more commonly involved young, healthy persons.\nProviders should review the package insert before using amantadine or rimantadine for any patient. The patient's age, weight, renal function, other medications, presence of other medical conditions, and indications for use of amantadine or rimantadine (prophylaxis or therapy) must be considered, and the dosage and duration of treatment must be adjusted appropriately. Modifications in dosage may be required for persons who have impaired renal or hepatic function, the elderly, children, and persons with a history of seizures. The following are guidelines for the use of amantadine and rimantadine in certain patient populations. Dosage recommendations are also summarized (Table 1).\n\n# Persons Who Have Impaired Renal Function\n\n# Amantadine\nAmantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion. Thus, renal clearance of amantadine is reduced substantially in persons with renal insufficiency. A reduction in dosage is recommended for patients with creatinine clearance ≤50 mL/min. Guidelines for amantadine dosage based on creatinine clearance are found in the packet insert. However, because recommended dosages based on creatinine clearance may provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully so that adverse reactions can be recognized promptly and either the dose can be further reduced or the drug can be discontinued, if necessary. Hemodialysis contributes little to drug clearance.\n\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration. Further studies are needed to determine the multiple-dose pharmacokinetics and the most appropriate dosages for these patients.\nIn a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that in healthy controls of the same age. Hemodialysis did not contribute to drug clearance. In studies among persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were *The drug package insert should be consulted for dosage recommendations for administering amantadine to persons with creatinine clearance ≤50 mL/min. † 5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22 lbs. § Children ≥10 years of age who weigh 100 mg/day should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. Elderly nursing-home residents should be administered only 100 mg/day of rimantadine. A reduction in dose to 100 mg/day should be considered for all persons ≥65 years of age if they experience possible side effects when taking 200 mg/day. NA=Not applicable.\nhigher compared with control patients without renal disease who were the same weight, age, and sex.\nA reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance ≤10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including elderly persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary.\n\n# Persons ≥65 Years of Age\n\n# Amantadine\nBecause renal function declines with increasing age, the daily dose for persons ≥65 years of age should not exceed 100 mg for prophylaxis or treatment. For some elderly persons, the dose should be further reduced. Studies suggest that because of their smaller average body size, elderly women are more likely than elderly men to experience side effects at a daily dose of 100 mg.\n\n# Rimantadine\nThe incidence and severity of CNS side effects among elderly persons appear to be substantially lower among those taking rimantadine at a dose of 200 mg/day compared with elderly persons taking the same dose of amantadine. However, when rimantadine has been administered at a dosage of 200 mg/day to chronically ill elderly persons, they have had a higher incidence of CNS and gastrointestinal symptoms than healthy, younger persons taking rimantadine at the same dosage. After longterm administration of rimantadine at a dosage of 200 mg/day, serum rimantadine concentrations among elderly nursing-home residents have been two to four times greater than those reported in younger adults.\nThe dosage of rimantadine should be reduced to 100 mg/day for treatment or prophylaxis of elderly nursing-home residents. Although further studies are needed to determine the optimal dose for other elderly persons, a reduction in dosage to 100 mg/day should be considered for all persons ≥65 years of age if they experience signs and symptoms that may represent side effects when taking a dosage of 200 mg/day.\n\n# Persons Who Have Liver Disease\n\n# Amantadine\nNo increase in adverse reactions to amantadine has been observed among persons with liver disease.\n\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine have only been evaluated after single-dose administration. In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations were observed after a single dose. However, in persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease. A dose reduction to 100 mg/day is recommended for persons with severe hepatic dysfunction.\n\n# Persons Who Have Seizure Disorders\n\n# Amantadine\nAn increased incidence of seizures has been reported in patients with a history of seizure disorders who have received amantadine. Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.\n\n# Rimantadine\nIn clinical trials, seizures (or seizure-like activity) have been observed in a few persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine. The extent to which rimantadine may increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated, because such persons have usually been excluded from participating in clinical trials of rimantadine.\n\n# Children\n\n# Amantadine\nThe use of amantadine in children <1 year of age has not been adequately evaluated. The FDA-approved dosage for children 1-9 years of age is 4.4-8.8 mg/kg/day, not to exceed 150 mg/day. Although further studies to determine the optimal dosage for children are needed, physicians should consider prescribing only 5 mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children ≥10 years of age is 200 mg/day; however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable.\n\n# Rimantadine\nThe use of rimantadine in children <1 year of age has not been adequately evaluated. In children 1-9 years of age, rimantadine should be administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day. The approved dosage for children ≥10 years of age is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, also is recommended.\n\n# Drug Interactions\n\n# Amantadine\nCareful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants.\n\n# Rimantadine\nNo clinically significant drug interactions have been identified. For more detailed information concerning potential drug interactions for either drug, the package insert should be consulted.\n\n# Advisory Committee on Immunization Practices\nMembership List, October 1994 -Continued\n\n# SOURCES OF INFORMATION ON INFLUENZA-CONTROL PROGRAMS\nInformation regarding influenza surveillance is available through the CDC Voice Information System (influenza update), telephone (404) 332-4551, or through the CDC Information Service on the Public Health Network electronic bulletin board. From October through May, the information is updated at least every other week. In addition, periodic updates about influenza are published in the weekly MMWR. State and local health departments should be consulted regarding availability of influenza vaccine, access to vaccination programs, and information about state or local influenza activity."},"raw_text":{"kind":"string","value":"# Prevention and Control of Influenza:\nPart II, Antiviral Agents Recommendations of the Advisory Committee on Immunization Practices (ACIP) Summary These recommendations provide information about two antiviral agents: amantadine hydrochloride and rimantadine hydrochloride. These recommendations supersede MMWR 1992;41(No. RR-9). The primary changes include information about the recently licensed drug rimantadine, expanded information on the potential for adverse reactions to amantadine and rimantadine, and guidelines for the use of these drugs among certain persons.\n# INTRODUCTION\nThe two antiviral agents with specific activity against influenza A viruses are amantadine hydrochloride and rimantadine hydrochloride. These chemically related drugs interfere with the replication cycle of type A (but not type B) influenza viruses. When administered prophylactically to healthy adults or children before and throughout the epidemic period, both drugs are approximately 70%-90% effective in preventing illness caused by naturally occurring strains of type A influenza viruses. Because antiviral agents taken prophylactically may prevent illness but not subclinical infection, some persons who take these drugs may still develop immune responses that will protect them when they are exposed to antigenically related viruses in later years.\nIn otherwise healthy adults, amantadine and rimantadine can reduce the severity and duration of signs and symptoms of influenza A illness when administered within 48 hours of illness onset. Studies evaluating the efficacy of treatment for children with either amantadine or rimantadine are limited. Amantadine was approved for treatment and prophylaxis of all influenza type A virus infections in 1976. Although few placebo-controlled studies were conducted to determine the efficacy of amantadine treatment among children prior to approval, amantadine is indicated for treatment and prophylaxis of adults and children ≥1 year of age. Rimantadine was approved in 1993 for treatment and prophylaxis in adults but was approved only for prophylaxis in children. Further studies may provide the data needed to support future approval of rimantadine treatment in this age group.\nAs with all drugs, amantadine and rimantadine may cause adverse reactions in some persons. Such adverse reactions are rarely severe; however, for some categories of patients, severe adverse reactions are more likely to occur. Amantadine has been associated with a higher incidence of adverse central nervous system (CNS) reactions than rimantadine (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment).\n# RECOMMENDATIONS FOR THE USE OF AMANTADINE AND RIMANTADINE\n\n# Use as Prophylaxis\nChemoprophylaxis is not a substitute for vaccination. Recommendations for chemoprophylaxis are provided primarily to help health-care providers make decisions regarding persons who are at greatest risk of severe illness and complications if infected with influenza A virus (i.e., persons at high risk). Groups at high risk for influenza-related complications include:\n• persons ≥65 years of age;\n• residents of nursing homes and other chronic-care facilities that house persons of any age with chronic medical conditions;\n• adults and children with chronic disorders of the pulmonary or cardiovascular systems, including children with asthma;\n• adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications); and • children and teenagers (6 months-18 years of age) who are receiving long-term aspirin therapy and therefore may be at risk for developing Reye syndrome after influenza.\nWhen amantadine or rimantadine is administered as prophylaxis, factors such as cost, compliance, and potential side effects should be considered when determining the period of prophylaxis. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost effective, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community.\n# Persons at High Risk Vaccinated After Influenza A Activity Has Begun\nPersons at high risk can still be vaccinated after an outbreak of influenza A has begun in a community. However, the development of antibodies in adults after vaccination can take as long as 2 weeks, during which time chemoprophylaxis should be considered. Children who receive influenza vaccine for the first time may require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 2 weeks after the second dose of vaccine has been received). Amantadine and rimantadine do not interfere with the antibody response to the vaccine.\n# Persons Providing Care to Those at High Risk\nTo reduce the spread of virus to persons at high risk, chemoprophylaxis may be considered during community outbreaks for a) unvaccinated persons who have frequent contact with persons at high risk (e.g., household members, visiting nurses, and volunteer workers) and b) unvaccinated employees of hospitals, clinics, and chroniccare facilities. For those persons who cannot be vaccinated, chemoprophylaxis during the period of peak influenza activity may be considered. For those persons who receive vaccine at a time when influenza A is present in the community, chemoprophylaxis can be administered for 2 weeks after vaccination. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that may not be controlled by the vaccine.\n# Persons Who Have Immune Deficiency\nChemoprophylaxis may be indicated for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons with human immunodeficiency virus (HIV) infection, especially those with advanced HIV disease. No data are available on possible interactions with other drugs used in the management of patients with HIV infection. Such patients should be monitored closely if amantadine or rimantadine chemoprophylaxis is administered.\n# Persons for Whom Influenza Vaccine Is Contraindicated\nChemoprophylaxis throughout the influenza season or during peak influenza activity may be appropriate for persons at high risk who should not be vaccinated. Influenza vaccine may be contraindicated in persons with severe anaphylactic hypersensitivity to egg protein or other vaccine components.\n# Other Persons\nAmantadine or rimantadine also can be administered prophylactically to anyone who wishes to avoid influenza A illness. The health-care provider and patient should make this decision on an individual basis.\n# Use of Antivirals as Therapy\nAmantadine and rimantadine can reduce the severity and shorten the duration of influenza A illness among healthy adults when administered within 48 hours of illness onset. Whether antiviral therapy will prevent complications of influenza type A among high-risk persons is unknown. Insufficient data exist to determine the efficacy of rimantadine treatment in children. Thus, rimantadine is currently approved only for prophylaxis in children, but it is not approved for treatment in this age group. Amantadine-and rimantadine-resistant influenza A viruses can emerge when either of these drugs is administered for treatment; amantadine-resistant strains are cross-resistant to rimantadine and vice versa. Both the frequency with which resistant viruses emerge and the extent of their transmission are unknown, but data indicate that amantadine-and rimantadine-resistant viruses are no more virulent or transmissible than amantadine-and rimantadine-sensitive viruses.\nThe screening of naturally occurring epidemic strains of influenza type A has rarely detected amantadine-and rimantadine-resistant viruses. Resistant viruses have most frequently been isolated from persons taking one of these drugs as therapy for influenza A infection. Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy. Persons who have influenza-like illness should avoid contact with uninfected persons as much as possible, regardless of whether they are being treated with amantadine or rimantadine. Persons who have influenza type A infection and who are treated with either drug may shed amantadine-or rimantadine-sensitive viruses early in the course of treatment, but may later shed drug-resistant viruses, especially after 5-7 days of therapy. Such persons can benefit from therapy even when resistant viruses emerge; however, they also can transmit infection to other persons with whom they come in contact. Because of possible induction of amantadine or rimantadine resistance, treatment of persons who have influenza-like illness should be discontinued as soon as clinically warranted, generally after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. Laboratory isolation of influenza viruses obtained from persons who are receiving amantadine or rimantadine should be reported to CDC through state health departments, and the isolates should be saved for antiviral sensitivity testing.\n# Outbreak Control in Institutions\nWhen confirmed or suspected outbreaks of influenza A occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. Contingency planning is needed to ensure rapid administration of amantadine or rimantadine to residents. This planning should include preapproved medication orders or plans to obtain physicians' orders on short notice. When amantadine or rimantadine is used for outbreak control, the drug should be administered to all residents of the institution-regardless of whether they received influenza vaccine the previous fall. The drug should be continued for at least 2 weeks or until approximately 1 week after the end of the outbreak. The dose for each resident should be determined after consulting the dosage recommendations and precautions (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment) and the manufacturer's package insert. To reduce the spread of virus and to minimize disruption of patient care, chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that is not controlled by the vaccine.\nChemoprophylaxis also may be considered for controlling influenza A outbreaks in other closed or semi-closed settings (e.g., dormitories or other settings where persons live in close proximity). To reduce the spread of infection and the chances of prophylaxis failure due to transmission of drug-resistant virus, measures should be taken to reduce contact as much as possible between persons on chemoprophylaxis and those taking drug for treatment.\n# CONSIDERATIONS FOR SELECTING AMANTADINE OR RIMANTADINE FOR CHEMOPROPHYLAXIS OR TREATMENT Side Effects/Toxicity\nDespite the similarities between the two drugs, amantadine and rimantadine differ in their pharmacokinetic properties. More than 90% of amantadine is excreted unchanged, whereas approximately 75% of rimantadine is metabolized by the liver. However, both drugs and their metabolites are excreted by the kidney. The pharmacokinetic differences between amantadine and rimantadine may partially explain differences in side effects. Although both drugs can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine compared with those taking rimantadine. In a 6-week study of prophylaxis in healthy adults, approximately 6% of participants taking rimantadine at a dose of 200 mg/day experienced at least one CNS symptom, compared with approximately 14% of those taking the same dose of amantadine and 4% of those taking placebo. The incidence of gastrointestinal side effects (e.g., nausea and anorexia) is approximately 3% in persons taking either drug, compared with 1%-2% of persons receiving the placebo. Side effects associated with both drugs are usually mild and cease soon after discontinuing the drug. Side effects may diminish or disappear after the first week despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects, and recommendations for reduced dosages for these groups of patients have been made. Because rimantadine has only recently been approved for marketing, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently. Clinical trials of rimantadine have more commonly involved young, healthy persons.\nProviders should review the package insert before using amantadine or rimantadine for any patient. The patient's age, weight, renal function, other medications, presence of other medical conditions, and indications for use of amantadine or rimantadine (prophylaxis or therapy) must be considered, and the dosage and duration of treatment must be adjusted appropriately. Modifications in dosage may be required for persons who have impaired renal or hepatic function, the elderly, children, and persons with a history of seizures. The following are guidelines for the use of amantadine and rimantadine in certain patient populations. Dosage recommendations are also summarized (Table 1).\n# Persons Who Have Impaired Renal Function\n\n# Amantadine\nAmantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion. Thus, renal clearance of amantadine is reduced substantially in persons with renal insufficiency. A reduction in dosage is recommended for patients with creatinine clearance ≤50 mL/min. Guidelines for amantadine dosage based on creatinine clearance are found in the packet insert. However, because recommended dosages based on creatinine clearance may provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully so that adverse reactions can be recognized promptly and either the dose can be further reduced or the drug can be discontinued, if necessary. Hemodialysis contributes little to drug clearance.\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration. Further studies are needed to determine the multiple-dose pharmacokinetics and the most appropriate dosages for these patients.\nIn a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that in healthy controls of the same age. Hemodialysis did not contribute to drug clearance. In studies among persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were *The drug package insert should be consulted for dosage recommendations for administering amantadine to persons with creatinine clearance ≤50 mL/min. † 5 mg/kg of amantadine or rimantadine syrup = 1 tsp/22 lbs. § Children ≥10 years of age who weigh <40 kg should be administered amantadine or rimantadine at a dose of 5 mg/kg/day. ¶ A reduction in dose to 100 mg/day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance ≤10 mL/min. Other persons with less severe hepatic or renal dysfunction taking >100 mg/day should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary. ** Elderly nursing-home residents should be administered only 100 mg/day of rimantadine. A reduction in dose to 100 mg/day should be considered for all persons ≥65 years of age if they experience possible side effects when taking 200 mg/day. NA=Not applicable.\nhigher compared with control patients without renal disease who were the same weight, age, and sex.\nA reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance ≤10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including elderly persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary.\n# Persons ≥65 Years of Age\n\n# Amantadine\nBecause renal function declines with increasing age, the daily dose for persons ≥65 years of age should not exceed 100 mg for prophylaxis or treatment. For some elderly persons, the dose should be further reduced. Studies suggest that because of their smaller average body size, elderly women are more likely than elderly men to experience side effects at a daily dose of 100 mg.\n# Rimantadine\nThe incidence and severity of CNS side effects among elderly persons appear to be substantially lower among those taking rimantadine at a dose of 200 mg/day compared with elderly persons taking the same dose of amantadine. However, when rimantadine has been administered at a dosage of 200 mg/day to chronically ill elderly persons, they have had a higher incidence of CNS and gastrointestinal symptoms than healthy, younger persons taking rimantadine at the same dosage. After longterm administration of rimantadine at a dosage of 200 mg/day, serum rimantadine concentrations among elderly nursing-home residents have been two to four times greater than those reported in younger adults.\nThe dosage of rimantadine should be reduced to 100 mg/day for treatment or prophylaxis of elderly nursing-home residents. Although further studies are needed to determine the optimal dose for other elderly persons, a reduction in dosage to 100 mg/day should be considered for all persons ≥65 years of age if they experience signs and symptoms that may represent side effects when taking a dosage of 200 mg/day.\n# Persons Who Have Liver Disease\n\n# Amantadine\nNo increase in adverse reactions to amantadine has been observed among persons with liver disease.\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine have only been evaluated after single-dose administration. In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations were observed after a single dose. However, in persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease. A dose reduction to 100 mg/day is recommended for persons with severe hepatic dysfunction.\n# Persons Who Have Seizure Disorders\n\n# Amantadine\nAn increased incidence of seizures has been reported in patients with a history of seizure disorders who have received amantadine. Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.\n# Rimantadine\nIn clinical trials, seizures (or seizure-like activity) have been observed in a few persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine. The extent to which rimantadine may increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated, because such persons have usually been excluded from participating in clinical trials of rimantadine.\n# Children\n\n# Amantadine\nThe use of amantadine in children <1 year of age has not been adequately evaluated. The FDA-approved dosage for children 1-9 years of age is 4.4-8.8 mg/kg/day, not to exceed 150 mg/day. Although further studies to determine the optimal dosage for children are needed, physicians should consider prescribing only 5 mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children ≥10 years of age is 200 mg/day; however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable.\n# Rimantadine\nThe use of rimantadine in children <1 year of age has not been adequately evaluated. In children 1-9 years of age, rimantadine should be administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day. The approved dosage for children ≥10 years of age is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, also is recommended.\n# Drug Interactions\n\n# Amantadine\nCareful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants.\n# Rimantadine\nNo clinically significant drug interactions have been identified. For more detailed information concerning potential drug interactions for either drug, the package insert should be consulted.\n# Advisory Committee on Immunization Practices\nMembership List, October 1994 -Continued\n# SOURCES OF INFORMATION ON INFLUENZA-CONTROL PROGRAMS\nInformation regarding influenza surveillance is available through the CDC Voice Information System (influenza update), telephone (404) 332-4551, or through the CDC Information Service on the Public Health Network electronic bulletin board. From October through May, the information is updated at least every other week. In addition, periodic updates about influenza are published in the weekly MMWR. State and local health departments should be consulted regarding availability of influenza vaccine, access to vaccination programs, and information about state or local influenza activity. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":281,"cells":{"id":{"kind":"string","value":"a7fa1391a44c61d819d26fb23ab93572c601a2ea"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"# Preventing and Controlling Oral and Pharyngeal Cancer\nRecommendations from a National Strategic Planning Conference Summary In August 1996, CDC convened a national conference to develop strategies for preventing and controlling oral and pharyngeal cancer in the United States. The conference, which was cosponsored by the National Institute of Dental Research of the National Institutes of Health and the American Dental Association, included 125 experts in oral and pharyngeal cancer prevention, treatment, and research; both the private and public sectors were represented. Participants at the conference developed recommendations concerning advocacy, collaboration, and coalition building; public health policy; public education; professional education and practice; and data collection, evaluation, and research.\nA follow-up meeting consisting of selected participants of the 1996 conference was held in September 1997. During this meeting, changes that had occurred in the political and scientific arenas since the 1996 conference were considered, and 10 recommended strategies from the conference were selected for priority implementation. These 10 strategies were to a) establish a mechanism to implement and monitor the recommended strategies developed during the conference; b) urge oral health professionals to become more actively involved in community health; c) require instruction in preventing and controlling tobacco and alcohol use at all levels of training in dental, medical, nursing, and other related health-care disciplines; d) encourage Medicaid, Medicare, traditional insurance plans, and managed-care entities to consider making oral cancer examinations an integral part of comprehensive physical and oral examinations; e) designate federal funding for a national program of oral cancer prevention, early detection, and control; f) after assessing local needs, develop, implement, and evaluate statewide models to educate all relevant groups; g) develop and conduct a national promotional campaign to raise public awareness of oral cancer and its link to tobacco use and heavy alcohol consumption; h) develop health-care curricula that require competency in prevention, diagnosis, and multidisciplinary management of oral and pharyngeal cancer; i) sponsor and promote continuing education for health-care professionals on the multidisciplinary management of all phases of oral cancer and its sequelae; and j) strengthen organizational approaches to reducing oral cancer by developing organized cooperative and collaborative arrangements, funding formal centers, and involving commercial firms.\nCDC will use these recommended strategies to develop programs to reduce the burden of oral and pharyngeal cancer in the United States. Through the Oral Cancer Roundtable, a group of conference and meeting participants, CDC will communicate to interested agencies, organizations, and state health departments ways in which they can implement elements of the national plan. The Roundtable will help CDC track the efforts and progress of these groups.\n\n# INTRODUCTION\nDuring the past decade, federal health agencies have focused on reducing the incidence of oral and pharyngeal cancer and increasing the 5-year survival rate from these cancers in the United States. Beginning with a consortium of health agencies in 1992 (and including a strategic planning conference in 1996 and a follow-up meeting in 1997), CDC has been involved in concerted efforts to establish a national plan for preventing and controlling these cancers. This report presents recommended strategies for action from the 1996 conference and a list of priority recommendations from the 1997 meeting. These recommendations will enable CDC to develop a coordinated national plan to reduce morbidity and mortality from oral and pharyngeal cancer in the United States.\n\n# ORAL AND PHARYNGEAL CANCER\nOral cancer (i.e., cancer of the lip, tongue, floor of the mouth, palate, gingiva and alveolar mucosa, buccal mucosa, or oropharynx)- accounts for 2%-4% of cancers diagnosed annually in the United States; approximately two thirds occur in the oral cavity, and the remainder occurs in the oropharynx (1 ). In 1998, this diagnosis will be made in an estimated 30,300 Americans; approximately 8,000 deaths (5,200 males and 2,800 females) are expected in this year (2 ). Ninety-five percent of cases of oral cancer occur among persons aged >40 years, and the average age at diagnosis is 60 years (3 ). In 1950, the male-to-female ratio of oral cancer incidence was approximately 6:1; by 1997, it was approximately 2:1. The changing ratio is likely the result of the increase in smoking among women in the past three decades (3 ). In addition, cancer is an age-related disease, and in the United States, the number of women aged >65 years now exceeds the number of men aged >65 years by almost 50% (3 ). During 1990-1994, the annual incidence rate among black males in the United States was 1.6 times higher than the rate among white males (20.1 versus 12.9 new cases per 100,000) and the annual mortality rate among black males was 2.5 times higher (7.6 versus 3.1 deaths per 100,000); the annual incidence rate among black females was slightly higher than that among white females (5.6 versus 4.9 new cases per 100,000), as was the annual mortality rate (1.8 versus 1.2 deaths per 100,000) (4 ). Despite agressive combinations of surgery, radiation therapy, and chemotherapy, the 5-year survival rate for oral cancer is poor (blacks: 35%; whites: 55%) (1,5 ).\nTobacco smoking (i.e., cigarette, pipe, or cigar smoking), particularly when combined with heavy alcohol consumption (i.e., ≥30 drinks per week), has been identified as the primary risk factor for approximately 75% of oral cancers in the United States (6 ) . The use of tobacco in other forms (i.e., snuff and chew) has also been identified as a risk factor (7-9 ), as have certain other lifestyle and environmental factors (e.g., diet and occupational exposure to sunlight) (10 ).\nApproximately 90% of oral cancer lesions are squamous cell carcinomas. Persons who have oral cancer often develop multiple primary lesions (i.e., field cancerization), and they develop second primary tumors at a rate of approximately 4% annually (11 ). Persons having primary oral cancer are more likely to develop a second primary cancer of the aerodigestive tract (i.e., oral cavity, pharynx, esophagus, larynx, and lungs) *Hereafter, pharyngeal cancer is also included in the term oral cancer. (12,13 ). The initally diagnosed disease accounts for one half of the deaths caused by oral cancer; one fourth of these deaths are due to a second primary cancer, and the remaining one fourth are attributable to other illnesses (13 ).\nDiagnosing cancers at an early stage is crucial to improving survival rate and reducing morbidity. At the time of diagnosis of oral cancer, 36% of persons have localized disease, 43% have regional disease, and 9% have distant disease (for 12% the disease is unstaged) (4 ). The 5-year survival rate for persons having oral cancer is 81% for those with localized disease, 42% for patients with regional disease, and 17% for those with distant metastases (4 ). During the past decade, at diagnosis stage has not changed significantly (3 ).\n\n# ORAL CANCER STRATEGIC PLANNING CONFERENCE Background\nIn 1992, a consortium of health agencies led by CDC and the National Institute of Dental Research (NIDR) of the National Institutes of Health began to establish goals, objectives, and programs to reduce oral cancer morbidity and mortality in the United States. The Oral Cancer Work Group, which was formed as part of this initiative, subsequently developed short-term and long-term goals for preventing and controlling oral cancer. A list of these goals was disseminated to interested organizations and individuals in 1993.\nOne of the recommendations of the Oral Cancer Work Group was to summarize the state of the science regarding oral cancer. In response, CDC commissioned nine background papers regarding the prevention, control, and treatment of the disease and addressing current knowledge, emerging trends, opportunities, and barriers to further progress. The authors, representing several specialties and expertise, drew on current literature reviews, in-depth critiques, and personal experience.\nThe Oral Cancer Work Group also suggested that CDC convene a conference to develop national strategies to help make oral cancer prevention and control a higher public health priority. Subsequently, CDC, in partnership with NIDR and the American Dental Association (ADA), formed a conference planning group. The planning group, along with a larger cadre of oral cancer experts, developed a draft set of strategies. This draft and the nine background papers were distributed to invited participants before the conference.\n\n# Conference Format\nThe Oral Cancer Strategic Planning Conference was held August 7-9, 1996, at the ADA headquarters in Chicago. Participants included 125 invited experts in oral cancer prevention, treatment, and research; both the private and public sectors were represented. Following brief welcoming remarks by ADA, CDC, and NIDR representatives, nationally recognized experts made presentations on the etiology of oral cancer, its epidemiology, ongoing and needed research, and clinical experience with five other cancers (i.e., leukemia and breast, cervical, lung, and prostate cancers). A survivor of oral cancer described the human impact of the disease.\nConference participants broke into five work groups: advocacy, collaboration, and coalition building; public health policy; public education; professional education and practice; and data collection, evaluation, and research. Each work group had a chairperson and co-chairperson who were preselected from the conference participants; toward the conclusion of the conference, chairpersons presented their work groups' recommended strategies to all conference participants, who provided oral and written feedback. The work groups made revisions, including comments raised during the general session.\nAfter the conference, the recommended strategies were disseminated to all participants for final review and comments. These last comments were incorporated to produce the finalized recommended strategies to reduce oral cancer morbidity and mortality in the United States.\n\n# Recommended Strategies from Work Groups Advocacy, Collaboration, and Coalition Building\nThe work group on advocacy, collaboration, and coalition building (e.g., formation by the oral health community of partnerships with other health professionals and public or private organizations to facilitate increased awareness of the risk factors for oral cancer) developed three main recommended strategies.\n- Establish an ongoing, institutionalized mechanism to implement and monitor progress made regarding the recommended strategies developed during the conference.\n- Urge professionals in oral health and other health disciplines to become more actively involved in community health concerns, especially in preventing tobacco and heavy alcohol use, by -developing a comprehensive advocacy training program for a core group of oral health professionals; -recruiting persons from the health community and enrolling them in a national database for tobacco and oral cancer advocacy; -designing outreach programs to encourage local and state dental societies to be proactive in oral cancer and related coalitions; -establishing an advocacy network of oral cancer survivors; and -developing a speakers bureau of sports figures and other prominent persons willing to speak about risk factors for oral cancer and the importance of its early detection. - Increase excise taxes on tobacco and alcohol products to provide targeted funding for oral cancer prevention programs.\n- Strengthen and enforce laws regarding youth access to tobacco and alcohol.\n- Give the U.S. Food and Drug Administration regulatory authority over tobacco, because nicotine is an addictive drug.\n- Prohibit all advertising and promotional activities by the tobacco industry and conduct a well-funded counteradvertising campaign that focuses on cigarettes, cigars, pipe tobacco, and spit tobacco.\n- Deny federal health and medical research funding to organizations that accept health research funding from the tobacco industry or its research institutes.*\n- Increase excise taxes on spit tobacco to an amount equal to or greater than the taxes on cigarettes.\n- Encourage professional sports teams to ban the use of tobacco products among team members during practices and games.\n- Add strong statements to tobacco and alcohol warning labels about the risk of oral cancer. Ensure that tobacco warning labels cover 25%-30% of the front or back of a product's package and advertising copy. Model warnings after those used in Australia and Canada.\n\n# Professional Knowledge and Behaviors. †\n- Require instruction in preventing and controlling tobacco and alcohol use, including tobacco cessation, at all levels of training in dental, medical, nursing, and related health-care disciplines.\n- Ensure that clinicians learn procedures to detect oral cancer that are appropriate to their professional practice.\n- Urge all health professionals to routinely assess tobacco and alcohol intake by their patients.\n- Encourage health-care agencies and professionals to recommend that all clinicians who deliver primary health care routinely examine their patients for oral cancer. § *This strategy generated considerable discussion among the conference participants. The work group recognized this strategy could negatively affect research support for oral cancer but still recommended it. † These strategies complement those developed by the work group on professional education and practice but are listed here because of their implications for public policy. § The U.S. Preventive Services Task Force states that \"there is insufficient evidence to recommend for or against routine screening of asymptomatic persons for oral cancer by primary care physicians\" but that \"clinicians should remain alert to signs and symptoms of oral cancer and premalignancy in persons who use tobacco and alcohol\" (16 ). The work group, however, believed that all persons should be routinely examined and chose a stronger recommendation.\n\n# Compensation.\n- Work with the ADA and the American Medical Association to reaffirm that existing codes for reimbursement (e.g., Common Procedure Terminology and Common Dental Terminology) appropriately identify oral cancer examinations as part of the standard oral examination.\n- Encourage Medicaid, Medicare, traditional insurance plans, and managed-care entities to make oral cancer examinations an integral part of comprehensive physical and oral examinations.\n- Base reimbursement for oral cancer examinations on the service provided rather than the academic degree of the provider.\n\n# National Programs.\n- Designate federal funding for a national program of oral cancer prevention, early detection, and control that includes support for outcomes assessment and policy-based research.\n\n# Public Education\nSeven major strategies were recommended by the work group on public education.\n- Develop and disseminate guidelines and lists of resources to assist communities (e.g., states, counties, cities, towns, and members of organizations and institutions) in developing, implementing, and evaluating models for oral cancer education. This effort could include an inventory of available guidelines, literature, processes, and educational models.\n- Develop, implement, and evaluate statewide models to educate all relevant groups. These models should be tailored to local needs, practical, culturally appropriate, and user friendly and should include the following content areas:\n-risk factors for oral cancer (e.g., tobacco use, alcohol use, and nutritional deficiencies); -signs and symptoms of oral cancer; -procedures for a thorough oral cancer examination and the ease with which the examination can be performed; and -methods of public advocacy.\n- Pursuade relevant CDC and National Institutes of Health decisionmakers, members of Congress, and members of other organizations to secure funding for statewide oral cancer model demonstration projects and to establish an oral health component in CDC's Initiatives to Mobilize for the Prevention and Control of Tobacco Use (IMPACT) program.\n- Develop and conduct a national campaign to raise public awareness of oral cancer and its link to tobacco use and heavy alcohol consumption. The campaign might include a mascot or logo, sports figures or other distinguished persons as spokespersons, or a national oral cancer awareness week.\n- Ensure that behavioral and educational research in oral cancer is included in the budget of organizations that sponsor such research (e.g., the National Institutes of Health, universities, and foundations).\n- Increase the representation of educators, behavioral scientists, and oral cancer specialists on the grant review committees of cancer and dental research institutions.\n- Ensure that a national research agenda is developed that includes the following:\n-ongoing surveillance to monitor knowledge, opinions, attitudes, and practices of the public, especially populations at high risk for oral cancer; -surveys of the knowledge, opinions, attitudes, and practices of relevant healthcare providers regarding oral cancer; -evaluations of the effectiveness of educational interventions among targeted populations; -changes in existing survey instruments (e.g., the National Health Interview Survey) to include items on oral cancer comparable to items on other cancers; -inclusion of oral cancer questions in state Behavioral Risk Factor Surveillance System surveys; -determination of the proficiency of persons who have been taught to perform an oral cancer self-examination; and -assessment of the quality (e.g., reading level or scientific accuracy), quantity, and availability of educational materials directed to the public about oral cancer.\n\n# Professional Education and Practice\nThis work group developed five recommended strategies.\n- Develop health-care curricula that require competency in prevention, diagnosis, and multidisciplinary management of oral cancer, including the prevention and cessation of tobacco use and alcohol abuse.\n- Promote soft tissue examination for oral cancer as a standard part of a complete patient examination.\n- Develop, promote, and maintain a database of all professional education materials related to oral cancer.\n- Define, identify, develop, and promote centers of excellence in oral cancer management.\n- Sponsor and promote continuing education for health-care professionals on the multidisciplinary management of all phases of oral cancer and its sequelae.\nIn addition, the work group identified seven initiatives that would facilitate achievement of their recommended strategies: develop educational standards and standards of care for oral cancer; standardize techniques for oral cancer examination and implement them consistently; create a national speakers bureau with standardized educational materials; place an oral cancer home page on the World Wide Web; create guidelines for developing screening and detection programs; develop self-instructional materials for health professionals on a range of topics (e.g., risk factors, early detection, and counseling of high-risk patients); and identify and catalog professional education materials, determine deficits in these materials, and ensure access to the cataloged materials. appropriate biopsy specimens, research subjects and patients, and research findings so that researchers can maximize the information gained from biological studies; and developing laboratory assays that conserve specimens, thus allowing for multiple assessments of the same tissue; and -evaluating innovative approaches for identifying persons at greatest risk for oral cancer and recruiting them for research studies (e.g., form partnerships with organizations serving residents of homeless shelters or clients of alcohol treatment centers).\n- Develop valid and reliable patient-oriented indices of health, quality of life, and functioning.\n- - Create multidisciplinary groups to facilitate movement of findings in two directions-from basic research to applied research and from research in the clinical sciences, epidemiology, and health-services delivery to basic science-thus helping to focus basic research efforts. Such strategies may include the following:\n-developing innovative science transfer techniques (e.g., Internet applications) for researchers, clinicians, and the public; -develop effective means of communicating the complex biological processes to clinicians, students, and the public; and -increasing research on how health-care practitioners and the public understand and act on the concept of risk of a disease and its consequences.\n- Strengthen organizational approaches to reducing oral cancer by developing cooperative and collaborative arrangements, funding formal centers, and involving commercial firms. The following means are suggested:\n-consortia of researchers and medical and dental practitioners could share patient sources, standardize clinical protocols, achieve adequate sample sizes, recruit patients and at-risk persons for research studies, and enhance science transfer; individual practitioners as well as organizations (e.g., alcohol treatment centers) that serve populations at risk for oral cancer or its sequelae could be sources of study subjects; -other formal centers could be established in addition to those funded by NIDR and the National Cancer Institute; and -commercial firms could use their marketing and distribution systems to enhance science transfer, health promotion, and disease prevention activities; in addition, they could join with academic or government groups to fund or otherwise facilitate research.\n\n# ORAL CANCER WORKING GROUP\nThe Oral Cancer Working Group, a multidisciplinary group who attended the 1996 Oral Cancer Strategic Planning Conference, met September 29-30, 1997, to identify 10 strategies from the 1996 meeting recommendations to receive immediate attention and implementation by the agencies they represented. The Oral Cancer Working Group considered political and scientific changes that had occurred after the 1996 conference (e.g., the U.S. Food and Drug Administration had been given regulatory authority over tobacco, legal cases involving tobacco had been settled in several states, national tobacco legislation had been proposed, and four comprehensive oral cancer research centers had been funded by NIDR) and selected strategies the group could effect (as opposed to strategies already under way as a result of the leadership and support of other groups). Leadership at the 1997 meeting was shared by representatives of ADA, the American Association of Dental Research, the Association of State and Territorial Dental Directors, CDC, the International Society of Oral Oncology, NIDR, and Oral Health America. The 10 priority strategies are as follows.\n\n# Advocacy, Collaboration, and Coalition Building\n- Establish a mechanism to implement and monitor progress made regarding the recommended strategies developed during the 1996 national conference.\n- Urge oral health professionals to become more actively involved in community health concerns.\n\n# Public Health Policy\n- Require instruction in preventing and controlling tobacco and alcohol use at all levels of training in dental, medical, nursing, and related health-care disciplines.\n- Encourage Medicaid, Medicare, traditional insurance plans, and managed-care entities to make oral cancer examinations an integral part of comprehensive physical and oral examinations.\n- Designate federal funding for a national program of oral cancer prevention, early detection, and control.\n\n# Public Education\n- After assessing local needs, develop, implement, and evaluate statewide models to educate all relevant groups.\n- Develop and conduct a national campaign to raise public awareness of oral cancer and its link to tobacco use and heavy alcohol consumption.\n\n# Professional Education and Practice\n- Develop health-care curricula that require competency in prevention, diagnosis, and multidisciplinary management of oral cancer.\n\n# Public Health Policy\nThis work group presented its recommended strategies in four categories.\n\n# Prevention and Control of Tobacco and Alcohol Use.\n\n# Data Collection, Evaluation, and Research\nThese recommended strategies would facilitate research regarding the etiology, prevention, and treatment of oral cancer and would translate research findings into effective public health action.\n- Increase funding or target existing funding to initiate and sustain research concerning oral cancer.\n- Improve the capacity of individual health practitioners and small medical centers to participate in research regarding prevention strategies and therapeutic approaches.*\n- Develop curricula for basic preparation and continuing education for health professionals that will improve their knowledge of the nature, value, implementation, and importance of well-designed and well-conducted research studies.\n- Improve researchers' access to tissues, study populations, and data sources.\nPossible approaches include -using population-based cancer registries for follow-up studies; -combining information from state-based population-based cancer registries and from national registries (e.g., the Surveillance, Epidemiology, and End Results program) to help develop an enhanced descriptive epidemiology of oral cancer, particularly for smaller subpopulations insufficiently represented in the SEER or state registries; -encouraging the use of existing databases, either singly or in combination, to address questions about oral cancer care, consequences, and costs (e.g., one such database combines SEER incidence and survival data for Medicare beneficiaries with their Medicare claims data); -developing a systematic approach to providing researchers with access to tissue specimens and detailed information about the behavioral and medical characteristics of persons who are at high risk for oral cancer, have premalignant lesions, or currently have oral cancer; finding creative ways to share - This strategy would facilitate execution of multicenter studies, which are often needed to produce highly generalizable findings and to provide adequate statistical power to detect relatively small differences. It also recognizes the growing trend toward treating oral cancer in ambulatory settings and within managed-care delivery systems. Differences in treatment outcomes for all the major delivery systems and settings cannot be assessed completely if physicians' and dentists' offices are not included in research studies of small medical centers.\n- Sponsor and promote continuing education for health-care professionals on the multidisciplinary management of all phases of oral cancer and its sequelae.\n\n# Data Collection, Evaluation, and Research\n- Strengthen organizational approaches to reducing oral cancer by developing cooperative and collaborative arrangements, funding formal centers, and involving commercial firms.\nAt the 1997 follow-up meeting, the Oral Cancer Working Group created a smaller group known as the Oral Cancer Roundtable. Members of the Roundtable will communicate among themselves to discuss implemention of the priority recommendations and the recommendations from the 1996 conference and to share information on progress made. Through the Roundtable, CDC will communicate to interested agencies, organizations, and state health departmets ways in which they can implement elements of the national plan. The Roundtable will help CDC track the efforts and progress of these groups.\n\n# CONCLUSION\nNational efforts to reduce morbidity and mortality associated with oral cancer must focus on two areas: primary prevention (i.e., reducing risk factors) and early detection. Although persons at high risk for the disease are more likely to visit a physician than a dentist, physicians may be less likely than dentists to perform an oral cancer examination on such patients (17)(18)(19)(20)(21). Thus, all primary-care providers must assume more responsiblity for counseling patients about behaviors that put them at risk for developing this cancer, examining patients who are at high risk for developing the disease because of tobacco use or excessive alcohol consumption (22 ), and referring patients to an appropriate specialist for management of a suspicious oral lesion. Comprehensive education of medical and dental practitioners in diagnosing and promptly managing early lesions could facilitate the multidisciplinary collaboration necessary to detect oral cancer in its earliest stages. Furthermore, because of the public's lack of knowlege about the risk factors for oral cancer and because this disease can often be detected in its early stages (21,23 ), the public's awareness of oral cancer (including its risk factors, signs, and symptoms) must also be increased.\nOral cancer occurs in sites that lend themselves to early detection by most primary health-care providers and, to a lesser extent, by self-examination. Heightened awareness in the general population could help with early detection of this cancer and could stimulate dialogue between patients and their primary health-care providers about behaviors that may increase the risk for developing oral cancer. Recent advances in understanding the molecular events involved in developing cancer might provide the tools needed to design novel preventive, diagnostic, prognostic, and therapeutic regimens to combat oral cancer. Acquiring greater knowledge of the biology, immunology, and pathology of the oral mucosa may also help to reduce the morbidity and mortality from this disease.\n\n# The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on"},"raw_text":{"kind":"string","value":"# Preventing and Controlling Oral and Pharyngeal Cancer\nRecommendations from a National Strategic Planning Conference Summary In August 1996, CDC convened a national conference to develop strategies for preventing and controlling oral and pharyngeal cancer in the United States. The conference, which was cosponsored by the National Institute of Dental Research of the National Institutes of Health and the American Dental Association, included 125 experts in oral and pharyngeal cancer prevention, treatment, and research; both the private and public sectors were represented. Participants at the conference developed recommendations concerning advocacy, collaboration, and coalition building; public health policy; public education; professional education and practice; and data collection, evaluation, and research.\nA follow-up meeting consisting of selected participants of the 1996 conference was held in September 1997. During this meeting, changes that had occurred in the political and scientific arenas since the 1996 conference were considered, and 10 recommended strategies from the conference were selected for priority implementation. These 10 strategies were to a) establish a mechanism to implement and monitor the recommended strategies developed during the conference; b) urge oral health professionals to become more actively involved in community health; c) require instruction in preventing and controlling tobacco and alcohol use at all levels of training in dental, medical, nursing, and other related health-care disciplines; d) encourage Medicaid, Medicare, traditional insurance plans, and managed-care entities to consider making oral cancer examinations an integral part of comprehensive physical and oral examinations; e) designate federal funding for a national program of oral cancer prevention, early detection, and control; f) after assessing local needs, develop, implement, and evaluate statewide models to educate all relevant groups; g) develop and conduct a national promotional campaign to raise public awareness of oral cancer and its link to tobacco use and heavy alcohol consumption; h) develop health-care curricula that require competency in prevention, diagnosis, and multidisciplinary management of oral and pharyngeal cancer; i) sponsor and promote continuing education for health-care professionals on the multidisciplinary management of all phases of oral cancer and its sequelae; and j) strengthen organizational approaches to reducing oral cancer by developing organized cooperative and collaborative arrangements, funding formal centers, and involving commercial firms.\nCDC will use these recommended strategies to develop programs to reduce the burden of oral and pharyngeal cancer in the United States. Through the Oral Cancer Roundtable, a group of conference and meeting participants, CDC will communicate to interested agencies, organizations, and state health departments ways in which they can implement elements of the national plan. The Roundtable will help CDC track the efforts and progress of these groups.\n# INTRODUCTION\nDuring the past decade, federal health agencies have focused on reducing the incidence of oral and pharyngeal cancer and increasing the 5-year survival rate from these cancers in the United States. Beginning with a consortium of health agencies in 1992 (and including a strategic planning conference in 1996 and a follow-up meeting in 1997), CDC has been involved in concerted efforts to establish a national plan for preventing and controlling these cancers. This report presents recommended strategies for action from the 1996 conference and a list of priority recommendations from the 1997 meeting. These recommendations will enable CDC to develop a coordinated national plan to reduce morbidity and mortality from oral and pharyngeal cancer in the United States.\n# ORAL AND PHARYNGEAL CANCER\nOral cancer (i.e., cancer of the lip, tongue, floor of the mouth, palate, gingiva and alveolar mucosa, buccal mucosa, or oropharynx)* accounts for 2%-4% of cancers diagnosed annually in the United States; approximately two thirds occur in the oral cavity, and the remainder occurs in the oropharynx (1 ). In 1998, this diagnosis will be made in an estimated 30,300 Americans; approximately 8,000 deaths (5,200 males and 2,800 females) are expected in this year (2 ). Ninety-five percent of cases of oral cancer occur among persons aged >40 years, and the average age at diagnosis is 60 years (3 ). In 1950, the male-to-female ratio of oral cancer incidence was approximately 6:1; by 1997, it was approximately 2:1. The changing ratio is likely the result of the increase in smoking among women in the past three decades (3 ). In addition, cancer is an age-related disease, and in the United States, the number of women aged >65 years now exceeds the number of men aged >65 years by almost 50% (3 ). During 1990-1994, the annual incidence rate among black males in the United States was 1.6 times higher than the rate among white males (20.1 versus 12.9 new cases per 100,000) and the annual mortality rate among black males was 2.5 times higher (7.6 versus 3.1 deaths per 100,000); the annual incidence rate among black females was slightly higher than that among white females (5.6 versus 4.9 new cases per 100,000), as was the annual mortality rate (1.8 versus 1.2 deaths per 100,000) (4 ). Despite agressive combinations of surgery, radiation therapy, and chemotherapy, the 5-year survival rate for oral cancer is poor (blacks: 35%; whites: 55%) (1,5 ).\nTobacco smoking (i.e., cigarette, pipe, or cigar smoking), particularly when combined with heavy alcohol consumption (i.e., ≥30 drinks per week), has been identified as the primary risk factor for approximately 75% of oral cancers in the United States (6 ) . The use of tobacco in other forms (i.e., snuff and chew) has also been identified as a risk factor (7-9 ), as have certain other lifestyle and environmental factors (e.g., diet and occupational exposure to sunlight) (10 ).\nApproximately 90% of oral cancer lesions are squamous cell carcinomas. Persons who have oral cancer often develop multiple primary lesions (i.e., field cancerization), and they develop second primary tumors at a rate of approximately 4% annually (11 ). Persons having primary oral cancer are more likely to develop a second primary cancer of the aerodigestive tract (i.e., oral cavity, pharynx, esophagus, larynx, and lungs) *Hereafter, pharyngeal cancer is also included in the term oral cancer. (12,13 ). The initally diagnosed disease accounts for one half of the deaths caused by oral cancer; one fourth of these deaths are due to a second primary cancer, and the remaining one fourth are attributable to other illnesses (13 ).\nDiagnosing cancers at an early stage is crucial to improving survival rate and reducing morbidity. At the time of diagnosis of oral cancer, 36% of persons have localized disease, 43% have regional disease, and 9% have distant disease (for 12% the disease is unstaged) (4 ). The 5-year survival rate for persons having oral cancer is 81% for those with localized disease, 42% for patients with regional disease, and 17% for those with distant metastases (4 ). During the past decade, at diagnosis stage has not changed significantly (3 ).\n# ORAL CANCER STRATEGIC PLANNING CONFERENCE Background\nIn 1992, a consortium of health agencies led by CDC and the National Institute of Dental Research (NIDR) of the National Institutes of Health began to establish goals, objectives, and programs to reduce oral cancer morbidity and mortality in the United States. The Oral Cancer Work Group, which was formed as part of this initiative, subsequently developed short-term and long-term goals for preventing and controlling oral cancer. A list of these goals was disseminated to interested organizations and individuals in 1993.\nOne of the recommendations of the Oral Cancer Work Group was to summarize the state of the science regarding oral cancer. In response, CDC commissioned nine background papers regarding the prevention, control, and treatment of the disease and addressing current knowledge, emerging trends, opportunities, and barriers to further progress. The authors, representing several specialties and expertise, drew on current literature reviews, in-depth critiques, and personal experience.\nThe Oral Cancer Work Group also suggested that CDC convene a conference to develop national strategies to help make oral cancer prevention and control a higher public health priority. Subsequently, CDC, in partnership with NIDR and the American Dental Association (ADA), formed a conference planning group. The planning group, along with a larger cadre of oral cancer experts, developed a draft set of strategies. This draft and the nine background papers were distributed to invited participants before the conference.\n# Conference Format\nThe Oral Cancer Strategic Planning Conference was held August 7-9, 1996, at the ADA headquarters in Chicago. Participants included 125 invited experts in oral cancer prevention, treatment, and research; both the private and public sectors were represented. Following brief welcoming remarks by ADA, CDC, and NIDR representatives, nationally recognized experts made presentations on the etiology of oral cancer, its epidemiology, ongoing and needed research, and clinical experience with five other cancers (i.e., leukemia and breast, cervical, lung, and prostate cancers). A survivor of oral cancer described the human impact of the disease.\nConference participants broke into five work groups: advocacy, collaboration, and coalition building; public health policy; public education; professional education and practice; and data collection, evaluation, and research. Each work group had a chairperson and co-chairperson who were preselected from the conference participants; toward the conclusion of the conference, chairpersons presented their work groups' recommended strategies to all conference participants, who provided oral and written feedback. The work groups made revisions, including comments raised during the general session.\nAfter the conference, the recommended strategies were disseminated to all participants for final review and comments. These last comments were incorporated to produce the finalized recommended strategies to reduce oral cancer morbidity and mortality in the United States.\n# Recommended Strategies from Work Groups Advocacy, Collaboration, and Coalition Building\nThe work group on advocacy, collaboration, and coalition building (e.g., formation by the oral health community of partnerships with other health professionals and public or private organizations to facilitate increased awareness of the risk factors for oral cancer) developed three main recommended strategies.\n• Establish an ongoing, institutionalized mechanism to implement and monitor progress made regarding the recommended strategies developed during the conference.\n• Urge professionals in oral health and other health disciplines to become more actively involved in community health concerns, especially in preventing tobacco and heavy alcohol use, by -developing a comprehensive advocacy training program for a core group of oral health professionals; -recruiting persons from the health community and enrolling them in a national database for tobacco and oral cancer advocacy; -designing outreach programs to encourage local and state dental societies to be proactive in oral cancer and related coalitions; -establishing an advocacy network of oral cancer survivors; and -developing a speakers bureau of sports figures and other prominent persons willing to speak about risk factors for oral cancer and the importance of its early detection. • Increase excise taxes on tobacco and alcohol products to provide targeted funding for oral cancer prevention programs.\n• Strengthen and enforce laws regarding youth access to tobacco and alcohol.\n• Give the U.S. Food and Drug Administration regulatory authority over tobacco, because nicotine is an addictive drug.\n• Prohibit all advertising and promotional activities by the tobacco industry and conduct a well-funded counteradvertising campaign that focuses on cigarettes, cigars, pipe tobacco, and spit tobacco.\n• Deny federal health and medical research funding to organizations that accept health research funding from the tobacco industry or its research institutes.*\n• Increase excise taxes on spit tobacco to an amount equal to or greater than the taxes on cigarettes.\n• Encourage professional sports teams to ban the use of tobacco products among team members during practices and games.\n• Add strong statements to tobacco and alcohol warning labels about the risk of oral cancer. Ensure that tobacco warning labels cover 25%-30% of the front or back of a product's package and advertising copy. Model warnings after those used in Australia and Canada.\n# Professional Knowledge and Behaviors. †\n• Require instruction in preventing and controlling tobacco and alcohol use, including tobacco cessation, at all levels of training in dental, medical, nursing, and related health-care disciplines.\n• Ensure that clinicians learn procedures to detect oral cancer that are appropriate to their professional practice.\n• Urge all health professionals to routinely assess tobacco and alcohol intake by their patients.\n• Encourage health-care agencies and professionals to recommend that all clinicians who deliver primary health care routinely examine their patients for oral cancer. § *This strategy generated considerable discussion among the conference participants. The work group recognized this strategy could negatively affect research support for oral cancer but still recommended it. † These strategies complement those developed by the work group on professional education and practice but are listed here because of their implications for public policy. § The U.S. Preventive Services Task Force states that \"there is insufficient evidence to recommend for or against routine screening of asymptomatic persons for oral cancer by primary care physicians\" but that \"clinicians should remain alert to signs and symptoms of oral cancer and premalignancy in persons who use tobacco and alcohol\" (16 ). The work group, however, believed that all persons should be routinely examined and chose a stronger recommendation.\n# Compensation.\n• Work with the ADA and the American Medical Association to reaffirm that existing codes for reimbursement (e.g., Common Procedure Terminology and Common Dental Terminology) appropriately identify oral cancer examinations as part of the standard oral examination.\n• Encourage Medicaid, Medicare, traditional insurance plans, and managed-care entities to make oral cancer examinations an integral part of comprehensive physical and oral examinations.\n• Base reimbursement for oral cancer examinations on the service provided rather than the academic degree of the provider.\n# National Programs.\n• Designate federal funding for a national program of oral cancer prevention, early detection, and control that includes support for outcomes assessment and policy-based research.\n# Public Education\nSeven major strategies were recommended by the work group on public education.\n• Develop and disseminate guidelines and lists of resources to assist communities (e.g., states, counties, cities, towns, and members of organizations and institutions) in developing, implementing, and evaluating models for oral cancer education. This effort could include an inventory of available guidelines, literature, processes, and educational models.\n• Develop, implement, and evaluate statewide models to educate all relevant groups. These models should be tailored to local needs, practical, culturally appropriate, and user friendly and should include the following content areas:\n-risk factors for oral cancer (e.g., tobacco use, alcohol use, and nutritional deficiencies); -signs and symptoms of oral cancer; -procedures for a thorough oral cancer examination and the ease with which the examination can be performed; and -methods of public advocacy.\n• Pursuade relevant CDC and National Institutes of Health decisionmakers, members of Congress, and members of other organizations to secure funding for statewide oral cancer model demonstration projects and to establish an oral health component in CDC's Initiatives to Mobilize for the Prevention and Control of Tobacco Use (IMPACT) program.\n• Develop and conduct a national campaign to raise public awareness of oral cancer and its link to tobacco use and heavy alcohol consumption. The campaign might include a mascot or logo, sports figures or other distinguished persons as spokespersons, or a national oral cancer awareness week.\n• Ensure that behavioral and educational research in oral cancer is included in the budget of organizations that sponsor such research (e.g., the National Institutes of Health, universities, and foundations).\n• Increase the representation of educators, behavioral scientists, and oral cancer specialists on the grant review committees of cancer and dental research institutions.\n• Ensure that a national research agenda is developed that includes the following:\n-ongoing surveillance to monitor knowledge, opinions, attitudes, and practices of the public, especially populations at high risk for oral cancer; -surveys of the knowledge, opinions, attitudes, and practices of relevant healthcare providers regarding oral cancer; -evaluations of the effectiveness of educational interventions among targeted populations; -changes in existing survey instruments (e.g., the National Health Interview Survey) to include items on oral cancer comparable to items on other cancers; -inclusion of oral cancer questions in state Behavioral Risk Factor Surveillance System surveys; -determination of the proficiency of persons who have been taught to perform an oral cancer self-examination; and -assessment of the quality (e.g., reading level or scientific accuracy), quantity, and availability of educational materials directed to the public about oral cancer.\n# Professional Education and Practice\nThis work group developed five recommended strategies.\n• Develop health-care curricula that require competency in prevention, diagnosis, and multidisciplinary management of oral cancer, including the prevention and cessation of tobacco use and alcohol abuse.\n• Promote soft tissue examination for oral cancer as a standard part of a complete patient examination.\n• Develop, promote, and maintain a database of all professional education materials related to oral cancer.\n• Define, identify, develop, and promote centers of excellence in oral cancer management.\n• Sponsor and promote continuing education for health-care professionals on the multidisciplinary management of all phases of oral cancer and its sequelae.\nIn addition, the work group identified seven initiatives that would facilitate achievement of their recommended strategies: develop educational standards and standards of care for oral cancer; standardize techniques for oral cancer examination and implement them consistently; create a national speakers bureau with standardized educational materials; place an oral cancer home page on the World Wide Web; create guidelines for developing screening and detection programs; develop self-instructional materials for health professionals on a range of topics (e.g., risk factors, early detection, and counseling of high-risk patients); and identify and catalog professional education materials, determine deficits in these materials, and ensure access to the cataloged materials. appropriate biopsy specimens, research subjects and patients, and research findings so that researchers can maximize the information gained from biological studies; and developing laboratory assays that conserve specimens, thus allowing for multiple assessments of the same tissue; and -evaluating innovative approaches for identifying persons at greatest risk for oral cancer and recruiting them for research studies (e.g., form partnerships with organizations serving residents of homeless shelters or clients of alcohol treatment centers).\n• Develop valid and reliable patient-oriented indices of health, quality of life, and functioning.\n• • Create multidisciplinary groups to facilitate movement of findings in two directions-from basic research to applied research and from research in the clinical sciences, epidemiology, and health-services delivery to basic science-thus helping to focus basic research efforts. Such strategies may include the following:\n-developing innovative science transfer techniques (e.g., Internet applications) for researchers, clinicians, and the public; -develop effective means of communicating the complex biological processes to clinicians, students, and the public; and -increasing research on how health-care practitioners and the public understand and act on the concept of risk of a disease and its consequences.\n• Strengthen organizational approaches to reducing oral cancer by developing cooperative and collaborative arrangements, funding formal centers, and involving commercial firms. The following means are suggested:\n-consortia of researchers and medical and dental practitioners could share patient sources, standardize clinical protocols, achieve adequate sample sizes, recruit patients and at-risk persons for research studies, and enhance science transfer; individual practitioners as well as organizations (e.g., alcohol treatment centers) that serve populations at risk for oral cancer or its sequelae could be sources of study subjects; -other formal centers could be established in addition to those funded by NIDR and the National Cancer Institute; and -commercial firms could use their marketing and distribution systems to enhance science transfer, health promotion, and disease prevention activities; in addition, they could join with academic or government groups to fund or otherwise facilitate research.\n# ORAL CANCER WORKING GROUP\nThe Oral Cancer Working Group, a multidisciplinary group who attended the 1996 Oral Cancer Strategic Planning Conference, met September 29-30, 1997, to identify 10 strategies from the 1996 meeting recommendations to receive immediate attention and implementation by the agencies they represented. The Oral Cancer Working Group considered political and scientific changes that had occurred after the 1996 conference (e.g., the U.S. Food and Drug Administration had been given regulatory authority over tobacco, legal cases involving tobacco had been settled in several states, national tobacco legislation had been proposed, and four comprehensive oral cancer research centers had been funded by NIDR) and selected strategies the group could effect (as opposed to strategies already under way as a result of the leadership and support of other groups). Leadership at the 1997 meeting was shared by representatives of ADA, the American Association of Dental Research, the Association of State and Territorial Dental Directors, CDC, the International Society of Oral Oncology, NIDR, and Oral Health America. The 10 priority strategies are as follows.\n# Advocacy, Collaboration, and Coalition Building\n• Establish a mechanism to implement and monitor progress made regarding the recommended strategies developed during the 1996 national conference.\n• Urge oral health professionals to become more actively involved in community health concerns.\n# Public Health Policy\n• Require instruction in preventing and controlling tobacco and alcohol use at all levels of training in dental, medical, nursing, and related health-care disciplines.\n• Encourage Medicaid, Medicare, traditional insurance plans, and managed-care entities to make oral cancer examinations an integral part of comprehensive physical and oral examinations.\n• Designate federal funding for a national program of oral cancer prevention, early detection, and control.\n# Public Education\n• After assessing local needs, develop, implement, and evaluate statewide models to educate all relevant groups.\n• Develop and conduct a national campaign to raise public awareness of oral cancer and its link to tobacco use and heavy alcohol consumption.\n# Professional Education and Practice\n• Develop health-care curricula that require competency in prevention, diagnosis, and multidisciplinary management of oral cancer.\n# Public Health Policy\nThis work group presented its recommended strategies in four categories.\n# Prevention and Control of Tobacco and Alcohol Use.\n\n# Data Collection, Evaluation, and Research\nThese recommended strategies would facilitate research regarding the etiology, prevention, and treatment of oral cancer and would translate research findings into effective public health action.\n• Increase funding or target existing funding to initiate and sustain research concerning oral cancer.\n• Improve the capacity of individual health practitioners and small medical centers to participate in research regarding prevention strategies and therapeutic approaches.*\n• Develop curricula for basic preparation and continuing education for health professionals that will improve their knowledge of the nature, value, implementation, and importance of well-designed and well-conducted research studies.\n• Improve researchers' access to tissues, study populations, and data sources.\nPossible approaches include -using population-based cancer registries for follow-up studies; -combining information from state-based population-based cancer registries and from national registries (e.g., the Surveillance, Epidemiology, and End Results [SEER] program) to help develop an enhanced descriptive epidemiology of oral cancer, particularly for smaller subpopulations insufficiently represented in the SEER or state registries; -encouraging the use of existing databases, either singly or in combination, to address questions about oral cancer care, consequences, and costs (e.g., one such database combines SEER incidence and survival data for Medicare beneficiaries with their Medicare claims data); -developing a systematic approach to providing researchers with access to tissue specimens and detailed information about the behavioral and medical characteristics of persons who are at high risk for oral cancer, have premalignant lesions, or currently have oral cancer; finding creative ways to share * This strategy would facilitate execution of multicenter studies, which are often needed to produce highly generalizable findings and to provide adequate statistical power to detect relatively small differences. It also recognizes the growing trend toward treating oral cancer in ambulatory settings and within managed-care delivery systems. Differences in treatment outcomes for all the major delivery systems and settings cannot be assessed completely if physicians' and dentists' offices are not included in research studies of small medical centers.\n• Sponsor and promote continuing education for health-care professionals on the multidisciplinary management of all phases of oral cancer and its sequelae.\n# Data Collection, Evaluation, and Research\n• Strengthen organizational approaches to reducing oral cancer by developing cooperative and collaborative arrangements, funding formal centers, and involving commercial firms.\nAt the 1997 follow-up meeting, the Oral Cancer Working Group created a smaller group known as the Oral Cancer Roundtable. Members of the Roundtable will communicate among themselves to discuss implemention of the priority recommendations and the recommendations from the 1996 conference and to share information on progress made. Through the Roundtable, CDC will communicate to interested agencies, organizations, and state health departmets ways in which they can implement elements of the national plan. The Roundtable will help CDC track the efforts and progress of these groups.\n# CONCLUSION\nNational efforts to reduce morbidity and mortality associated with oral cancer must focus on two areas: primary prevention (i.e., reducing risk factors) and early detection. Although persons at high risk for the disease are more likely to visit a physician than a dentist, physicians may be less likely than dentists to perform an oral cancer examination on such patients (17)(18)(19)(20)(21). Thus, all primary-care providers must assume more responsiblity for counseling patients about behaviors that put them at risk for developing this cancer, examining patients who are at high risk for developing the disease because of tobacco use or excessive alcohol consumption (22 ), and referring patients to an appropriate specialist for management of a suspicious oral lesion. Comprehensive education of medical and dental practitioners in diagnosing and promptly managing early lesions could facilitate the multidisciplinary collaboration necessary to detect oral cancer in its earliest stages. Furthermore, because of the public's lack of knowlege about the risk factors for oral cancer and because this disease can often be detected in its early stages (21,23 ), the public's awareness of oral cancer (including its risk factors, signs, and symptoms) must also be increased.\nOral cancer occurs in sites that lend themselves to early detection by most primary health-care providers and, to a lesser extent, by self-examination. Heightened awareness in the general population could help with early detection of this cancer and could stimulate dialogue between patients and their primary health-care providers about behaviors that may increase the risk for developing oral cancer. Recent advances in understanding the molecular events involved in developing cancer might provide the tools needed to design novel preventive, diagnostic, prognostic, and therapeutic regimens to combat oral cancer. Acquiring greater knowledge of the biology, immunology, and pathology of the oral mucosa may also help to reduce the morbidity and mortality from this disease. \n# The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":282,"cells":{"id":{"kind":"string","value":"8b96b7ae1309f9f046783485fed2205f7c8c8f52"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"The term nosocomial infection is retained to refer only to infections acquired in hospitals. The term healthcare-associated infection (HAI) is used to refer to infections associated with healthcare delivery in any setting (e.g., hospitals, long-term care facilities, ambulatory settings, home care). This term reflects the inability to determine with certainty where the pathogen is acquired since patients may be colonized with or exposed to potential pathogens outside of the healthcare setting, before receiving health care, or may develop infections caused by those pathogens when exposed to the conditions associated with delivery of healthcare. Additionally, patients frequently move among the various settings within a healthcare system 8 . A new addition to the practice recommendations for Standard Precautions is Respiratory Hygiene/Cough Etiquette. While Standard Precautions generally apply to the recommended practices of healthcare personnel during patient care, Respiratory Hygiene/Cough Etiquette applies broadly to all persons who enter a healthcare setting, including healthcare personnel, patients and visitors. These recommendations evolved from observations during the SARS epidemic that failure to implement basic source control measures with patients, visitors, and healthcare personnel with signs and symptoms of respiratory tract infection may have contributed to SARS coronavirus (SARS-CoV) transmission. This concept has been incorporated into CDC planning documents for SARS and pandemic influenza 9, 10 . The term \"Airborne Precautions\" has been supplemented with the term \"Airborne Infection Isolation Room (AIIR)\" for consistency with the Guidelines for Environmental Infection Control in Healthcare Facilities 11 , the Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings 2005 12 and the American Institute of Architects (AIA) guidelines for design and construction of hospitals, 2006 13 A set of prevention measures termed Protective Environment has been added to the precautions used to prevent HAIs. These measures, which have been defined in other guidelines , consist of engineering and design interventions that decrease the risk of exposure to environmental fungi for severely immunocompromised allogeneic hematiopoietic stem cell transplant (HSCT) patients during their highest risk phase, usually the first 100 days post transplant, or longer in the presence of graft-versus-host disease 11, . Recommendations for a Protective Environment apply only to acute care hospitals that provide care to HSCT patients. Scope This guideline, like its predecessors, focuses primarily on interactions between patients and healthcare providers. The Guidelines for the Prevention of MDRO Infection were published separately in November 2006, and are available online at www.cdc.gov/ncidod/dhqp/index.html. Several other HICPAC# TABLE OF CONTENTS\nExecutive\n\n# Tables\nTable 1. Recent history of guidelines for prevention of healthcare-associated infections...... Table 2. Clinical syndromes or conditions warranting additional empiric transmissionbased precautions pending confirmation of diagnosis…………………………......... Table 3. Infection control considerations for high-priority (CDC Category A) diseases that Table 4. Recommendations for application of Standard Precautions for the care of all may result from bioterrorist attacks or are considered to be bioterrorist threats ..\n\n# EXECUTIVE SUMMARY\nThe Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings updates and expands the 1996 Guideline for Isolation Precautions in Hospitals. The following developments led to revision of the 1996 guideline:\n1. The transition of healthcare delivery from primarily acute care hospitals to other healthcare settings (e.g., home care, ambulatory care, free-standing specialty care sites, long-term care) created a need for recommendations that can be applied in all healthcare settings using common principles of infection control practice, yet can be modified to reflect setting-specific needs. Accordingly, the revised guideline addresses the spectrum of healthcare delivery settings. Furthermore, the term \"nosocomial infections\" is replaced by \"healthcareassociated infections\" (HAIs) to reflect the changing patterns in healthcare delivery and difficulty in determining the geographic site of exposure to an infectious agent and/or acquisition of infection. 2. The emergence of new pathogens (e.g., SARS-CoV associated with the severe acute respiratory syndrome , Avian influenza in humans), renewed concern for evolving known pathogens (e.g., C. difficile, noroviruses, communityassociated MRSA ), development of new therapies (e.g., gene therapy), and increasing concern for the threat of bioweapons attacks, established a need to address a broader scope of issues than in previous isolation guidelines. 3. The successful experience with Standard Precautions, first recommended in the 1996 guideline, has led to a reaffirmation of this approach as the foundation for preventing transmission of infectious agents in all healthcare settings. New additions to the recommendations for Standard Precautions are Respiratory Hygiene/Cough Etiquette and safe injection practices, including the use of a mask when performing certain high-risk, prolonged procedures involving spinal canal punctures (e.g., myelography, epidural anesthesia). The need for a recommendation for Respiratory Hygiene/Cough Etiquette grew out of observations during the SARS outbreaks where failure to implement simple source control measures with patients, visitors, and healthcare personnel with respiratory symptoms may have contributed to SARS coronavirus (SARS-CoV) transmission. The recommended practices have a strong evidence base. The continued occurrence of outbreaks of hepatitis B and hepatitis C viruses in ambulatory settings indicated a need to re-iterate safe injection practice recommendations as part of Standard Precautions. The addition of a mask for certain spinal injections grew from recent evidence of an associated risk for developing meningitis caused by respiratory flora. 4. The accumulated evidence that environmental controls decrease the risk of lifethreatening fungal infections in the most severely immunocompromised patients (allogeneic hematopoietic stem-cell transplant patients) led to the update on the components of the Protective Environment (PE). 5. Evidence that organizational characteristics (e.g., nurse staffing levels and composition, establishment of a safety culture) influence healthcare personnel adherence to recommended infection control practices, and therefore are important factors in preventing transmission of infectious agents, led to a new emphasis and recommendations for administrative involvement in the development and support of infection control programs. 6. Continued increase in the incidence of HAIs caused by multidrug-resistant organisms (MDROs) in all healthcare settings and the expanded body of knowledge concerning prevention of transmission of MDROs created a need for more specific recommendations for surveillance and control of these pathogens that would be practical and effective in various types of healthcare settings.\nThis document is intended for use by infection control staff, healthcare epidemiologists, healthcare administrators, nurses, other healthcare providers, and persons responsible for developing, implementing, and evaluating infection control programs for healthcare settings across the continuum of care. The reader is referred to other guidelines and websites for more detailed information and for recommendations concerning specialized infection control problems.\n\n# Parts I -III: Review of the Scientific Data Regarding Transmission of Infectious\nAgents in Healthcare Settings Part I reviews the relevant scientific literature that supports the recommended prevention and control practices. As with the 1996 guideline, the modes and factors that influence transmission risks are described in detail. New to the section on transmission are discussions of bioaerosols and of how droplet and airborne transmission may contribute to infection transmission. This became a concern during the SARS outbreaks of 2003, when transmission associated with aerosol-generating procedures was observed. Also new is a definition of \"epidemiologically important organisms\" that was developed to assist in the identification of clusters of infections that require investigation (i.e. multidrug-resistant organisms, C. difficile). Several other pathogens that hold special infection control interest (i.e., norovirus, SARS, Category A bioterrorist agents, prions, monkeypox, and the hemorrhagic fever viruses) also are discussed to present new information and infection control lessons learned from experience with these agents. This section of the guideline also presents information on infection risks associated with specific healthcare settings and patient populations.\nPart II updates information on the basic principles of hand hygiene, barrier precautions, safe work practices and isolation practices that were included in previous guidelines. However, new to this guideline, is important information on healthcare system components that influence transmission risks, including those under the influence of healthcare administrators. An important administrative priority that is described is the need for appropriate infection control staffing to meet the ever-expanding role of infection control professionals in the modern, complex healthcare system. Evidence presented also demonstrates another administrative concern, the importance of nurse staffing levels, including numbers of appropriately trained nurses in ICUs for preventing HAIs. The role of the clinical microbiology laboratory in supporting infection control is described to emphasize the need for this service in healthcare facilites. Other factors that influence transmission risks are discussed i.e., healthcare worker adherence to recommended infection control practices, organizational safety culture or climate, education and training Discussed for the first time in an isolation guideline is surveillance of healthcare-associated infections. The information presented will be useful to new infection control professionals as well as persons involved in designing or responding to state programs for public reporting of HAI rates.\nPart III describes each of the categories of precautions developed by the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Centers for Disease Control and Prevention (CDC) and provides guidance for their application in various healthcare settings. The categories of Transmission-Based Precautions are unchanged from those in the 1996 guideline: Contact, Droplet, and Airborne. One important change is the recommendation to don the indicated personal protective equipment (gowns, gloves, mask) upon entry into the patient's room for patients who are on Contact and/or Droplet Precautions since the nature of the interaction with the patient cannot be predicted with certainty and contaminated environmental surfaces are important sources for transmission of pathogens.\nIn addition, the Protective Environment (PE) for allogeneic hematopoietic stem cell transplant patients, described in previous guidelines, has been updated.\n\n# Tables, Appendices, and other Information\nThere are several tables that summarize important information: 1) a summary of the evolution of this document; 2) guidance on using empiric isolation precautions according to a clinical syndrome; 3) a summary of infection control recommendations for category A agents of bioterrorism; 4) components of Standard Precautions and recommendations for their application; 5) components of the Protective Environment; and 6) a glossary of definitions used in this guideline. New in this guideline is a figure that shows a recommended sequence for donning and removing personal protective equipment used for isolation precautions to optimize safety and prevent self-contamination during removal.\n\n# Appendix A: Type and Duration of Precautions Recommended for Selected Infections and Conditions\nAppendix A consists of an updated alphabetical list of most infectious agents and clinical conditions for which isolation precautions are recommended. A preamble to the Appendix provides a rationale for recommending the use of one or more Transmission-Based Precautions, in addition to Standard Precautions, based on a review of the literature and evidence demonstrating a real or potential risk for person-to-person transmission in healthcare settings.The type and duration of recommended precautions are presented with additional comments concerning the use of adjunctive measures or other relevant considerations to prevent transmission of the specific agent. Relevant citations are included.\n\n# Pre-Publication of the Guideline on Preventing Transmission of MDROs\nNew to this guideline is a comprehensive review and detailed recommendations for prevention of transmission of MDROs. This portion of the guideline was published electronically in October 2006 and updated in November, 2006 (Siegel JD, Rhinehart E, Jackson M, Chiarello L and HICPAC. Management of Multidrug-Resistant Organisms in Healthcare Settings 2006 www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf), and is considered a part of the Guideline for Isolation Precautions. This section provides a detailed review of the complex topic of MDRO control in healthcare settings and is intended to provide a context for evaluation of MDRO at individual healthcare settings. A rationale and institutional requirements for developing an effective MDRO control program are summarized. Although the focus of this guideline is on measures to prevent transmission of MDROs in healthcare settings, information concerning the judicious use of antimicrobial agents is presented since such practices are intricately related to the size of the reservoir of MDROs which in turn influences transmission (e.g. colonization pressure). There are two tables that summarize recommended prevention and control practices using the following seven categories of interventions to control MDROs: administrative measures, education of healthcare personnel, judicious antimicrobial use, surveillance, infection control precautions, environmental measures, and decolonization. Recommendations for each category apply to and are adapted for the various healthcare settings. With the increasing incidence and prevalence of MDROs, all healthcare facilities must prioritize effective control of MDRO transmission. Facilities should identify prevalent MDROs at the facility, implement control measures, assess the effectiveness of control programs, and demonstrate decreasing MDRO rates. A set of intensified MDRO prevention interventions is presented to be added 1) if the incidence of transmission of a target MDRO is NOT decreasing despite implementation of basic MDRO infection control measures, and 2) when the first case(s) of an epidemiologically important MDRO is identified within a healthcare facility.\n\n# Summary\nThis updated guideline responds to changes in healthcare delivery and addresses new concerns about transmission of infectious agents to patients and healthcare workers in the United States and infection control. The primary objective of the guideline is to improve the safety of the nation's healthcare delivery system by reducing the rates of HAIs. Objectives and methods The objectives of this guideline are to 1) provide infection control recommendations for all components of the healthcare delivery system, including hospitals, long-term care facilities, ambulatory care, home care and hospice; 2) reaffirm Standard Precautions as the foundation for preventing transmission during patient care in all healthcare settings; 3) reaffirm the importance of implementing Transmission-Based Precautions based on the clinical presentation or syndrome and likely pathogens until the infectious etiology has been determined (Table 2); and 4) provide epidemiologically sound and, whenever possible, evidence-based recommendations. This guideline is designed for use by individuals who are charged with administering infection control programs in hospitals and other healthcare settings. The information also will be useful for other healthcare personnel, healthcare administrators, and anyone needing information about infection control measures to prevent transmission of infectious agents. Commonly used abbreviations are provided on page 12 and terms used in the guideline are defined in the Glossary (page 137). Med-line and Pub Med were used to search for relevant studies published in English, focusing on those published since 1996. Much of the evidence cited for preventing transmission of infectious agents in healthcare settings is derived from studies that used \"quasi-experimental designs\", also referred to as nonrandomized, pre-post-intervention study designs 2 . Although these types of studies can provide valuable information regarding the effectiveness of various interventions, several factors decrease the certainty of attributing improved outcome to a specific intervention. These include: difficulties in controlling for important confounding variables; the use of multiple interventions during an outbreak; and results that are explained by the statistical principle of regression to the mean, (e.g., improvement over time without any intervention) 3 . Observational studies remain relevant and have been used to evaluate infection control interventions 4,5 . The quality of studies, consistency of results and correlation with results from randomized, controlled trials when available were considered during the literature review and assignment of evidence-based categories (See Part IV: Recommendations) to the recommendations in this guideline. Several authors have summarized properties to consider when evaluating studies for the purpose of determining if the results should change practice or in designing new studies 2,6,7 .\n\n# Abbreviations Used in the Guideline\nAIIR\nguidelines to prevent transmission of infectious agents associated with healthcare delivery are cited; e.g., Guideline for Hand Hygiene, Guideline for Environmental Infection Control, Guideline for Prevention of Healthcare-Associated Pneumonia, and Guideline for Infection Control in Healthcare Personnel 11,14,16,17 . In combination, these provide comprehensive guidance on the primary infection control measures for ensuring a safe environment for patients and healthcare personnel.\nThis guideline does not discuss in detail specialized infection control issues in defined populations that are addressed elsewhere, (e.g., Recommendations for Preventing Transmission of Infections among Chronic Hemodialysis Patients ,\n\n# Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Facilities 2005, Guidelines for Infection Control in Dental Health-Care Settings and Infection Control Recommendations for Patients with Cystic\nFibrosis 12, . An exception has been made by including abbreviated guidance for a Protective Environment used for allogeneic HSCT recipients because components of the Protective Environment have been more completely defined since publication of the Guidelines for Preventing Opportunistic Infections Among HSCT Recipients in 2000 and the Guideline for Environmental Infection Control in Healthcare Facilities 11, 15 .\n\n# I.B. Rationale for Standard and Transmission-Based Precautions in healthcare settings\nTransmission of infectious agents within a healthcare setting requires three elements: a source (or reservoir) of infectious agents, a susceptible host with a portal of entry receptive to the agent, and a mode of transmission for the agent. This section describes the interrelationship of these elements in the epidemiology of HAIs.\n\n# I.B.1. Sources of infectious agents\nInfectious agents transmitted during healthcare derive primarily from human sources but inanimate environmental sources also are implicated in transmission. Human reservoirs include patients , healthcare personnel 29-35 17, 36-39 , and household members and other visitors . Such source individuals may have active infections, may be in the asymptomatic and/or incubation period of an infectious disease, or may be transiently or chronically colonized with pathogenic microorganisms, particularly in the respiratory and gastrointestinal tracts. The endogenous flora of patients (e.g., bacteria residing in the respiratory or gastrointestinal tract) also are the source of HAIs .\n\n# I.B.2. Susceptible hosts\nInfection is the result of a complex interrelationship between a potential host and an infectious agent. Most of the factors that influence infection and the occurrence and severity of disease are related to the host. However, characteristics of the host-agent interaction as it relates to pathogenicity, virulence and antigenicity are also important, as are the infectious dose, mechanisms of disease production and route of exposure 55 . There is a spectrum of possible outcomes following exposure to an infectious agent. Some persons exposed to pathogenic microorganisms never develop symptomatic disease while others become severely ill and even die. Some individuals are prone to becoming transiently or permanently colonized but remain asymptomatic. Still others progress from colonization to symptomatic disease either immediately following exposure, or after a period of asymptomatic colonization. The immune state at the time of exposure to an infectious agent, interaction between pathogens, and virulence factors intrinsic to the agent are important predictors of an individuals' outcome. Host factors such as extremes of age and underlying disease (e.g. diabetes 56,57 ), human immunodeficiency virus/acquired immune deficiency syndrome 58,59 , malignancy, and transplants 18,60,61 can increase susceptibility to infection as do a variety of medications that alter the normal flora (e.g., antimicrobial agents, gastric acid suppressants, corticosteroids, antirejection drugs, antineoplastic agents, and immunosuppressive drugs). Surgical procedures and radiation therapy impair defenses of the skin and other involved organ systems. Indwelling devices such as urinary catheters, endotracheal tubes, central venous and arterial catheters and synthetic implants facilitate development of HAIs by allowing potential pathogens to bypass local defenses that would ordinarily impede their invasion and by providing surfaces for development of bioflms that may facilitate adherence of microorganisms and protect from antimicrobial activity 65 . Some infections associated with invasive procedures result from transmission within the healthcare facility; others arise from the patient's endogenous flora . High-risk patient populations with noteworthy risk factors for infection are discussed further in Sections I.D, I.E., and I.F.\n\n# I.B.3. Modes of transmission\nSeveral classes of pathogens can cause infection, including bacteria, viruses, fungi, parasites, and prions. The modes of transmission vary by type of organism and some infectious agents may be transmitted by more than one route: some are transmitted primarily by direct or indirect contact, (e.g., Herpes simplex virus , respiratory syncytial virus, Staphylococcus aureus), others by the droplet, (e.g., influenza virus, B. pertussis) or airborne routes (e.g., M. tuberculosis). Other infectious agents, such as bloodborne viruses (e.g., hepatitis B and C viruses and HIV are transmitted rarely in healthcare settings, via percutaneous or mucous membrane exposure. Importantly, not all infectious agents are transmitted from person to person. These are distinguished in Appendix A. The three principal routes of transmission are summarized below.\n\n# I.B.3.a. Contact transmission\nThe most common mode of transmission, contact transmission is divided into two subgroups: direct contact and indirect contact.\n\n# I.B.3.a.i. Direct contact transmission\nDirect transmission occurs when microorganisms are transferred from one infected person to another person without a contaminated intermediate object or person. Opportunities for direct contact transmission between patients and healthcare personnel have been summarized in the Guideline for Infection Control in Healthcare Personnel, 1998 17 and include:\n- blood or other blood-containing body fluids from a patient directly enters a caregiver's body through contact with a mucous membrane 66 or breaks (i.e., cuts, abrasions) in the skin 67 . - mites from a scabies-infested patient are transferred to the skin of a caregiver while he/she is having direct ungloved contact with the patient's skin 68,69 . - a healthcare provider develops herpetic whitlow on a finger after contact with HSV when providing oral care to a patient without using gloves or HSV is transmitted to a patient from a herpetic whitlow on an ungloved hand of a healthcare worker (HCW) 70,71 .\n\n# I.B.3.a.ii. Indirect contact transmission\nIndirect transmission involves the transfer of an infectious agent through a contaminated intermediate object or person. In the absence of a point-source outbreak, it is difficult to determine how indirect transmission occurs. However, extensive evidence cited in the Guideline for Hand Hygiene in Health-Care Settings suggests that the contaminated hands of healthcare personnel are important contributors to indirect contact transmission 16 . Examples of opportunities for indirect contact transmission include:\n- Hands of healthcare personnel may transmit pathogens after touching an infected or colonized body site on one patient or a contaminated inanimate object, if hand hygiene is not performed before touching another patient. 72,73 . - Patient-care devices (e.g., electronic thermometers, glucose monitoring devices) may transmit pathogens if devices contaminated with blood or body fluids are shared between patients without cleaning and disinfecting between patients 74 75-77 . - Shared toys may become a vehicle for transmitting respiratory viruses (e.g., respiratory syncytial virus 24,78,79 or pathogenic bacteria (e.g., Pseudomonas aeruginosa 80 ) among pediatric patients. - Instruments that are inadequately cleaned between patients before disinfection or sterilization (e.g., endoscopes or surgical instruments) or that have manufacturing defects that interfere with the effectiveness of reprocessing 86,87 may transmit bacterial and viral pathogens. Clothing, uniforms, laboratory coats, or isolation gowns used as personal protective equipment (PPE), may become contaminated with potential pathogens after care of a patient colonized or infected with an infectious agent, (e.g., MRSA 88 , VRE 89 , and C. difficile 90 . Although contaminated clothing has not been implicated directly in transmission, the potential exists for soiled garments to transfer infectious agents to successive patients.\n\n# I.B.3.b. Droplet transmission\nDroplet transmission is, technically, a form of contact transmission, and some infectious agents transmitted by the droplet route also may be transmitted by the direct and indirect contact routes. However, in contrast to contact transmission, respiratory droplets carrying infectious pathogens transmit infection when they travel directly from the respiratory tract of the infectious individual to susceptible mucosal surfaces of the recipient, generally over short distances, necessitating facial protection. Respiratory droplets are generated when an infected person coughs, sneezes, or talks 91,92 or during procedures such as suctioning, endotracheal intubation, , cough induction by chest physiotherapy 97 and cardiopulmonary resuscitation 98,99 . Evidence for droplet transmission comes from epidemiological studies of disease outbreaks , experimental studies 104 and from information on aerosol dynamics 91,105 . Studies have shown that the nasal mucosa, conjunctivae and less frequently the mouth, are susceptible portals of entry for respiratory viruses 106 . The maximum distance for droplet transmission is currently unresolved, although pathogens transmitted by the droplet route have not been transmitted through the air over long distances, in contrast to the airborne pathogens discussed below. Historically, the area of defined risk has been a distance of <3 feet around the patient and is based on epidemiologic and simulated studies of selected infections 103,104 . Using this distance for donning masks has been effective in preventing transmission of infectious agents via the droplet route. However, experimental studies with smallpox 107,108 and investigations during the global SARS outbreaks of 2003 101 suggest that droplets from patients with these two infections could reach persons located 6 feet or more from their source. It is likely that the distance droplets travel depends on the velocity and mechanism by which respiratory droplets are propelled from the source, the density of respiratory secretions, environmental factors such as temperature and humidity, and the ability of the pathogen to maintain infectivity over that distance 105 . Thus, a distance of <3 feet around the patient is best viewed as an example of what is meant by \"a short distance from a patient\" and should not be used as the sole criterion for deciding when a mask should be donned to protect from droplet exposure. Based on these considerations, it may be prudent to don a mask when within 6 to 10 feet of the patient or upon entry into the patient's room, especially when exposure to emerging or highly virulent pathogens is likely. More studies are needed to improve understanding of droplet transmission under various circumstances.\nDroplet size is another variable under discussion. Droplets traditionally have been defined as being >5 µm in size. Droplet nuclei, particles arising from desiccation of suspended droplets, have been associated with airborne transmission and defined as <5 µm in size 105 , a reflection of the pathogenesis of pulmonary tuberculosis which is not generalizeable to other organisms. Observations of particle dynamics have demonstrated that a range of droplet sizes, including those with diameters of 30µm or greater, can remain suspended in the air 109 . The behavior of droplets and droplet nuclei affect recommendations for preventing transmission. Whereas fine airborne particles containing pathogens that are able to remain infective may transmit infections over long distances, requiring AIIR to prevent its dissemination within a facility; organisms transmitted by the droplet route do not remain infective over long distances, and therefore do not require special air handling and ventilation. Examples of infectious agents that are transmitted via the droplet route include Bordetella pertussis 110 , influenza virus 23 , adenovirus 111 , rhinovirus 104 , Mycoplasma pneumoniae 112 , SARS-associated coronavirus (SARS-CoV) 21,96,113 , group A streptococcus 114 , and Neisseria meningitidis 95,103,115 . Although respiratory syncytial virus may be transmitted by the droplet route, direct contact with infected respiratory secretions is the most important determinant of transmission and consistent adherence to Standard plus Contact Precautions prevents transmission in healthcare settings 24,116,117 .\nRarely, pathogens that are not transmitted routinely by the droplet route are dispersed into the air over short distances. For example, although S. aureus is transmitted most frequently by the contact route, viral upper respiratory tract infection has been associated with increased dispersal of S. aureus from the nose into the air for a distance of 4 feet under both outbreak and experimental conditions and is known as the \"cloud baby\" and \"cloud adult\" phenomenon .\n\n# I.B.3.c. Airborne transmission\nAirborne transmission occurs by dissemination of either airborne droplet nuclei or small particles in the respirable size range containing infectious agents that remain infective over time and distance (e.g., spores of Aspergillus spp, and Mycobacterium tuberculosis). Microorganisms carried in this manner may be dispersed over long distances by air currents and may be inhaled by susceptible individuals who have not had face-to-face contact with (or been in the same room with) the infectious individual . Preventing the spread of pathogens that are transmitted by the airborne route requires the use of special air handling and ventilation systems (e.g., AIIRs) to contain and then safely remove the infectious agent 11,12 . Infectious agents to which this applies include Mycobacterium tuberculosis , rubeola virus (measles) 122 , and varicella-zoster virus (chickenpox) 123 . In addition, published data suggest the possibility that variola virus (smallpox) may be transmitted over long distances through the air under unusual circumstances and AIIRs are recommended for this agent as well; however, droplet and contact routes are the more frequent routes of transmission for smallpox 108,128,129 . In addition to AIIRs, respiratory protection with NIOSH certified N95 or higher level respirator is recommended for healthcare personnel entering the AIIR to prevent acquisition of airborne infectious agents such as M. tuberculosis 12 .\nFor certain other respiratory infectious agents, such as influenza 130,131 and rhinovirus 104 , and even some gastrointestinal viruses (e.g., norovirus 132 and rotavirus 133 ) there is some evidence that the pathogen may be transmitted via small-particle aerosols, under natural and experimental conditions. Such transmission has occurred over distances longer than 3 feet but within a defined airspace (e.g., patient room), suggesting that it is unlikely that these agents remain viable on air currents that travel long distances. AIIRs are not required routinely to prevent transmission of these agents. Additional issues concerning examples of small particle aerosol transmission of agents that are most frequently transmitted by the droplet route are discussed below.\n\n# I.B.3.d. Emerging issues concerning airborne transmission of infectious agents.\n\n# I.B.3.d.i. Transmission from patients\nThe emergence of SARS in 2002, the importation of monkeypox into the United States in 2003, and the emergence of avian influenza present challenges to the assignment of isolation categories because of conflicting information and uncertainty about possible routes of transmission. Although SARS-CoV is transmitted primarily by contact and/or droplet routes, airborne transmission over a limited distance (e.g. within a room), has been suggested, though not proven . This is true of other infectious agents such as influenza virus 130 and noroviruses 132,142,143 . Influenza viruses are transmitted primarily by close contact with respiratory droplets 23,102 and acquisition by healthcare personnel has been prevented by Droplet Precautions, even when positive pressure rooms were used in one center 144 However, inhalational transmission could not be excluded in an outbreak of influenza in the passengers and crew of a single aircraft 130 . Observations of a protective effect of UV lights in preventing influenza among patients with tuberculosis during the influenza pandemic of 1957-'58 have been used to suggest airborne transmission 145,146 . In contrast to the strict interpretation of an airborne route for transmission (i.e., long distances beyond the patient room environment), short distance transmission by small particle aerosols generated under specific circumstances (e.g., during endotracheal intubation) to persons in the immediate area near the patient has been demonstrated. Also, aerosolized particles <100 μm can remain suspended in air when room air current velocities exceed the terminal settling velocities of the particles 109 . SARS-CoV transmission has been associated with endotracheal intubation, noninvasive positive pressure ventilation, and cardiopulmonary resuscitation 93,94,96,98,141 . Although the most frequent routes of transmission of noroviruses are contact and food and waterborne routes, several reports suggest that noroviruses may be transmitted through aerosolization of infectious particles from vomitus or fecal material 142,143,147,148 . It is hypothesized that the aerosolized particles are inhaled and subsequently swallowed.\nRoy and Milton proposed a new classification for aerosol transmission when evaluating routes of SARS transmission: 1) obligate: under natural conditions, disease occurs following transmission of the agent only through inhalation of small particle aerosols (e.g., tuberculosis); 2) preferential: natural infection results from transmission through multiple routes, but small particle aerosols are the predominant route (e.g. measles, varicella); and 3) opportunistic: agents that naturally cause disease through other routes, but under special circumstances may be transmitted via fine particle aerosols 149 . This conceptual framework can explain rare occurrences of airborne transmission of agents that are transmitted most frequently by other routes (e.g., smallpox, SARS, influenza, noroviruses). Concerns about unknown or possible routes of transmission of agents associated with severe disease and no known treatment often result in more extreme prevention strategies than may be necessary; therefore, recommended precautions could change as the epidemiology of an emerging infection is defined and controversial issues are resolved.\n\n# I.B.3.d.ii.\nTransmission from the environment Some airborne infectious agents are derived from the environment and do not usually involve person-toperson transmission. For example, anthrax spores present in a finely milled powdered preparation can be aerosolized from contaminated environmental surfaces and inhaled into the respiratory tract 150,151 . Spores of environmental fungi (e.g., Aspergillus spp.) are ubiquitous in the environment and may cause disease in immunocompromised patients who inhale aerosolized (e.g., via construction dust) spores 152,153 . As a rule, neither of these organisms is subsequently transmitted from infected patients. However, there is one welldocumented report of person-to-person transmission of Aspergillus sp. in the ICU setting that was most likey due to the aerosolization of spores during wound debridement 154 . A Protective Environment refers to isolation practices designed to decrease the risk of exposure to environmental fungal agents in allogeneic HSCT patients 11,14,15, . Environmental sources of respiratory pathogens (eg. Legionella) transmitted to humans through a common aerosol source is distinct from direct patient-topatient transmission.\n\n# I.B.3.e. Other sources of infection\nTransmission of infection from sources other than infectious individuals include those associated with common environmental sources or vehicles (e.g. contaminated food, water, or medications (e.g. intravenous fluids). Although Aspergillus spp. have been recovered from hospital water systems 159 , the role of water as a reservoir for immunosuppressed patients remains uncertain. Vectorborne transmission of infectious agents from mosquitoes, flies, rats, and other vermin also can occur in healthcare settings. Prevention of vector borne transmission is not addressed in this document.\n\n# I.C. Infectious agents of special infection control interest for healthcare settings\nSeveral infectious agents with important infection control implications that either were not discussed extensively in previous isolation guidelines or have emerged recently are discussed below. These are epidemiologically important organisms (e.g., C. difficile), agents of bioterrorism, prions, SARS-CoV, monkeypox, noroviruses, and the hemorrhagic fever viruses. Experience with these agents has broadened the understanding of modes of transmission and effective preventive measures. These agents are included for purposes of information and, for some (i.e., SARS-CoV, monkeypox), because of the lessons that have been learned about preparedness planning and responding effectively to new infectious agents.\n\n# I.C.1. Epidemiologically important organisms\nAny infectious agents transmitted in healthcare settings may, under defined conditions, become targeted for control because they are epidemiologically important. C. difficile is specifically discussed below because of wide recognition of its current importance in U.S. healthcare facilities. In determining what constitutes an \"epidemiologically important organism\", the following characteristics apply:\n- A propensity for transmission within healthcare facilities based on published reports and the occurrence of temporal or geographic clusters of > 2 patients, (e.g., C..difficile, norovirus, respiratory syncytial virus (RSV), influenza, rotavirus, Enterobacter spp; Serratia spp., group A streptococcus). A single case of healthcare-associated invasive disease caused by certain pathogens (e.g., group A streptococcus post-operatively 14, 163 160 , in burn units 161 , or in a LTCF 162 ; Legionella sp. , Aspergillus sp. 164 ) is generally considered a trigger for investigation and enhanced control measures because of the risk of additional cases and severity of illness associated with these infections. Antimicrobial resistance - Resistance to first-line therapies (e.g., MRSA, VISA, VRSA, VRE, ESBLproducing organisms). - Common and uncommon microorganisms with unusual patterns of resistance within a facility (e.g., the first isolate of Burkholderia cepacia complex or Ralstonia spp. in non-CF patients or a quinolone-resistant strain of Pseudomonas aeruginosa in a facility). - Difficult to treat because of innate or acquired resistance to multiple classes of antimicrobial agents (e.g., Stenotrophomonas maltophilia, Acinetobacter spp.). - Association with serious clinical disease, increased morbidity and mortality (e.g., MRSA and MSSA, group A streptococcus) - A newly discovered or reemerging pathogen I.C.1.a. C.difficile C. difficile is a spore-forming gram positive anaerobic bacillus that was first isolated from stools of neonates in 1935 165 and identified as the most commonly identified causative agent of antibiotic-associated diarrhea and pseudomembranous colitis in 1977 166 . This pathogen is a major cause of healthcare-associated diarrhea and has been responsible for many large outbreaks in healthcare settings that were extremely difficult to control. Important factors that contribute to healthcare-associated outbreaks include environmental contamination, persistence of spores for prolonged periods of time, resistance of spores to routinely used disinfectants and antiseptics, hand carriage by healthcare personnel to other patients, and exposure of patients to frequent courses of antimicrobial agents 167 . Antimicrobials most frequently associated with increased risk of C. difficile include third generation cephalosporins, clindamycin, vancomycin, and fluoroquinolones.\nSince 2001, outbreaks and sporadic cases of C. difficile with increased morbidity and mortality have been observed in several U.S. states, Canada, England and the Netherlands . The same strain of C. difficile has been implicated in these outbreaks 173 . This strain, toxinotype III, North American PFGE type 1, and PCR-ribotype 027 (NAP1/027). has been found to hyperproduce toxin A (16 fold increase) and toxin B (23 fold increase) compared with isolates from 12 different pulsed-field gel electrophoresisPFGE types. A recent survey of U.S. infectious disease physicians found that 40% perceived recent increases in the incidence and severity of C. difficile disease 174 . Standardization of testing methodology and surveillance definitions is needed for accurate comparisons of trends in rates among hospitals 175 . It is hypothesized that the incidence of disease and apparent heightened transmissibility of this new strain may be due, at least in part, to the greater production of toxins A and B, increasing the severity of diarrhea and resulting in more environmental contamination. Considering the greater morbidity, mortality, length of stay, and costs associated with C. difficile disease in both acute care and long term care facilities, control of this pathogen is now even more important than previously. Prevention of transmission focuses on syndromic application of Contact Precautions for patients with diarrhea, accurate identification of patients, environmental measures (e.g., rigorous cleaning of patient rooms) and consistent hand hygiene. Use of soap and water, rather than alcohol based handrubs, for mechanical removal of spores from hands, and a bleach-containing disinfectant (5000 ppm) for environmental disinfection, may be valuable when there is transmission in a healthcare facility. See Appendix A for specific recommendations.\n\n# I.C.1. b. Multidrug-Resistant Organisms (MDROs)\nIn general, MDROs are defined as microorganisms -predominantly bacteria -that are resistant to one or more classes of antimicrobial agents 176 . Although the names of certain MDROs suggest resistance to only one agent (e.g., methicillin-resistant Staphylococcus aureus , vancomycin resistant enterococcus ), these pathogens are usually resistant to all but a few commercially available antimicrobial agents. This latter feature defines MDROs that are considered to be epidemiologically important and deserve special attention in healthcare facilities 177 . Other MDROs of current concern include multidrug-resistant Streptococcus pneumoniae (MDRSP) which is resistant to penicillin and other broad-spectrum agents such as macrolides and fluroquinolones, multidrug-resistant gram-negative bacilli (MDR-GNB), especially those producing extended spectrum beta-lactamases (ESBLs); and strains of S. aureus that are intermediate or resistant to vancomycin (i.e., VISA and VRSA) 178-197 198 .\nMDROs are transmitted by the same routes as antimicrobial susceptible infectious agents. Patient-to-patient transmission in healthcare settings, usually via hands of HCWs, has been a major factor accounting for the increase in MDRO incidence and prevalence, especially for MRSA and VRE in acute care facilities . Preventing the emergence and transmission of these pathogens requires a comprehensive approach that includes administrative involvement and measures (e.g., nurse staffing, communication systems, performance improvement processes to ensure adherence to recommended infection control measures), education and training of medical and other healthcare personnel, judicious antibiotic use, comprehensive surveillance for targeted MDROs, application of infection control precautions during patient care, environmental measures (e.g., cleaning and disinfection of the patient care environment and equipment, dedicated single-patient-use of non-critical equipment), and decolonization therapy when appropriate.\nThe prevention and control of MDROs is a national priority -one that requires that all healthcare facilities and agencies assume responsibility and participate in community-wide control programs 176,177 . A detailed discussion of this topic and recommendations for prevention was published in 2006 may be found at I.C.2. Agents of bioterrorism CDC has designated the agents that cause anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulism as Category A (high priority) because these agents can be easily disseminated environmentally and/or transmitted from person to person; can cause high mortality and have the potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness 202 . General information relevant to infection control in healthcare settings for Category A agents of bioterrorism is summarized in Table 3. Consult www.bt.cdc.gov for additional, updated Category A agent information as well as information concerning Category B and C agents of bioterrorism and updates. Category B and C agents are important but are not as readily disseminated and cause less morbidity and mortality than Category A agents.\nHealthcare facilities confront a different set of issues when dealing with a suspected bioterrorism event as compared with other communicable diseases. An understanding of the epidemiology, modes of transmission, and clinical course of each disease, as well as carefully drafted plans that provide an approach and relevant websites and other resources for disease-specific guidance to healthcare, administrative, and support personnel, are essential for responding to and managing a bioterrorism event. Infection control issues to be addressed include: 1) identifying persons who may be exposed or infected; 2) preventing transmission among patients, healthcare personnel, and visitors; 3) providing treatment, chemoprophylaxis or vaccine to potentially large numbers of people; 4) protecting the environment including the logistical aspects of securing sufficient numbers of AIIRs or designating areas for patient cohorts when there are an insufficient number of AIIRs available;5) providing adequate quantities of appropriate personal protective equipment; and 6) identifying appropriate staff to care for potentially infectious patients (e.g., vaccinated healthcare personnel for care of patients with smallpox). The response is likely to differ for exposures resulting from an intentional release compared with naturally occurring disease because of the large number persons that can be exposed at the same time and possible differences in pathogenicity.\nA variety of sources offer guidance for the management of persons exposed to the most likely agents of bioterrorism. Federal agency websites (e.g., www.usamriid.army.mil/publications/index.html , www.bt.cdc.gov ) and state and county health department web sites should be consulted for the most up-to-date information. Sources of information on specific agents include: anthrax 203 ; smallpox ; plague 207,208 ; botulinum toxin 209 ; tularemia 210 ; and hemorrhagic fever viruses: 211,212 .\n\n# I.C.2.a.\nPre-event administration of smallpox (vaccinia) vaccine to healthcare personnel Vaccination of personnel in preparation for a possible smallpox exposure has important infection control implications . These include the need for meticulous screening for vaccine contraindications in persons who are at increased risk for adverse vaccinia events; containment and monitoring of the vaccination site to prevent transmission in the healthcare setting and at home; and the management of patients with vaccinia-related adverse events 216,217 . The pre-event U.S. smallpox vaccination program of 2003 is an example of the effectiveness of carefully developed recommendations for both screening potential vaccinees for contraindications and vaccination site care and monitoring. Approximately 760,000 individuals were vaccinated in the Department of Defense and 40,000 in the civilian or public health populations from December 2002 to February 2005, including approximately 70,000 who worked in healthcare settings. There were no cases of eczema vaccinatum, progressive vaccinia, fetal vaccinia, or contact transfer of vaccinia in healthcare settings or in military workplaces 218,219 . Outside the healthcare setting, there were 53 cases of contact transfer from military vaccinees to close personal contacts (e.g., bed partners or contacts during participation in sports such as wrestling 220 ). All contact transfers were from individuals who were not following recommendations to cover their vaccination sites. Vaccinia virus was confirmed by culture or PCR in 30 cases, and two of the confirmed cases resulted from tertiary transfer. All recipients, including one breast-fed infant, recovered without complication. Subsequent studies using viral culture and PCR techniques have confirmed the effectiveness of semipermeable dressings to contain vaccinia . This experience emphasizes the importance of ensuring that newly vaccinated healthcare personnel adhere to recommended vaccination-site care, especially if they are to care for high-risk patients. Recommendations for preevent smallpox vaccination of healthcare personnel and vaccinia-related infection control recommendations are published in the MMWR 216,225 with updates posted on the CDC bioterrorism web site 205 .\n\n# I.C.3. Prions\nCreutzfeldt-Jakob disease (CJD) is a rapidly progressive, degenerative, neurologic disorder of humans with an incidence in the United States of approximately 1 person/million population/year 226,227 (www.cdc.gov/ncidod/diseases/cjd/cjd.htm). CJD is believed to be caused by a transmissible proteinaceous infectious agent termed a prion. Infectious prions are isoforms of a host-encoded glycoprotein known as the prion protein. The incubation period (i.e., time between exposure and and onset of symptoms) varies from two years to many decades. However, death typically occurs within 1 year of the onset of symptoms. Approximately 85% of CJD cases occur sporadically with no known environmental source of infection and 10% are familial. Iatrogenic transmission has occurred with most resulting from treatment with human cadaveric pituitary-derived growth hormone or gonadotropin 228,229 , from implantation of contaminated human dura mater grafts 230 or from corneal transplants 231 ). Transmission has been linked to the use of contaminated neurosurgical instruments or stereotactic electroencephalogram electrodes 232, 233 , 234 , 235 .\nPrion diseases in animals include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE, or \"mad cow disease\") in cattle, and chronic wasting disease in deer and elk 236 . BSE, first recognized in the United Kingdom (UK) in 1986, was associated with a major epidemic among cattle that had consumed contaminated meat and bone meal.\nThe possible transmission of BSE to humans causing variant CJD (vCJD) was first described in 1996 and subsequently found to be associated with consumption of BSE-contaminated cattle products primarily in the United Kingdom. There is strong epidemiologic and laboratory evidence for a causal association between the causative agent of BSE and vCJD 237 . Although most cases of vCJD have been reported from the UK, a few cases also have been reported from Europe, Japan, Canada, and the United States. Most vCJD cases worldwide lived in or visited the UK during the years of a large outbreak of BSE (1980-96) and may have consumed contaminated cattle products during that time (www.cdc.gov/ncidod/diseases/cjd/cjd.htm). Although there has been no indigenously acquired vCJD in the United States, the sporadic occurrence of BSE in cattle in North America has heightened awareness of the possibility that such infections could occur and have led to increased surveillance activities. Updated information may be found on the following website: www.cdc.gov/ncidod/diseases/cjd/cjd.htm. The public health impact of prion diseases has been reviewed 238 .\nvCJD in humans has different clinical and pathologic characteristics from sporadic or classic CJD 239 , including the following: 1) younger median age at death: 28 (range 16-48) vs. 68 years; 2) longer duration of illness: median 14 months vs. 4-6 months; 3) increased frequency of sensory symptoms and early psychiatric symptoms with delayed onset of frank neurologic signs; and 4) detection of prions in tonsillar and other lymphoid tissues from vCJD patients but not from sporadic CJD patients 240 . Similar to sporadic CJD, there have been no reported cases of direct human-to-human transmission of vCJD by casual or environmental contact, droplet, or airborne routes. Ongoing blood safety surveillance in the U.S. has not detected sporadic CJD transmission through blood transfusion . However, bloodborne transmission of vCJD is believed to have occurred in two UK patients 244,245 . The following FDA websites provide information on steps that are being taken in the US to protect the blood supply from CJD and vCJD: ; .\nStandard Precautions are used when caring for patients with suspected or confirmed CJD or vCJD. However, special precautions are recommended for tissue handling in the histology laboratory and for conducting an autopsy, embalming, and for contact with a body that has undergone autopsy 246 . Recommendations for reprocessing surgical instruments to prevent transmission of CJD in healthcare settings have been published by the World Health Organization (WHO) and are currently under review at CDC. Questions concerning notification of patients potentially exposed to CJD or vCJD through contaminated instruments and blood products from patients with CJD or vCJD or at risk of having vCJD may arise. The risk of transmission associated with such exposures is believed to be extremely low but may vary based on the specific circumstance. Therefore consultation on appropriate options is advised. The United Kingdom has developed several documents that clinicians and patients in the US may find useful ().\n\n# I.C.4. Severe Acute Respiratory Syndrome (SARS)\nSARS is a newly discovered respiratory disease that emerged in China late in 2002 and spread to several countries 135,140 ; Mainland China, Hong Kong, Hanoi, Singapore, and Toronto were affected significantly. SARS is caused by SARS CoV, a previously unrecognized member of the coronavirus family 247,248 . The incubation period from exposure to the onset of symptoms is 2 to 7 days but can be as long as 10 days and uncommonly even longer 249 . The illness is initially difficult to distinguish from other common respiratory infections. Signs and symptoms usually include fever >38.0 o C and chills and rigors, sometimes accompanied by headache, myalgia, and mild to severe respiratory symptoms. Radiographic finding of atypical pneumonia is an important clinical indicator of possible SARS. Compared with adults, children have been affected less frequently, have milder disease, and are less likely to transmit SARS-CoV 135, . The overall case fatality rate is approximately 6.0%; underlying disease and advanced age increase the risk of mortality (www.who.int/csr/sarsarchive/2003_05_07a/en/).\nOutbreaks in healthcare settings, with transmission to large numbers of healthcare personnel and patients have been a striking feature of SARS; undiagnosed, infectious patients and visitors were important initiators of these outbreaks 21, . The relative contribution of potential modes of transmission is not precisely known. There is ample evidence for droplet and contact transmission 96,101,113 ; however, opportunistic airborne transmission cannot be excluded 101, 135-139, 149, 255 . For example, exposure to aerosol-generating procedures (e.g., endotracheal intubation, suctioning) was associated with transmission of infection to large numbers of healthcare personnel outside of the United States 93,94,96,98,253 .Therefore, aerosolization of small infectious particles generated during these and other similar procedures could be a risk factor for transmission to others within a multi-bed room or shared airspace. A review of the infection control literature generated from the SARS outbreaks of 2003 concluded that the greatest risk of transmission is to those who have close contact, are not properly trained in use of protective infection control procedures, do not consistently use PPE; and that N95 or higher respirators may offer additional protection to those exposed to aerosol-generating procedures and high risk activities 256,257 . Organizational and individual factors that affected adherence to infection control practices for SARS also were identified 257 .\nControl of SARS requires a coordinated, dynamic response by multiple disciplines in a healthcare setting 9 . Early detection of cases is accomplished by screening persons with symptoms of a respiratory infection for history of travel to areas experiencing community transmission or contact with SARS patients, followed by implementation of Respiratory Hygiene/Cough Etiquette (i.e., placing a mask over the patient's nose and mouth) and physical separation from other patients in common waiting areas.The precise combination of precautions to protect healthcare personnel has not been determined. At the time of this publication, CDC recommends Standard Precautions, with emphasis on the use of hand hygiene, Contact Precautions with emphasis on environmental cleaning due to the detection of SARS CoV RNA by PCR on surfaces in rooms occupied by SARS patients 138,254,258 , Airborne Precautions, including use of fit-tested NIOSH-approved N95 or higher level respirators, and eye protection 259 . In Hong Kong, the use of Droplet and Contact Precautions, which included use of a mask but not a respirator, was effective in protecting healthcare personnel 113 . However, in Toronto, consistent use of an N95 respirator was slightly more protective than a mask 93 . It is noteworthy that there was no transmission of SARS-CoV to public hospital workers in Vietnam despite inconsistent use of infection control measures, including use of PPE, which suggests other factors (e.g., severity of disease, frequency of high risk procedures or events, environmental features) may influence opportunities for transmission 260 . SARS-CoV also has been transmitted in the laboratory setting through breaches in recommended laboratory practices. Research laboratories where SARS-CoV was under investigation were the source of most cases reported after the first series of outbreaks in the winter and spring of 2003 261,262 . Studies of the SARS outbreaks of 2003 and transmissions that occurred in the laboratory re-affirm the effectiveness of recommended infection control precautions and highlight the importance of consistent adherence to these measures.\nLessons from the SARS outbreaks are useful for planning to respond to future public health crises, such as pandemic influenza and bioterrorism events. Surveillance for cases among patients and healthcare personnel, ensuring availability of adequate supplies and staffing, and limiting access to healthcare facilities were important factors in the response to SARS that have been summarized 9 . Guidance for infection control precautions in various settings is available at www.cdc.gov/ncidod/sars. I.C.5. Monkeypox Monkeypox is a rare viral disease found mostly in the rain forest countries of Central and West Africa. The disease is caused by an orthopoxvirus that is similar in appearance to smallpox but causes a milder disease. The only recognized outbreak of human monkeypox in the United States was detected in June 2003 after several people became ill following contact with sick pet prairie dogs. Infection in the prairie dogs was subsequently traced to their contact with a shipment of animals from Africa, including giant Gambian rats 263 . This outbreak demonstrates the importance of recognition and prompt reporting of unusual disease presentations by clinicians to enable prompt identification of the etiology; and the potential of epizootic diseases to spread from animal reservoirs to humans through personal and occupational exposure 264 .\nLimited data on transmission of monkeypox are available. Transmission from infected animals and humans is believed to occur primarily through direct contact with lesions and respiratory secretions; airborne transmission from animals to humans is unlikely but cannot be excluded, and may have occurred in veterinary practices (e.g., during administration of nebulized medications to ill prairie dogs 265 ). Among humans, four instances of monkeypox transmission within hospitals have been reported in Africa among children, usually related to sharing the same ward or bed 266,267 . Additional recent literature documents transmission of Congo Basin monkeypox in a hospital compound for an extended number of generations 268 .\nThere has been no evidence of airborne or any other person-to-person transmission of monkeypox in the United States, and no new cases of monkeypox have been identified since the outbreak in June 2003 269 . The outbreak strain is a clade of monkeypox distinct from the Congo Basin clade and may have different epidemiologic properties (including human-to-human transmission potential) from monkeypox strains of the Congo Basin 270 ; this awaits further study. Smallpox vaccine is 85% protective against Congo Basin monkeypox 271 . Since there is an associated case fatality rate of <10%, administration of smallpox vaccine within 4 days to individuals who have had direct exposure to patients or animals with monkeypox is a reasonable consideration 272 . For the most current information on monkeypox, see www.cdc.gov/ncidod/monkeypox/clinicians.htm. I.C.6. Noroviruses Noroviruses, formerly referred to as Norwalk-like viruses, are members of the Caliciviridae family. These agents are transmitted via contaminated food or water and from person-to-person, causing explosive outbreaks of gastrointestinal disease 273 . Environmental contamination also has been documented as a contributing factor in ongoing transmission during outbreaks 274,275 . Although noroviruses cannot be propagated in cell culture, DNA detection by molecular diagnostic techniques has facilitated a greater appreciation of their role in outbreaks of gastrointestinal disease 276 . Reported outbreaks in hospitals 132,142,277 , nursing homes 275, , cruise ships 284,285 , hotels 143,147 , schools 148 , and large crowded shelters established for hurricane evacuees 286 , demonstrate their highly contagious nature, the disruptive impact they have in healthcare facilities and the community, and the difficulty of controlling outbreaks in settings where people share common facilites and space. Of note, there is nearly a 5 fold increase in the risk to patients in outbreaks where a patient is the index case compared with exposure of patients during outbreaks where a staff member is the index case 287 .\nThe average incubation period for gastroenteritis caused by noroviruses is 12-48 hours and the clinical course lasts 12-60 hours 273 . Illness is characterized by acute onset of nausea, vomiting, abdominal cramps, and/or diarrhea. The disease is largely self-limited; rarely, death caused by severe dehydration can occur, particularly among the elderly with debilitating health conditions.\nThe epidemiology of norovirus outbreaks shows that even though primary cases may result from exposure to a fecally-contaminated food or water, secondary and tertiary cases often result from person-to-person transmission that is facilitated by contamination of fomites 273,288 and dissemination of infectious particles, especially during the process of vomiting 132,142,143,147,148,273,279,280 . Widespread, persistent and inapparent contamination of the environment and fomites can make outbreaks extremely difficult to control 147,275,284 .These clinical observations and the detection of norovirus DNA on horizontal surfaces 5 feet above the level that might be touched normally suggest that, under certain circumstances, aerosolized particles may travel distances beyond 3 feet 147 . It is hypothesized that infectious particles may be aerosolized from vomitus, inhaled, and swallowed. In addition, individuals who are responsible for cleaning the environment may be at increased risk of infection. Development of disease and transmission may be facilitated by the low infectious dose (i.e., <100 viral particles) 289 and the resistance of these viruses to the usual cleaning and disinfection agents (i.e., may survive < 10 ppm chlorine) . An alternate phenolic agent that was shown to be effective against feline calicivirus was used for environmental cleaning in one outbreak 275,293 . There are insufficient data to determine the efficacy of alcohol-based hand rubs against noroviruses when the hands are not visibly soiled 294 . Absence of disease in certain individuals during an outbreak may be explained by protection from infection conferred by the B histo-blood group antigen 295 . Consultation on outbreaks of gastroenteritis is available through CDC's Division of Viral and Rickettsial Diseases 296 .\n\n# I.C.7. Hemorrhagic fever viruses (HFV)\nThe hemorrhagic fever viruses are a mixed group of viruses that cause serious disease with high fever, skin rash, bleeding diathesis, and in some cases, high mortality; the disease caused is referred to as viral hemorrhagic fever (VHF). Among the more commonly known HFVs are Ebola and Marburg viruses (Filoviridae), Lassa virus (Arenaviridae), Crimean-Congo hemorrhagic fever and Rift Valley Fever virus (Bunyaviridae), and Dengue and Yellow fever viruses (Flaviviridae) 212,297 . These viruses are transmitted to humans via contact with infected animals or via arthropod vectors. While none of these viruses is endemic in the United States, outbreaks in affected countries provide potential opportunities for importation by infected humans and animals. Furthermore, there are concerns that some of these agents could be used as bioweapons 212 . Person-to-person transmission is documented for Ebola, Marburg, Lassa and Crimean-Congo hemorrhagic fever viruses. In resource-limited healthcare settings, transmission of these agents to healthcare personnel, patients and visitors has been described and in some outbreaks has accounted for a large proportion of cases . Transmissions within households also have occurred among individuals who had direct contact with ill persons or their body fluids, but not to those who did not have such contact 301 .\nEvidence concerning the transmission of HFVs has been summarized 212,302 . Person-to-person transmission is associated primarily with direct blood and body fluid contact. Percutaneous exposure to contaminated blood carries a particularly high risk for transmission and increased mortality 303,304 . The finding of large numbers of Ebola viral particles in the skin and the lumina of sweat glands has raised concern that transmission could occur from direct contact with intact skin though epidemiologic evidence to support this is lacking 305 . Postmortem handling of infected bodies is an important risk for transmission 301,306,307 . In rare situations, cases in which the mode of transmission was unexplained among individuals with no known direct contact , have led to speculation that airborne transmission could have occurred 298 . However, airborne transmission of naturally occurring HFVs in humans has not been seen. In one study of airplane passengers exposed to an in-flight index case of Lassa fever, there was no transmission to any passengers 308 .\nIn the laboratory setting, animals have been infected experimentally with Marburg or Ebola viruses via direct inoculation of the nose, mouth and/or conjunctiva 309,310 and by using mechanically generated virus-containing aerosols 311,312 . Transmission of Ebola virus among laboratory primates in an animal facility has been described 313 . Secondarily infected animals were in individual cages and separated by approximately 3 meters. Although the possibility of airborne transmission was suggested, the authors were not able to exclude droplet or indirect contact transmission in this incidental observation.\nGuidance on infection control precautions for HVFs that are transmitted personto-person have been published by CDC 1, 211 and by the Johns Hopkins Center for Civilian Biodefense Strategies 212 . The most recent recommendations at the time of publication of this document were posted on the CDC website on 5/19/05 314 . Inconsistencies among the various recommendations have raised questions about the appropriate precautions to use in U.S. hospitals. In less developed countries, outbreaks of HFVs have been controlled with basic hygiene, barrier precautions, safe injection practices, and safe burial practices 299,306 . The preponderance of evidence on HFV transmission indicates that Standard, Contact and Droplet Precautions with eye protection are effective in protecting healthcare personnel and visitors who may attend an infected patient. Single gloves are adequate for routine patient care; double-gloving is advised during invasive procedures (e.g., surgery) that pose an increased risk for blood exposure. Routine eye protection (i.e. goggles or face shield) is particularly important. Fluid-resistant gowns should be worn for all patient contact. Airborne Precautions are not required for routine patient care; however, use of AIIRs is prudent when procedures that could generate infectious aerosols are performed (e.g., endotracheal intubation, bronchoscopy, suctioning, autopsy procedures involving oscillating saws). N95 or higher level respirators may provide added protection for individuals in a room during aerosol-generating procedures (Table 3, Appendix A). When a patient with a syndrome consistent with hemorrhagic fever also has a history of travel to an endemic area, precautions are initiated upon presentation and then modified as more information is obtained (Table 2). Patients with hemorrhagic fever syndrome in the setting of a suspected bioweapon attack should be managed using Airborne Precautions, including AIIRs, since the epidemiology of a potentially weaponized hemorrhagic fever virus is unpredictable.\n\n# I.D. Transmission risks associated with specific types of healthcare settings\nNumerous factors influence differences in transmission risks among the various healthcare settings. These include the population characteristics (e.g., increased susceptibility to infections, type and prevalence of indwelling devices), intensity of care, exposure to environmental sources, length of stay, and frequency of interaction between patients/residents with each other and with HCWs. These factors, as well as organizational priorities, goals, and resources, influence how different healthcare settings adapt transmission prevention guidelines to meet their specific needs 315,316 . Infection control management decisions are informed by data regarding institutional experience/epidemiology, trends in community and institutional HAIs, local, regional, and national epidemiology, and emerging infectious disease threats.\n\n# I.D.1. Hospitals\nInfection transmission risks are present in all hospital settings. However, certain hospital settings and patient populations have unique conditions that predispose patients to infection and merit special mention. These are often sentinel sites for the emergence of new transmission risks that may be unique to that setting or present opportunities for transmission to other settings in the hospital.\n\n# I.D.1.a. Intensive Care Units\nIntensive care units (ICUs) serve patients who are immunocompromised by disease state and/or by treatment modalities, as well as patients with major trauma, respiratory failure and other life-threatening conditions (e.g., myocardial infarction, congestive heart failure, overdoses, strokes, gastrointestinal bleeding, renal failure, hepatic failure, multi-organ system failure, and the extremes of age). Although ICUs account for a relatively small proportion of hospitalized patients, infections acquired in these units accounted for >20% of all HAIs 317 . In the National Nosocomial Infection Surveillance (NNIS) system, 26.6% of HAIs were reported from ICU and high risk nursery (NICU) patients in 2002 (NNIS, unpublished data). This patient population has increased susceptibility to colonization and infection, especially with MDROs and Candida sp. 318,319 , because of underlying diseases and conditions, the invasive medical devices and technology used in their care (e.g. central venous catheters and other intravascular devices, mechanical ventilators, extracorporeal membrane oxygenation (ECMO), hemodialysis/-filtration, pacemakers, implantable left ventricular assist devices), the frequency of contact with healthcare personnel, prolonged length of stay, and prolonged exposure to antimicrobial agents . Furthermore, adverse patient outcomes in this setting are more severe and are associated with a higher mortality 332 . Outbreaks associated with a variety of bacterial, fungal and viral pathogens due to commonsource and person-to-person transmissions are frequent in adult and pediatric ICUs 31, 333-336, 337 , 338 .\n\n# I.D.1.b. Burn Units\nBurn wounds can provide optimal conditions for colonization, infection, and transmission of pathogens; infection acquired by burn patients is a frequent cause of morbidity and mortality 320,339,340 . In patients with a burn injury involving >30% of the total body surface area (TBSA), the risk of invasive burn wound infection is particularly high 341,342 . Infections that occur in patients with burn injury involving <30% TBSA are usually associated with the use of invasive devices. Methicillin-susceptible Staphylococcus aureus, MRSA, enterococci, including VRE, gram-negative bacteria, and candida are prevalent pathogens in burn infections 53,340, and outbreaks of these organisms have been reported . Shifts over time in the predominance of pathogens causing infections among burn patients often lead to changes in burn care practices 343, . Burn wound infections caused by Aspergillus sp. or other environmental molds may result from exposure to supplies contaminated during construction 359 or to dust generated during construction or other environmental disruption 360 .\nHydrotherapy equipment is an important environmental reservoir of gramnegative organisms. Its use for burn care is discouraged based on demonstrated associations between use of contaminated hydrotherapy equipment and infections. Burn wound infections and colonization, as well as bloodstream infections, caused by multidrug-resistant P. aeruginosa 361 , A. baumannii 362 , and MRSA 352 have been associated with hydrotherapy; excision of burn wounds in operating rooms is preferred.\nAdvances in burn care, specifically early excision and grafting of the burn wound, use of topical antimicrobial agents, and institution of early enteral feeding, have led to decreased infectious complications. Other advances have included prophylactic antimicrobial usage, selective digestive decontamination (SDD), and use of antimicrobial-coated catheters (ACC), but few epidemiologic studies and no efficacy studies have been performed to show the relative benefit of these 357 measures .\nThere is no consensus on the most effective infection control practices to prevent transmission of infections to and from patients with serious burns (e.g., singlebed rooms 358 , laminar flow 363 and high efficiency particulate air filtration 360 or maintaining burn patients in a separate unit without exposure to patients or equipment from other units 364 ). There also is controversy regarding the need for and type of barrier precautions for routine care of burn patients. One retrospective study demonstrated efficacy and cost effectiveness of a simplified barrier isolation protocol for wound colonization, emphasizing handwashing and use of gloves, caps, masks and plastic impermeable aprons (rather than isolation gowns) for direct patient contact 365 . However, there have been no studies that define the most effective combination of infection control precautions for use in burn settings. Prospective studies in this area are needed.\n\n# I.D.1.c. Pediatrics\nStudies of the epidemiology of HAIs in children have identified unique infection control issues in this population 63,64, . Pediatric intensive care unit (PICU) patients and the lowest birthweight babies in the highrisk nursery (HRN) monitored in the NNIS system have had high rates of central venous catheter-associated bloodstream infections 64,320, . Additionally, there is a high prevalence of community-acquired infections among hospitalized infants and young children who have not yet become immune either by vaccination or by natural infection. The result is more patients and their sibling visitors with transmissible infections present in pediatric healthcare settings, especially during seasonal epidemics (e.g., pertussis 36,40,41 , respiratory viral infections including those caused by RSV 24 , influenza viruses 373 , parainfluenza virus 374 , human metapneumovirus 375 , and adenoviruses 376 ; rubeola 34 , varicella 377 , and rotavirus 38,378 ).\nClose physical contact between healthcare personnel and infants and young children (eg. cuddling, feeding, playing, changing soiled diapers, and cleaning copious uncontrolled respiratory secretions) provides abundant opportunities for transmission of infectious material. Practices and behaviors such as congregation of children in play areas where toys and bodily secretions are easily shared and family members rooming-in with pediatric patients can further increase the risk of transmission. Pathogenic bacteria have been recovered from toys used by hospitalized patients 379 ; contaminated bath toys were implicated in an outbreak of multidrug-resistant P. aeruginosa on a pediatric oncology unit 80 . In addition, several patient factors increase the likelihood that infection will result from exposure to pathogens in healthcare settings (e.g., immaturity of the neonatal immune system, lack of previous natural infection and resulting immunity, prevalence of patients with congenital or acquired immune deficiencies, congenital anatomic anomalies, and use of life-saving invasive devices in neontal and pediatric intensive care units) 63 . There are theoretical concerns that infection risk will increase in association with innovative practices used in the NICU for the purpose of improving developmental outcomes, Such factors include co-bedding 380 and kangaroo care 381 that may increase opportunity for skin-to-skin exposure of multiple gestation infants to each other and to their mothers, respectively; although infection risk smay actually be reduced among infants receiving kangaroo care 382 . Children who attend child care centers 383,384 and pediatric rehabilitation units 385 may increase the overall burden of antimicrobial resistance (eg. by contributing to the reservoir of community-associated MRSA ) . Patients in chronic care facilities may have increased rates of colonization with resistant GNBs and may be sources of introduction of resistant organisms to acute care settings 50 .\n\n# I.D.2. Nonacute healthcare settings\nHealthcare is provided in various settings outside of hospitals including facilities, such as long-term care facilities (LTCF) (e.g. nursing homes), homes for the developmentally disabled, settings where behavioral health services are provided, rehabilitation centers and hospices 392 . In addition, healthcare may be provided in nonhealthcare settings such as workplaces with occupational health clinics, adult day care centers, assisted living facilities, homeless shelters, jails and prisons, school clinics and infirmaries. Each of these settings has unique circumstances and population risks to consider when designing and implementing an infection control program. Several of the most common settings and their particular challenges are discussed below. While this Guideline does not address each setting, the principles and strategies provided may be adapted and applied as appropriate.\n\n# I.D.2.a. Long-term care\nThe designation LTCF applies to a diverse group of residential settings, ranging from institutions for the developmentally disabled to nursing homes for the elderly and pediatric chronic-care facilities . Nursing homes for the elderly predominate numerically and frequently represent longterm care as a group of facilities. Approximately 1.8 million Americans reside in the nation's 16,500 nursing homes 396 . Estimates of HAI rates of 1.8 to 13.5 per 1000 resident-care days have been reported with a range of 3 to 7 per 1000 resident-care days in the more rigorous studies . The infrastructure described in the Department of Veterans Affairs nursing home care units is a promising example for the development of a nationwide HAI surveillance system for LTCFs 402 .\nLCTFs are different from other healthcare settings in that elderly patients at increased risk for infection are brought together in one setting and remain in the facility for extended periods of time; for most residents, it is their home. An atmosphere of community is fostered and residents share common eating and living areas, and participate in various facility-sponsored activities 403,404 . Since able residents interact freely with each other, controlling transmission of infection in this setting is challenging 405 . Residents who are colonized or infected with certain microorganisms are, in some cases, restricted to their room. However, because of the psychosocial risks associated with such restriction, it has been recommended that psychosocial needs be balanced with infection control needs in the LTCF setting . Documented LTCF outbreaks have been caused by various viruses (e.g., influenza virus 35, , rhinovirus 413 , adenovirus (conjunctivitis) 414 , norovirus 278, 279 275, 281 ) and bacteria, including group A streptococcus 162 , B. pertussis 415 , non-susceptible S. pneumoniae 197,198 , other MDROs, and Clostridium difficile 416 ) These pathogens can lead to substantial morbidity and mortality, and increased medical costs; prompt detection and implementation of effective control measures are required.\nRisk factors for infection are prevalent among LTCF residents 395,417,418 . Agerelated declines in immunity may affect responses to immunizations for influenza and other infectious agents, and increase susceptibility to tuberculosis. Immobility, incontinence, dysphagia, underlying chronic diseases, poor functional status, and age-related skin changes increase susceptibility to urinary, respiratory and cutaneous and soft tissue infections, while malnutrition can impair wound healing . Medications (e.g., drugs that affect level of consciousness, immune function, gastric acid secretions, and normal flora, including antimicrobial therapy) and invasive devices (e.g., urinary catheters and feeding tubes) heighten susceptibility to infection and colonization in LTCF residents . Finally, limited functional status and total dependence on healthcare personnel for activities of daily living have been identified as independent risk factors for infection 401,417,427 and for colonization with MRSA 428,429 and ESBL-producing K. pneumoniae 430 . Several position papers and review articles have been published that provide guidance on various aspects of infection control and antimicrobial resistance in LTCFs . The Centers for Medicare and Medicaid Services (CMS) have established regulations for the prevention of infection in LTCFs 437 .\nBecause residents of LTCFs are hospitalized frequently, they can transfer pathogens between LTCFs and healthcare facilities in which they receive care 8, . This is also true for pediatric long-term care populations. Pediatric chronic care facilities have been associated with importing extended-spectrum cephalosporin-resistant, gram-negative bacilli into one PICU 50 . Children from pediatric rehabilitation units may contribute to the reservoir of communityassociated MRSA 385, .\n\n# I.D.2.b. Ambulatory Care\nIn the past decade, healthcare delivery in the United States has shifted from the acute, inpatient hospital to a variety of ambulatory and community-based settings, including the home. Ambulatory care is provided in hospital-based outpatient clinics, nonhospital-based clinics and physician offices, public health clinics, free-standing dialysis centers, ambulatory surgical centers, urgent care centers, and many others. In 2000, there were 83 million visits to hospital outpatient clinics and more than 823 million visits to physician offices 442 ; ambulatory care now accounts for most patient encounters with the health care system 443 . In these settings, adapting transmission prevention guidelines is challenging because patients remain in common areas for prolonged periods waiting to be seen by a healthcare provider or awaiting admission to the hospital, examination or treatment rooms are turned around quickly with limited cleaning, and infectious patients may not be recognized immediately. Furthermore, immunocompromised patients often receive chemotherapy in infusion rooms where they stay for extended periods of time along with other types of patients.\nThere are few data on the risk of HAIs in ambulatory care settings, with the exception of hemodialysis centers 18 , 444, 445 . Transmission of infections in outpatient settings has been reviewed in three publications . Goodman and Solomon summarized 53 clusters of infections associated with the outpatient setting from 1961-1990 446 . Overall, 29 clusters were associated with common source transmission from contaminated solutions or equipment, 14 with personto-person transmission from or involving healthcare personnel and ten associated with airborne or droplet transmission among patients and healthcare workers. Transmission of bloodborne pathogens (i.e., hepatitis B and C viruses and, rarely, HIV) in outbreaks, sometimes involving hundreds of patients, continues to occur in ambulatory settings. These outbreaks often are related to common source exposures, usually a contaminated medical device, multi-dose vial, or intravenous solution 82, . In all cases, transmission has been attributed to failure to adhere to fundamental infection control principles, including safe injection practices and aseptic technique.This subject has been reviewed and recommended infection control and safe injection practices summarized 454 .\nAirborne transmission of M.tuberculosis and measles in ambulatory settings, most frequently emergency departments, has been reported 34,127,446,448, . Measles virus was transmitted in physician offices and other outpatient settings during an era when immunization rates were low and measles outbreaks in the community were occurring regularly 34,122,458 . Rubella has been transmitted in the outpatient obstetric setting 33 ; there are no published reports of varicella transmission in the outpatient setting. In the ophthalmology setting, adenovirus type 8 epidemic keratoconjunctivitis has been transmitted via incompletely disinfected ophthalmology equipment and/or from healthcare workers to patients, presumably by contaminated hands 17,446,448, .\nIf transmission in outpatient settings is to be prevented, screening for potentially infectious symptomatic and asymptomatic individuals, especially those who may be at risk for transmitting airborne infectious agents (e.g., M. tuberculosis, varicella-zoster virus, rubeola ), is necessary at the start of the initial patient encounter. Upon identification of a potentially infectious patient, implementation of prevention measures, including prompt separation of potentially infectious patients and implementation of appropriate control measures (e.g., Respiratory Hygiene/Cough Etiquette and Transmission-Based Precautions) can decrease transmission risks 9,12 . Transmission of MRSA and VRE in outpatient settings has not been reported, but the association of CA-MRSA in healthcare personnel working in an outpatient HIV clinic with environmental CA-MRSA contamination in that clinic, suggests the possibility of transmission in that setting 463 . Patient-to-patient transmission of Burkholderia species and Pseudomonas aeruginosa in outpatient clinics for adults and children with cystic fibrosis has been confirmed 464,465 .\n\n# I.D.2.c. Home Care Home care in the United\nStates is delivered by over 20,000 provider agencies that include home health agencies, hospices, durable medical equipment providers, home infusion therapy services, and personal care and support services providers. Home care is provided to patients of all ages with both acute and chronic conditions. The scope of services ranges from assistance with activities of daily living and physical and occupational therapy to the care of wounds, infusion therapy, and chronic ambulatory peritoneal dialysis (CAPD).\nThe incidence of infection in home care patients, other than those associated with infusion therapy is not well studied . However, data collection and calculation of infection rates have been accomplished for central venous catheter-associated bloodstream infections in patients receiving home infusion therapy and for the risk of blood contact through percutaneous or mucosal exposures, demonstrating that surveillance can be performed in this setting 475 . Draft definitions for home care associated infections have been developed 476 .\nTransmission risks during home care are presumed to be minimal. The main transmission risks to home care patients are from an infectious healthcare provider or contaminated equipment; providers also can be exposed to an infectious patient during home visits. Since home care involves patient care by a limited number of personnel in settings without multiple patients or shared equipment, the potential reservoir of pathogens is reduced. Infections of home care providers, that could pose a risk to home care patients include infections transmitted by the airborne or droplet routes (e.g., chickenpox, tuberculosis, influenza), and skin infestations (e.g., scabies 69 and lice) and infections (e.g.,impetigo) transmitted by direct or indirect contact. There are no published data on indirect transmission of MDROs from one home care patient to another, although this is theoretically possible if contaminated equipment is transported from an infected or colonized patient and used on another patient. Of note, investigation of the first case of VISA in homecare 186 and the first 2 reported cases of VRSA 178,180,181,183 found no evidence of transmission of VISA or VRSA to other home care recipients. Home health care also may contribute to antimicrobial resistance; a review of outpatient vancomycin use found 39% of recipients did not receive the antibiotic according to recommended guidelines 477 .\nAlthough most home care agencies implement policies and procedures to prevent transmission of organisms, the current approach is based on the adaptation of the 1996 Guideline for Isolation Precautions in Hospitals 1 as well as other professional guidance 478,479 . This issue has been very challenging in the home care industry and practice has been inconsistent and frequently not evidence-based. For example, many home health agencies continue to observe \"nursing bag technique,\" a practice that prescribes the use of barriers between the nursing bag and environmental surfaces in the home 480 . While the home environment may not always appear clean, the use of barriers between two noncritical surfaces has been questioned 481,482 . Opportunites exist to conduct research in home care related to infection transmission risks 483 .\n\n# I.D.2.d. Other sites of healthcare delivery\nFacilities that are not primarily healthcare settings but in which healthcare is delivered include clinics in correctional facilities and shelters. Both settings can have suboptimal features, such as crowded conditions and poor ventilation. Economically disadvantaged individuals who may have chronic illnesses and healthcare problems related to alcoholism, injection drug use, poor nutrition, and/or inadequate shelter often receive their primary healthcare at sites such as these 484 . Infectious diseases of special concern for transmission include tuberculosis, scabies, respiratory infections (e.g., N. meningitides, S. pneumoniae), sexually transmitted and bloodborne diseases (e.g.,HIV, HBV, HCV, syphilis, gonorrhea), hepatitis A virus (HAV), diarrheal agents such as norovirus, and foodborne diseases 286, . A high index of suspicion for tuberculosis and CA-MRSA in these populations is needed as outbreaks in these settings or among the populations they serve have been reported .\nPatient encounters in these types of facilities provide an opportunity to deliver recommended immunizations and screen for M. tuberculosis infection in addition to diagnosing and treating acute illnesses 498 . Recommended infection control measures in these non-traditional areas designated for healthcare delivery are the same as for other ambulatory care settings. Therefore, these settings must be equipped to observe Standard Precautions and, when indicated, Transmission-based Precautions.\n\n# I.E. Transmission risks associated with special patient populations\nAs new treatments emerge for complex diseases, unique infection control challenges associated with special patient populations need to be addressed.\n\n# I.E.1. Immunocompromised patients\nPatients who have congenital primary immune deficiencies or acquired disease (eg. treatment-induced immune deficiencies) are at increased risk for numerous types of infections while receiving healthcare and may be located throughout the healthcare facility. The specific defects of the immune system determine the types of infections that are most likely to be acquired (e.g., viral infections are associated with T-cell defects and fungal and bacterial infections occur in patients who are neutropenic). As a general group, immunocompromised patients can be cared for in the same environment as other patients; however, it is always advisable to minimize exposure to other patients with transmissible infections such as influenza and other respiratory viruses 499,500 . The use of more intense chemotherapy regimens for treatment of childhood leukemia may be associated with prolonged periods of neutropenia and suppression of other components of the immune system, extending the period of infection risk and raising the concern that additional precautions may be indicated for select groups 501,502 . With the application of newer and more intense immunosuppressive therapies for a variety of medical conditions (e.g., rheumatologic disease 503,504 , inflammatory bowel disease 505 ), immunosuppressed patients are likely to be more widely distributed throughout a healthcare facility rather than localized to single patient units (e.g. hematology-oncology). Guidelines for preventing infections in certain groups of immunocompromised patients have been published 15,506,507 .\nPublished data provide evidence to support placing allogeneic HSCT patients in a Protective Environment 15,157,158 . Also, three guidelines have been developed that address the special requirements of these immunocompromised patients, including use of antimicrobial prophylaxis and engineering controls to create a Protective Environment for the prevention of infections caused by Aspergillus spp. and other environmental fungi 11,14,15 . As more intense chemotherapy regimens associated with prolonged periods of neutropenia or graft-versus-host disease are implemented, the period of risk and duration of environmental protection may need to be prolonged beyond the traditional 100 days 508 .\n\n# I.E.2. Cystic fibrosis patients\nPatients with cystic fibrosis (CF) require special consideration when developing infection control guidelines. Compared to other patients, CF patients require additional protection to prevent transmission from contaminated respiratory therapy equipment . Infectious agents such as Burkholderia cepacia complex and P. aeruginosa 464,465,514,515 have unique clinical and prognostic significance. In CF patients, B. cepacia infection has been associated with increased morbidity and mortality , while delayed acquisition of chronic P.aeruginosa infection may be associated with an improved long-term clinical outcome 519,520 .\nPerson-to-person transmission of B. cepacia complex has been demonstrated among children 517 and adults 521 with CF in healthcare settings 464,522 , during various social contacts 523 , most notably attendance at camps for patients with CF 524 , and among siblings with CF 525 . Successful infection control measures used to prevent transmission of respiratory secretions include segregation of CF patients from each other in ambulatory and hospital settings (including use of private rooms with separate showers), environmental decontamination of surfaces and equipment contaminated with respiratory secretions, elimination of group chest physiotherapy sessions, and disbanding of CF camps 97,526 . The Cystic Fibrosis Foundation published a consensus document with evidencebased recommendations for infection control practices for CF patients 20 .\n\n# I.F. New therapies associated with potentially transmissible infectious agents\nI.F.1. Gene therapy Gene therapy has has been attempted using a number of different viral vectors, including nonreplicating retroviruses, adenoviruses, adenoassociated viruses, and replication-competent strains of poxviruses. Unexpected adverse events have restricted the prevalence of gene therapy protocols.\nThe infectious hazards of gene therapy are theoretical at this time, but require meticulous surveillance due to the possible occurrence of in vivo recombination and the subsequent emergence of a transmissible genetically altered pathogen. Greatest concern attends the use of replication-competent viruses, especially vaccinia. As of the time of publication, no reports have described transmission of a vector virus from a gene therapy recipient to another individual, but surveillance is ongoing. Recommendations for monitoring infection control issues throughout the course of gene therapy trials have been published .\n\n# I.F.2. Infections transmitted through blood, organs and other tissues\nThe potential hazard of transmitting infectious pathogens through biologic products is a small but ever present risk, despite donor screening. Reported infections transmitted by transfusion or transplantation include West Nile Virus infection 530 cytomegalovirus infection 531 , Creutzfeldt-Jacob disease 230 , hepatitis C 532 , infections with Clostridium spp. 533 and group A streptococcus 534 , malaria 535 , babesiosis 536 , Chagas disease 537 , lymphocytic choriomeningitis 538 , and rabies 539, 540 . Therefore, it is important to consider receipt of biologic products when evaluating patients for potential sources of infection.\n\n# I.F.3. Xenotransplantation\nThe transplantation of nonhuman cells, tissues, and organs into humans potentially exposes patients to zoonotic pathogens. Transmission of known zoonotic infections (e.g., trichinosis from porcine tissue), constitutes one concern, but also of concern is the possibility that transplantation of nonhuman cells, tissues, or organs may transmit previously unknown zoonotic infections (xenozoonoses) to immunosuppressed human recipients. Potential infections that might accompany transplantation of porcine organs have been described 541 . Guidelines from the U.S. Public Health Service address many infectious diseases and infection control issues that surround the developing field of xenotransplantation 542 ); work in this area is ongoing.\n\n# Part II:\nFundamental elements needed to prevent transmission of infectious agents in healthcare settings II.A. Healthcare system components that influence the effectiveness of precautions to prevent transmission II.A.1. Administrative measures Healthcare organizations can demonstrate a commitment to preventing transmission of infectious agents by incorporating infection control into the objectives of the organization's patient and occupational safety programs . An infrastructure to guide, support, and monitor adherence to Standard and Transmission-Based Precautions 434,548,549 will facilitate fulfillment of the organization's mission and achievement of the Joint Commission on Accreditation of Healthcare Organization's patient safety goal to decrease HAIs 550 . Policies and procedures that explain how Standard and Transmission-Based Precautions are applied, including systems used to identify and communicate information about patients with potentially transmissible infectious agents, are essential to ensure the success of these measures and may vary according to the characteristics of the organization.\nA key administrative measure is provision of fiscal and human resources for maintaining infection control and occupational health programs that are responsive to emerging needs. Specific components include bedside nurse 551 and infection prevention and control professional (ICP) staffing levels 552 , inclusion of ICPs in facility construction and design decisions 11 , clinical microbiology laboratory support 553,554 , adequate supplies and equipment including facility ventilation systems 11 , adherence monitoring 555 , assessment and correction of system failures that contribute to transmission 556,557 , and provision of feedback to healthcare personnel and senior administrators 434,548,549,558 . The positive influence of institutional leadership has been demonstrated repeatedly in studies of HCW adherence to recommended hand hygiene practices 176,177,434,548,549, . Healthcare administrator involvement in infection control processes can improve administrators' awareness of the rationale and resource requirements for following recommended infection control practices.\nSeveral administrative factors may affect the transmission of infectious agents in healthcare settings: institutional culture, individual worker behavior, and the work environment. Each of these areas is suitable for performance improvement monitoring and incorporation into the organization's patient safety goals 543,544,546,565 .\n\n# II.A.1.a.Scope of work and staffing needs for infection control professionals\nThe effectiveness of infection surveillance and control programs in preventing nosocomial infections in United States hospitals was assessed by the CDC through the Study on the Efficacy of Nosocomial Infection Control (SENIC Project) conducted 1970-76 566 . In a representative sample of US general hospitals, those with a trained infection control physician or microbiologist involved in an infection control program, and at least one infection control nurse per 250 beds, were associated with a 32% lower rate of four infections studied (CVC-associated bloodstream infections, ventilator-associated pneumonias, catheter-related urinary tract infections, and surgical site infections).\nSince that landmark study was published, responsibilities of ICPs have expanded commensurate with the growing complexity of the healthcare system, the patient populations served, and the increasing numbers of medical procedures and devices used in all types of healthcare settings. The scope of work of ICPs was first assessed in 1982 by the Certification Board of Infection Control (CBIC), and has been re-assessed every five years since that time 558, . The findings of these task analyses have been used to develop and update the Infection Control Certification Examination, offered for the first time in 1983. With each survey, it is apparent that the role of the ICP is growing in complexity and scope, beyond traditional infection control activities in acute care hospitals. Activities currently assigned to ICPs in response to emerging challenges include: 1) surveillance and infection prevention at facilities other than acute care hospitals e.g., ambulatory clinics, day surgery centers, long term care facilities, rehabilitation centers, home care; 2) oversight of employee health services related to infection prevention, e.g. assessment of risk and administration of recommended treatment following exposure to infectious agents, tuberculosis screening, influenza vaccination, respiratory protection fit testing, and administration of other vaccines as indicated, such as smallpox vaccine in 2003; 3) preparedness planning for annual influenza outbreaks, pandemic influenza, SARS, bioweapons attacks; 4) adherence monitoring for selected infection control practices; 5) oversight of risk assessment and implementation of prevention measures associated with construction and renovation; 6) prevention of transmission of MDROs; 7) evaluation of new medical products that could be associated with increased infection risk. e.g.,intravenous infusion materials; 9) communication with the public, facility staff, and state and local health departments concerning infection control-related issues; and 10) participation in local and multi-center research projects 434,549,552,558,573,574 .\nNone of the CBIC job analyses addressed specific staffing requirements for the identified tasks, although the surveys did include information about hours worked; the 2001 survey included the number of ICPs assigned to the responding facilities 558 . There is agreement in the literature that 1 ICP per 250 acute care beds is no longer adequate to meet current infection control needs; a Delphi project that assessed staffing needs of infection control programs in the 21 st century concluded that a ratio of 0.8 to 1.0 ICP per 100 occupied acute care beds is an appropriate level of staffing 552 . A survey of participants in the National Nosocomial Infections Surveillance (NNIS) system found the average daily census per ICP was 115 316 . Results of other studies have been similar: 3 per 500 beds for large acute care hospitals, 1 per 150-250 beds in long term care facilities, and 1.56 per 250 in small rural hospitals 573,575 . The foregoing demonstrates that infection control staffing can no longer be based on patient census alone, but rather must be determined by the scope of the program, characteristics of the patient population, complexity of the healthcare system, tools available to assist personnel to perform essential tasks (e.g., electronic tracking and laboratory support for surveillance), and unique or urgent needs of the institution and community 552 . Furthermore, appropriate training is required to optimize the quality of work performed 558, 572, 576 .\n\n# II.A.1.a.i. Infection Control Nurse Liaison\nDesignating a bedside nurse on a patient care unit as an infection control liaison or \"link nurse\" is reported to be an effective adjunct to enhance infection control at the unit level . Such individuals receive training in basic infection control and have frequent communication with the ICPs, but maintain their primary role as bedside caregiver on their units. The infection control nurse liaison increases the awareness of infection control at the unit level. He or she is especially effective in implementation of new policies or control interventions because of the rapport with individuals on the unit, an understanding of unit-specific challenges, and ability to promote strategies that are most likely to be successful in that unit. This position is an adjunct to, not a replacement for, fully trained ICPs. Furthermore, the infection control liaison nurses should not be counted when considering ICP staffing.\n\n# II.A.1.b. Bedside nurse staffing\nThere is increasing evidence that the level of bedside nurse-staffing influences the quality of patient care 583,584 . If there are adequate nursing staff, it is more likely that infection control practices, including hand hygiene and Standard and Transmission-Based Precautions, will be given appropriate attention and applied correctly and consistently 552 . A national multicenter study reported strong and consistent inverse relationships between nurse staffing and five adverse outcomes in medical patients, two of which were HAIs: urinary tract infections and pneumonia 583 . The association of nursing staff shortages with increased rates of HAIs has been demonstrated in several outbreaks in hospitals and long term care settings, and with increased transmission of hepatitis C virus in dialysis units 22,418,551, . In most cases, when staffing improved as part of a comprehensive control intervention, the outbreak ended or the HAI rate declined. In two studies 590,596 , the composition of the nursing staff (\"pool\" or \"float\" vs. regular staff nurses) influenced the rate of primary bloodstream infections, with an increased infection rate occurring when the proportion of regular nurses decreased and pool nurses increased.\n\n# II.A.1.c. Clinical microbiology laboratory support\nThe critical role of the clinical microbiology laboratory in infection control and healthcare epidemiology is described well 553,554, and is supported by the Infectious Disease Society of America policy statement on consolidation of clinical microbiology laboratories published in 2001 553 . The clinical microbiology laboratory contributes to preventing transmission of infectious diseases in healthcare settings by promptly detecting and reporting epidemiologically important organisms, identifying emerging patterns of antimicrobial resistance, and assisting in assessment of the effectiveness of recommended precautions to limit transmission during outbreaks 598 . Outbreaks of infections may be recognized first by laboratorians 162 . Healthcare organizations need to ensure the availability of the recommended scope and quality of laboratory services, a sufficient number of appropriately trained laboratory staff members, and systems to promptly communicate epidemiologically important results to those who will take action (e.g., providers of clinical care, infection control staff, healthcare epidemiologists, and infectious disease consultants) 601 . As concerns about emerging pathogens and bioterrorism grow, the role of the clinical microbiology laboratory takes on even greater importance. For healthcare organizations that outsource microbiology laboratory services (e.g., ambulatory care, home care, LTCFs, smaller acute care hospitals), it is important to specify by contract the types of services (e.g., periodic institution-specific aggregate susceptibility reports) required to support infection control.\nSeveral key functions of the clinical microbiology laboratory are relevant to this guideline:\n- Antimicrobial susceptibility by testing and interpretation in accordance with current guidelines developed by the National Committee for Clinical Laboratory Standards (NCCLS), known as the Clinical and Laboratory Standards Institute (CLSI) since 2005 602 , for the detection of emerging resistance patterns 603,604 , and for the preparation, analysis, and distribution of periodic cumulative antimicrobial susceptibility summary reports . While not required, clinical laboratories ideally should have access to rapid genotypic identification of bacteria and their antibiotic resistance genes 608 . - Performance of surveillance cultures when appropriate (including retention of isolates for analysis) to assess patterns of infection transmission and effectiveness of infection control interventions at the facility or organization. Microbiologists assist in decisions concerning the indications for initiating and discontinuing active surveillance programs and optimize the use of laboratory resources. - Molecular typing, on-site or outsourced, in order to investigate and control healthcare-associated outbreaks 609 . - Application of rapid diagnostic tests to support clinical decisions involving patient treatment, room selection, and implementation of control measures including barrier precautions and use of vaccine or chemoprophylaxis agents (e.g., influenza , B. pertussis 613 , RSV 614,615 , and enteroviruses 616 ). The microbiologist provides guidance to limit rapid testing to clinical situations in which rapid results influence patient management decisions, as well as providing oversight of point-of-care testing performed by non-laboratory healthcare workers 617 . - Detection and rapid reporting of epidemiologically important organisms, including those that are reportable to public health agencies. - Implementation of a quality control program that ensures testing services are appropriate for the population served, and stringently evaluated for sensitivity, specificity, applicability, and feasibility. - Participation in a multidisciplinary team to develop and maintain an effective institutional program for the judicious use of antimicrobial agents 618, 619 .\n\n# II.A.2. Institutional safety culture and organizational characteristics\nSafety culture (or safety climate) refers to a work environment where a shared commitment to safety on the part of management and the workforce is understood and followed 557,620,621 . The authors of the Institute of Medicine Report, To Err is Human 543 , acknowledge that causes of medical error are multifaceted but emphasize repeatedly the pivotal role of system failures and the benefits of a safety culture. A safety culture is created through 1) the actions management takes to improve patient and worker safety; 2) worker participation in safety planning; 3) the availability of appropriate protective equipment; 4) influence of group norms regarding acceptable safety practices; and 5) the organization's socialization process for new personnel. Safety and patient outcomes can be enhanced by improving or creating organizational characteristics within patient care units as demonstrated by studies of surgical ICUs 622, 623 . Each of these factors has a direct bearing on adherence to transmission prevention recommendations 257 . Measurement of an institutional culture of safety is useful for designing improvements in healthcare 624,625 . Several hospital-based studies have linked measures of safety culture with both employee adherence to safe practices and reduced exposures to blood and body fluids . One study of hand hygiene practices concluded that improved adherence requires integration of infection control into the organization's safety culture 561 . Several hospitals that are part of the Veterans Administration Healthcare System have taken specific steps toward improving the safety culture, including error reporting mechanisms, performing root cause analysis on problems identified, providing safety incentives, and employee education. .\n\n# II.A.3. Adherence of healthcare personnel to recommended guidelines\nAdherence to recommended infection control practices decreases transmission of infectious agents in healthcare settings 116,562, . However, several observational studies have shown limited adherence to recommended practices by healthcare personnel 559, . Observed adherence to universal precautions ranged from 43% to 89% 641,642,649,651,652 . However, the degree of adherence depended frequently on the practice that was assessed and, for glove use, the circumstance in which they were used. Appropriate glove use has ranged from a low of 15% 645 to a high of 82% 650 . However, 92% and 98% adherence with glove use have been reported during arterial blood gas collection and resuscitation, respectively, procedures where there may be considerable blood contact 643,656 . Differences in observed adherence have been reported among occupational groups in the same healthcare facility 641 and between experienced and nonexperienced professionals 645 . In surveys of healthcare personnel, selfreported adherence was generally higher than that reported in observational studies. Furthermore, where an observational component was included with a self-reported survey, self-perceived adherence was often greater than observed adherence 657 . Among nurses and physicians, increasing years of experience is a negative predictor of adherence 645,651 . Education to improve adherence is the primary intervention that has been studied. While positive changes in knowledge and attitude have been demonstrated, 640,658 , there often has been limited or no accompanying change in behavior 642,644 . Self-reported adherence is higher in groups that have received an educational intervention 630,659 . Educational interventions that incorporated videotaping and performance feedback were successful in improving adherence during the period of study; the long-term effect of these interventions is not known 654 .The use of videotape also served to identify system problems (e.g., communication and access to personal protective equipment) that otherwise may not have been recognized. Use of engineering controls and facility design concepts for improving adherence is gaining interest. While introduction of automated sinks had a negative impact on consistent adherence to hand washing 660 , use of electronic monitoring and voice prompts to remind healthcare workers to perform hand hygiene, and improving accessibility to hand hygiene products, increased adherence and contributed to a decrease in HAIs in one study 661 . More information is needed regarding how technology might improve adherence. Improving adherence to infection control practices requires a multifaceted approach that incorporates continuous assessment of both the individual and the work environment 559,561 . Using several behavioral theories, Kretzer and Larson concluded that a single intervention (e.g., a handwashing campaign or putting up new posters about transmission precautions) would likely be ineffective in improving healthcare personnel adherence 662 . Improvement requires that the organizational leadership make prevention an institutional priority and integrate infection control practices into the organization's safety culture 561 . A recent review of the literature concluded that variations in organizational factors (e.g., safety climate, policies and procedures, education and training) and individual factors (e.g., knowledge, perceptions of risk, past experience) were determinants of adherence to infection control guidelines for protection against SARS and other respiratory pathogens 257 .\n\n# II.B. Surveillance for healthcare-associated infections (HAIs)\nSurveillance is an essential tool for case-finding of single patients or clusters of patients who are infected or colonized with epidemiologically important organisms (e.g., susceptible bacteria such as S. aureus, S. pyogenes or Enterobacter-Klebsiella spp; MRSA, VRE, and other MDROs; C. difficile; RSV; influenza virus) for which transmission-based precautions may be required. Surveillance is defined as the ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health 663 . The work of Ignaz Semmelweis that described the role of person-to-person transmission in puerperal sepsis is the earliest example of the use of surveillance data to reduce transmission of infectious agents 664 . Surveillance of both process measures and the infection rates to which they are linked are important for evaluating the effectiveness of infection prevention efforts and identifying indications for change 555, .\nThe Study on the Efficacy of Nosocomial Infection Control (SENIC) found that different combinations of infection control practices resulted in reduced rates of nosocomial surgical site infections, pneumonia, urinary tract infections, and bacteremia in acute care hospitals 566 ; however, surveillance was the only component essential for reducing all four types of HAIs. Although a similar study has not been conducted in other healthcare settings, a role for surveillance and the need for novel strategies have been described in LTCFs 398,434,669,670 and in home care . The essential elements of a surveillance system are: 1) standardized definitions; 2) identification of patient populations at risk for infection; 3) statistical analysis (e.g. risk-adjustment, calculation of rates using appropriate denominators, trend analysis using methods such as statistical process control charts); and 4) feedback of results to the primary caregivers . Data gathered through surveillance of high-risk populations, device use, procedures, and/or facility locations (e.g., ICUs) are useful for detecting transmission trends . Identification of clusters of infections should be followed by a systematic epidemiologic investigation to determine commonalities in persons, places, and time; and guide implementation of interventions and evaluation of the effectiveness of those interventions.\nTargeted surveillance based on the highest risk areas or patients has been preferred over facility-wide surveillance for the most effective use of resources 673, 676 . However, surveillance for certain epidemiologically important organisms may need to be facility-wide. Surveillance methods will continue to evolve as healthcare delivery systems change 392,677 and user-friendly electronic tools become more widely available for electronic tracking and trend analysis 674,678,679 . Individuals with experience in healthcare epidemiology and infection control should be involved in selecting software packages for data aggregation and analysis to assure that the need for efficient and accurate HAI surveillance will be met. Effective surveillance is increasingly important as legislation requiring public reporting of HAI rates is passed and states work to develop effective systems to support such legislation 680 .\n\n# II.C. Education of HCWs, patients, and families\nEducation and training of healthcare personnel are a prerequisite for ensuring that policies and procedures for Standard and Transmission-Based Precautions are understood and practiced. Understanding the scientific rationale for the precautions will allow HCWs to apply procedures correctly, as well as safely modify precautions based on changing requirements, resources, or healthcare settings 14,655, . In one study, the likelihood of HCWs developing SARS was strongly associated with less than 2 hours of infection control training and lack of understanding of infection control procedures 689 . Education about the important role of vaccines (e.g., influenza, measles, varicella, pertussis, pneumococcal) in protecting healthcare personnel, their patients, and family members can help improve vaccination rates . Patients, family members, and visitors can be partners in preventing transmission of infections in healthcare settings 9,42, . Information about Standard Precautions, especially hand hygiene, Respiratory Hygiene/Cough Etiquette, vaccination (especially against influenza) and other routine infection prevention strategies may be incorporated into patient information materials that are provided upon admission to the healthcare facility. Additional information about Transmission-Based Precautions is best provided at the time they are initiated. Fact sheets, pamphlets, and other printed material may include information on the rationale for the additional precautions, risks to household members, room assignment for Transmission-Based Precautions purposes, explanation about the use of personal protective equipment by HCWs, and directions for use of such equipment by family members and visitors. Such information may be particularly helpful in the home environment where household members often have primary responsibility for adherence to recommended infection control practices. Healthcare personnel must be available and prepared to explain this material and answer questions as needed.\n\n# II.D. Hand hygiene\nHand hygiene has been cited frequently as the single most important practice to reduce the transmission of infectious agents in healthcare settings 559,712,713 and is an essential element of Standard Precautions. The term \"hand hygiene\" includes both handwashing with either plain or antiseptic-containing soap and water, and use of alcohol-based products (gels, rinses, foams) that do not require the use of water. In the absence of visible soiling of hands, approved alcoholbased products for hand disinfection are preferred over antimicrobial or plain soap and water because of their superior microbiocidal activity, reduced drying of the skin, and convenience 559 . Improved hand hygiene practices have been associated with a sustained decrease in the incidence of MRSA and VRE infections primarily in the ICU 561,562, . The scientific rationale, indications, methods, and products for hand hygiene are summarized in other publications 559, 717 .\nThe effectiveness of hand hygiene can be reduced by the type and length of fingernails 559,718,719 . Individuals wearing artifical nails have been shown to harbor more pathogenic organisms, especially gram negative bacilli and yeasts, on the nails and in the subungual area than those with native nails 720,721 . In 2002, CDC/HICPAC recommended (Category IA) that artificial fingernails and extenders not be worn by healthcare personnel who have contact with high-risk patients (e.g., those in ICUs, ORs) due to the association with outbreaks of gramnegative bacillus and candidal infections as confirmed by molecular typing of isolates 30,31,559, .The need to restrict the wearing of artificial fingernails by all healthcare personnel who provide direct patient care or by healthcare personnel who have contact with other high risk groups (e.g., oncology, cystic fibrosis patients), has not been studied, but has been recommended by some experts 20 . At this time such decisions are at the discretion of an individual facility's infection control program. There is less evidence that jewelry affects the quality of hand hygiene. Although hand contamination with potential pathogens is increased with ring-wearing 559,726 , no studies have related this practice to HCW-to-patient transmission of pathogens.\n\n# II.E. Personal protective equipment (PPE) for healthcare personnel\nPPE refers to a variety of barriers and respirators used alone or in combination to protect mucous membranes, airways, skin, and clothing from contact with infectious agents. The selection of PPE is based on the nature of the patient interaction and/or the likely mode(s) of transmission. Guidance on the use of PPE is discussed in Part III. A suggested procedure for donning and removing PPE that will prevent skin or clothing contamination is presented in the Figure.\nDesignated containers for used disposable or reusable PPE should be placed in a location that is convenient to the site of removal to facilitate disposal and containment of contaminated materials. Hand hygiene is always the final step after removing and disposing of PPE. The following sections highlight the primary uses and methods for selecting this equipment.\n\n# II.E.1. Gloves\nGloves are used to prevent contamination of healthcare personnel hands when 1) anticipating direct contact with blood or body fluids, mucous membranes, nonintact skin and other potentially infectious material; 2) having direct contact with patients who are colonized or infected with pathogens transmitted by the contact route e.g., VRE, MRSA, RSV 559,727,728 ; or 3) handling or touching visibly or potentially contaminated patient care equipment and environmental surfaces 72,73,559 . Gloves can protect both patients and healthcare personnel from exposure to infectious material that may be carried on hands 73 . The extent to which gloves will protect healthcare personnel from transmission of bloodborne pathogens (e.g., HIV, HBV, HCV) following a needlestick or other pucture that penetrates the glove barrier has not been determined. Although gloves may reduce the volume of blood on the external surface of a sharp by 46-86% 729 , the residual blood in the lumen of a hollowbore needle would not be affected; therefore, the effect on transmission risk is unknown. Gloves manufactured for healthcare purposes are subject to FDA evaluation and clearance 730 . Nonsterile disposable medical gloves made of a variety of materials (e.g., latex, vinyl, nitrile) are available for routine patient care 731 . The selection of glove type for non-surgical use is based on a number of factors, including the task that is to be performed, anticipated contact with chemicals and chemotherapeutic agents, latex sensitivity, sizing, and facility policies for creating a latex-free environment 17, . For contact with blood and body fluids during non-surgical patient care, a single pair of gloves generally provides adequate barrier protection 734 . However, there is considerable variability among gloves; both the quality of the manufacturing process and type of material influence their barrier effectiveness 735 . While there is little difference in the barrier properties of unused intact gloves 736 , studies have shown repeatedly that vinyl gloves have higher failure rates than latex or nitrile gloves when tested under simulated and actual clinical conditions 731, . For this reason either latex or nitrile gloves are preferable for clinical procedures that require manual dexterity and/or will involve more than brief patient contact. It may be necessary to stock gloves in several sizes. Heavier, reusable utility gloves are indicated for non-patient care activities, such as handling or cleaning contaminated equipment or surfaces 11, 14, . During patient care, transmission of infectious organisms can be reduced by adhering to the principles of working from \"clean\" to \"dirty\", and confining or limiting contamination to surfaces that are directly needed for patient care. It may be necessary to change gloves during the care of a single patient to prevent cross-contamination of body sites 559,740 . It also may be necessary to change gloves if the patient interaction also involves touching portable computer keyboards or other mobile equipment that is transported from room to room. Discarding gloves between patients is necessary to prevent transmission of infectious material. Gloves must not be washed for subsequent reuse because microorganisms cannot be removed reliably from glove surfaces and continued glove integrity cannot be ensured. Furthermore, glove reuse has been associated with transmission of MRSA and gram-negative bacilli . When gloves are worn in combination with other PPE, they are put on last. Gloves that fit snugly around the wrist are preferred for use with an isolation gown because they will cover the gown cuff and provide a more reliable continuous barrier for the arms, wrists, and hands. Gloves that are removed properly will prevent hand contamination (Figure). Hand hygiene following glove removal further ensures that the hands will not carry potentially infectious material that might have penetrated through unrecognized tears or that could contaminate the hands during glove removal 559,728,741 .\n\n# II.E.2. Isolation gowns\nIsolation gowns are used as specified by Standard and Transmission-Based Precautions, to protect the HCW's arms and exposed body areas and prevent contamination of clothing with blood, body fluids, and other potentially infectious material 24,88,262, . The need for and type of isolation gown selected is based on the nature of the patient interaction, including the anticipated degree of contact with infectious material and potential for blood and body fluid penetration of the barrier. The wearing of isolation gowns and other protective apparel is mandated by the OSHA Bloodborne Pathogens Standard 739 . Clinical and laboratory coats or jackets worn over personal clothing for comfort and/or purposes of identity are not considered PPE. When applying Standard Precautions, an isolation gown is worn only if contact with blood or body fluid is anticipated. However, when Contact Precautions are used (i.e., to prevent transmission of an infectious agent that is not interrupted by Standard Precautions alone and that is associated with environmental contamination), donning of both gown and gloves upon room entry is indicated to address unintentional contact with contaminated environmental surfaces 54,72,73,88 . The routine donning of isolation gowns upon entry into an intensive care unit or other high-risk area does not prevent or influence potential colonization or infection of patients in those areas 365, .\nIsolation gowns are always worn in combination with gloves, and with other PPE when indicated. Gowns are usually the first piece of PPE to be donned. Full coverage of the arms and body front, from neck to the mid-thigh or below will ensure that clothing and exposed upper body areas are protected. Several gown sizes should be available in a healthcare facility to ensure appropriate coverage for staff members. Isolation gowns should be removed before leaving the patient care area to prevent possible contamination of the environment outside the patient's room. Isolation gowns should be removed in a manner that prevents contamination of clothing or skin (Figure). The outer, \"contaminated\", side of the gown is turned inward and rolled into a bundle, and then discarded into a designated container for waste or linen to contain contamination.\n\n# II.E.3. Face protection: masks, goggles, face shields\nII.E.3.a. Masks Masks are used for three primary purposes in healthcare settings: 1) placed on healthcare personnel to protect them from contact with infectious material from patients e.g., respiratory secretions and sprays of blood or body fluids, consistent with Standard Precautions and Droplet Precautions; 2) placed on healthcare personnel when engaged in procedures requiring sterile technique to protect patients from exposure to infectious agents carried in a healthcare worker's mouth or nose, and 3) placed on coughing patients to limit potential dissemination of infectious respiratory secretions from the patient to others (i.e., Respiratory Hygiene/Cough Etiquette). Masks may be used in combination with goggles to protect the mouth, nose and eyes, or a face shield may be used instead of a mask and goggles, to provide more complete protection for the face, as discussed below. Masks should not be confused with particulate respirators that are used to prevent inhalation of small particles that may contain infectious agents transmitted via the airborne route as described below. The mucous membranes of the mouth, nose, and eyes are susceptible portals of entry for infectious agents, as can be other skin surfaces if skin integrity is compromised (e.g., by acne, dermatitis) 66, . Therefore, use of PPE to protect these body sites is an important component of Standard Precautions. The protective effect of masks for exposed healthcare personnel has been demonstrated 93,113,755,756 . Procedures that generate splashes or sprays of blood, body fluids, secretions, or excretions (e.g., endotracheal suctioning, bronchoscopy, invasive vascular procedures) require either a face shield (disposable or reusable) or mask and goggles 93-95, 96 , 113, 115, 262, 739, 757 .The wearing of masks, eye protection, and face shields in specified circumstances when blood or body fluid exposures are likely to occur is mandated by the OSHA Bloodborne Pathogens Standard 739 . Appropriate PPE should be selected based on the anticipated level of exposure. Two mask types are available for use in healthcare settings: surgical masks that are cleared by the FDA and required to have fluid-resistant properties, and procedure or isolation masks 758 #2688 . No studies have been published that compare mask types to determine whether one mask type provides better protection than another. Since procedure/isolation masks are not regulated by the FDA, there may be more variability in quality and performance than with surgical masks. Masks come in various shapes (e.g., molded and non-molded), sizes, filtration efficiency, and method of attachment (e.g., ties, elastic, ear loops). Healthcare facilities may find that different types of masks are needed to meet individual healthcare personnel needs.\n\n# II.E.3.b. Goggles, face shields\nGuidance on eye protection for infection control has been published 759 . The eye protection chosen for specific work situations (e.g., goggles or face shield) depends upon the circumstances of exposure, other PPE used, and personal vision needs. Personal eyeglasses and contact lenses are NOT considered adequate eye protection (www.cdc.gov/niosh/topics/eye/eye-infectious.html). NIOSH states that, eye protection must be comfortable, allow for sufficient peripheral vision, and must be adjustable to ensure a secure fit. It may be necessary to provide several different types, styles, and sizes of protective equipment. Indirectly-vented goggles with a manufacturer's anti-fog coating may provide the most reliable practical eye protection from splashes, sprays, and respiratory droplets from multiple angles. Newer styles of goggles may provide better indirect airflow properties to reduce fogging, as well as better peripheral vision and more size options for fitting goggles to different workers. Many styles of goggles fit adequately over prescription glasses with minimal gaps. While effective as eye protection, goggles do not provide splash or spray protection to other parts of the face. The role of goggles, in addition to a mask, in preventing exposure to infectious agents transmitted via respiratory droplets has been studied only for RSV. Reports published in the mid-1980s demonstrated that eye protection reduced occupational transmission of RSV 760,761 . Whether this was due to preventing hand-eye contact or respiratory droplet-eye contact has not been determined. However, subsequent studies demonstrated that RSV transmission is effectively prevented by adherence to Standard plus Contact Precations and that for this virus routine use of goggles is not necessary 24,116,117,684,762 . It is important to remind healthcare personnel that even if Droplet Precautions are not recommended for a specific respiratory tract pathogen, protection for the eyes, nose and mouth by using a mask and goggles, or face shield alone, is necessary when it is likely that there will be a splash or spray of any respiratory secretions or other body fluids as defined in Standard Precautions Disposable or non-disposable face shields may be used as an alternative to goggles 759 . As compared with goggles, a face shield can provide protection to other facial areas in addition to the eyes. Face shields extending from chin to crown provide better face and eye protection from splashes and sprays; face shields that wrap around the sides may reduce splashes around the edge of the shield. Removal of a face shield, goggles and mask can be performed safely after gloves have been removed, and hand hygiene performed. The ties, ear pieces and/or headband used to secure the equipment to the head are considered \"clean\" and therefore safe to touch with bare hands. The front of a mask, goggles and face shield are considered contaminated (Figure ).\n\n# II.E.4. Respiratory protection\nThe subject of respiratory protection as it applies to preventing transmission of airborne infectious agents, including the need for and frequency of fit-testing is under scientific review and was the subject of a CDC workshop in 2004 763 . Respiratory protection currently requires the use of a respirator with N95 or higher filtration to prevent inhalation of infectious particles. Information about respirators and respiratory protection programs is summarized in the Guideline for Preventing Transmission of Mycobacterium tuberculosis in Health-care Settings, 2005 (CDC.MMWR 2005; 54: RR-17 12 ). Respiratory protection is broadly regulated by OSHA under the general industry standard for respiratory protection (29CFR1910.134) 764 which requires that U.S. employers in all employment settings implement a program to protect employees from inhalation of toxic materials. OSHA program components include medical clearance to wear a respirator; provision and use of appropriate respirators, including fit-tested NIOSH-certified N95 and higher particulate filtering respirators; education on respirator use and periodic re-evaluation of the respiratory protection program. When selecting particulate respirators, models with inherently good fit characteristics (i.e., those expected to provide protection factors of 10 or more to 95% of wearers) are preferred and could theoretically relieve the need for fit testing 765,766 . Issues pertaining to respiratory protection remain the subject of ongoing debate. Information on various types of respirators may be found at www.cdc.gov/niosh/npptl/respirators/respsars.html and in published studies 765,767,768 . A user-seal check (formerly called a \"fit check\") should be performed by the wearer of a respirator each time a respirator is donned to minimize air leakage around the facepiece 769 . The optimal frequency of fit-testng has not been determined; re-testing may be indicated if there is a change in facial features of the wearer, onset of a medical condition that would affect respiratory function in the wearer, or a change in the model or size of the initially assigned respirator 12 . Respiratory protection was first recommended for protection of preventing U.S. healthcare personnel from exposure to M. tuberculosis in 1989. That recommendation has been maintained in two successive revisions of the Guidelines for Prevention of Transmission of Tuberculosis in Hospitals and other Healthcare Settings 12,126 . The incremental benefit from respirator use, in addition to administrative and engineering controls (i.e., AIIRs, early recognition of patients likely to have tuberculosis and prompt placement in an AIIR, and maintenance of a patient with suspected tuberculosis in an AIIR until no longer infectious), for preventing transmission of airborne infectious agents (e.g., M. tuberculosis) is undetermined. Although some studies have demonstrated effective prevention of M. tuberculosis transmission in hospitals where surgical masks, instead of respirators, were used in conjunction with other administrative and engineering controls 637,770,771 , CDC currently recommends N95 or higher level respirators for personnel exposed to patients with suspected or confirmed tuberculosis. Currently this is also true for other diseases that could be transmitted through the airborne route, including SARS 262 and smallpox 108,129,772 , until inhalational transmission is better defined or healthcare-specific protective equipment more suitable for for preventing infection are developed. Respirators are also currently recommended to be worn during the performance of aerosol-generating procedures (e.g., intubation, bronchoscopy, suctioning) on patients withSARS Co-V infection, avian influenza and pandemic influenza (See Appendix A). Although Airborne Precautions are recommended for preventing airborne transmission of measles and varicella-zoster viruses, there are no data upon which to base a recommendation for respiratory protection to protect susceptible personnel against these two infections; transmission of varicella-zoster virus has been prevented among pediatric patients using negative pressure isolation alone 773 . Whether respiratory protection (i.e., wearing a particulate respirator) would enhance protection from these viruses has not been studied. Since the majority of healthcare personnel have natural or acquired immunity to these viruses, only immune personnel generally care for patients with these infections . Although there is no evidence to suggest that masks are not adequate to protect healthcare personnel in these settings, for purposes of consistency and simplicity, or because of difficulties in ascertaining immunity, some facilities may require the use of respirators for entry into all AIIRs, regardless of the specific infectious agent.\nProcedures for safe removal of respirators are provided (Figure). In some healthcare settings, particulate respirators used to provide care for patients with M. tuberculosis are reused by the same HCW. This is an acceptable practice providing the respirator is not damaged or soiled, the fit is not compromised by change in shape, and the respirator has not been contaminated with blood or body fluids. There are no data on which to base a recommendation for the length of time a respirator may be reused.\n\n# II.F. Safe work practices to prevent HCW exposure to bloodborne pathogens\n\n# II.F.1. Prevention of needlesticks and other sharps-related injuries\nInjuries due to needles and other sharps have been associated with transmission of HBV, HCV and HIV to healthcare personnel 778,779 . The prevention of sharps injuries has always been an essential element of Universal and now Standard Precautions 1, 780 . These include measures to handle needles and other sharp devices in a manner that will prevent injury to the user and to others who may encounter the device during or after a procedure. These measures apply to routine patient care and do not address the prevention of sharps injuries and other blood exposures during surgical and other invasive procedures that are addressed elsewhere .\nSince 1991, when OSHA first issued its Bloodborne Pathogens Standard to protect healthcare personnel from blood exposure, the focus of regulatory and legislative activity has been on implementing a hierarchy of control measures. This has included focusing attention on removing sharps hazards through the development and use of engineering controls. The federal Needlestick Safety and Prevention Act signed into law in November, 2000 authorized OSHA's revision of its Bloodborne Pathogens Standard to more explicitly require the use of safety-engineered sharp devices 786 . CDC has provided guidance on sharps injury prevention 787,788 , including for the design, implementation and evaluation of a comprehensive sharps injury prevention 789 program .\n\n# II.F.2. Prevention of mucous membrane contact\nExposure of mucous membranes of the eyes, nose and mouth to blood and body fluids has been associated with the transmission of bloodborne viruses and other infectious agents to healthcare personnel 66,752,754,779 . The prevention of mucous membrane exposures has always been an element of Universal and now Standard Precautions for routine patient care 1, 753 and is subject to OSHA bloodborne pathogen regulations. Safe work practices, in addition to wearing PPE, are used to protect mucous membranes and non-intact skin from contact with potentially infectious material. These include keeping gloved and ungloved hands that are contaminated from touching the mouth, nose, eyes, or face; and positioning patients to direct sprays and splatter away from the face of the caregiver. Careful placement of PPE before patient contact will help avoid the need to make PPE adjustments and possible face or mucous membrane contamination during use. In areas where the need for resuscitation is unpredictable, mouthpieces, pocket resuscitation masks with one-way valves, and other ventilation devices provide an alternative to mouth-to-mouth resuscitation, preventing exposure of the caregiver's nose and mouth to oral and respiratory fluids during the procedure.\n\n# II.F.2.a. Precautions during aerosol-generating procedures\nThe performance of procedures that can generate small particle aerosols (aerosol-generating procedures), such as bronchoscopy, endotracheal intubation, and open suctioning of the respiratory tract, have been associated with transmission of infectious agents to healthcare personnel, including M. tuberculosis 790 , SARS-CoV 93,94,98 and N. meningitidis 95 . Protection of the eyes, nose and mouth, in addition to gown and gloves, is recommended during performance of these procedures in accordance with Standard Precautions. Use of a particulate respirator is recommended during aerosol-generating procedures when the aerosol is likely to contain M. tuberculosis, SARS-CoV, or avian or pandemic influenza viruses.\n\n# II.G. Patient placement\n\n# II.G.1. Hospitals and long-term care settings\nOptions for patient placement include single patient rooms, two patient rooms, and multi-bed wards. Of these, single patient rooms are prefered when there is a concern about transmission of an infectious agent. Although some studies have failed to demonstrate the efficacy of single patient rooms to prevent HAIs 791 , other published studies, including one commissioned by the American Institute of Architects and the Facility Guidelines Institute, have documented a beneficial relationship between private rooms and reduction in infectious and noninfectious adverse patient outcomes 792,793 . The AIA notes that private rooms are the trend in hospital planning and design. However, most hospitals and long-term care facilities have multi-bed rooms and must consider many competing priorities when determining the appropriate room placement for patients (e.g., reason for admission; patient characteristics, such as age, gender, mental status; staffing needs; family requests; psychosocial factors; reimbursement concerns). In the absence of obvious infectious diseases that require specified airborne infection isolation rooms (e.g., tuberculosis, SARS, chickenpox), the risk of transmission of infectious agents is not always considered when making placement decisions. When there are only a limited number of single-patient rooms, it is prudent to prioritize them for those patients who have conditions that facilitate transmission of infectious material to other patients (e.g., draining wounds, stool incontinence, uncontained secretions) and for those who are at increased risk of acquisition and adverse outcomes resulting from HAI (e.g., immunosuppression, open wounds, indwelling catheters, anticipated prolonged length of stay, total dependence on HCWs for activities of daily living) 15,24,43,430,794,795 . Single-patient rooms are always indicated for patients placed on Airborne Precautions and in a Protective Environment and are preferred for patients who require Contact or Droplet Precautions 23,24,410,435,796,797 . During a suspected or proven outbreak caused by a pathogen whose reservoir is the gastrointestinal tract, use of single patient rooms with private bathrooms limits opportunities for transmission, especially when the colonized or infected patient has poor personal hygiene habits, fecal incontinence, or cannot be expected to assist in maintaining procedures that prevent transmission of microorganisms (e.g., infants, children, and patients with altered mental status or developmental delay). In the absence of continued transmission, it is not necessary to provide a private bathroom for patients colonized or infected with enteric pathogens as long as personal hygiene practices and Standard Precautions, especially hand hygiene and appropriate environmental cleaning, are maintained. Assignment of a dedicated commode to a patient,and cleaning and disinfecting fixtures and equipment that may have fecal contamination (e.g., bathrooms, commodes 798 , scales used for weighing diapers) and the adjacent surfaces with appropriate agents may be especially important when a single-patient room can not be used since environmental contamination with intestinal tract pathogens is likely from both continent and incontinent patients 54,799 . Results of several studies to determine the benefit of a single-patient room to prevent transmission of Clostridium difficile are inconclusive 167, . Some studies have shown that being in the same room with a colonized or infected patient is not necessarily a risk factor for transmission 791, . However, for children, the risk of healthcare-associated diarrhea is increased with the increased number of patients per room 806 . Thus, patient factors are important determinants of infection transmission risks, and the need for a single-patient room and/or private bathroom for any patient is best determined on a case-by-case basis. Cohorting is the practice of grouping together patients who are colonized or infected with the same organism to confine their care to one area and prevent contact with other patients. Cohorts are created based on clinical diagnosis, microbiologic confirmation when available, epidemiology, and mode of transmission of the infectious agent. It is generally preferred not to place severely immunosuppressed patients in rooms with other patients. Cohorting has been used extensively for managing outbreaks of MDROs including MRSA 22,807 811 ; RSV 812,813 ; adenovirus keratoconjunctivitis 814 ; rotavirus 815 ; and SARS 816 . Modeling studies provide additional support for cohorting patients to control outbreaks Talon . However, cohorting often is implemented only after routine infection control measures have failed to control an outbreak. Assigning or cohorting healthcare personnel to care only for patients infected or colonized with a single target pathogen limits further transmission of the target pathogen to uninfected patients 740,819 but is difficult to achieve in the face of current staffing shortages in hospitals 583 and residential healthcare sites . However, when continued transmission is occurring after implementing routine infection control measures and creating patient cohorts, cohorting of healthcare personnel may be beneficial.\nDuring the seasons when RSV, human metapneumovirus 823 , parainfluenza, influenza, other respiratory viruses 824 , and rotavirus are circulating in the community, cohorting based on the presenting clinical syndrome is often a priority in facilities that care for infants and young children 825 . For example, during the respiratory virus season, infants may be cohorted based soley on the clinical diagnosis of bronchiolitis due to the logistical difficulties and costs associated with requiring microbiologic confirmation prior to room placement, and the predominance of RSV during most of the season. However, when available, single patient rooms are always preferred since a common clinical presentation (e.g., bronchiolitis), can be caused by more than one infectious agent 823,824,826 . Furthermore, the inability of infants and children to contain body fluids, and the close physical contact that occurs during their care, increases infection transmission risks for patients and personnel in this setting 24,795 .\n\n# II.G.2. Ambulatory settings\nPatients actively infected with or incubating transmissible infectious diseases are seen frequently in ambulatory settings (e.g., outpatient clinics, physicians' offices, emergency departments) and potentially expose healthcare personnel and other patients, family members and visitors 21,34,127,135,142,827 . In response to the global outbreak of SARS in 2003 and in preparation for pandemic influenza, healthcare providers working in outpatient settings are urged to implement source containment measures (e.g., asking couging patients to wear a surgical mask or cover their coughs with tissues) to prevent transmission of respiratory infections, beginning at the point of initial patient encounter 9, 262, 828 as described below in section III.A.1.a. Signs can be posted at the entrance to facilities or at the reception or registration desk requesting that the patient or individuals accompanying the patient promptly inform the receptionist if there are symptoms of a respiratory infection (e.g., cough, flu-like illness, increased production of respiratory secretions). The presence of diarrhea, skin rash, or known or suspected exposure to a transmissible disease (e.g., measles, pertussis, chickenpox, tuberculosis) also could be added. Placement of potentially infectious patients without delay in an examination room limits the number of exposed individuals, e.g., in the common waiting area.\nIn waiting areas, maintaining a distance between symptomatic and nonsymptomatic patients (e.g., >3 feet), in addition to source control measures, may limit exposures. However, infections transmitted via the airborne route (e.g., M tuberculosis, measles, chickenpox) require additional precautions 12,125,829 . Patients suspected of having such an infection can wear a surgical mask for source containment, if tolerated, and should be placed in an examination room, preferably an AIIR, as soon as possible. If this is not possible, having the patient wear a mask and segregate him/herself from other patients in the waiting area will reduce opportunities to expose others. Since the person(s) accompanying the patient also may be infectious, application of the same infection control precautions may need to be extended to these persons if they are symptomatic 21, 252, 830 . For example, family members accompanying children admitted with suspected M. tuberculosis have been found to have unsuspected pulmonary tuberculosis with cavitary lesions, even when asymptomatic 42,831 . Patients with underlying conditions that increase their susceptibility to infection (e.g., those who are immunocompromised 43,44 or have cystic fibrosis 20 ) require special efforts to protect them from exposures to infected patients in common waiting areas. By informing the receptionist of their infection risk upon arrival, appropriate steps may be taken to further protect them from infection. In some cystic fibrosis clinics, in order to avoid exposure to other patients who could be colonized with B. cepacia, patients have been given beepers upon registration so that they may leave the area and receive notification to return when an examination room becomes available 832 .\n\n# II.G.3. Home care\nIn home care, the patient placement concerns focus on protecting others in the home from exposure to an infectious household member. For individuals who are especially vulnerable to adverse outcomes associated with certain infections, it may be beneficial to either remove them from the home or segregate them within the home. Persons who are not part of the household may need to be prohibited from visiting during the period of infectivity. For example, if a patient with pulmonary tuberculosis is contagious and being cared for at home, very young children (<4 years of age) 833 and immunocompromised persons who have not yet been infected should be removed or excluded from the household. During the SARS outbreak of 2003, segregation of infected persons during the communicable phase of the illness was beneficial in preventing household transmission 249,834 .\n\n# II.H. Transport of patients\nSeveral principles are used to guide transport of patients requiring Transmission-Based Precautions. In the inpatient and residential settings these include 1) limiting transport of such patients to essential purposes, such as diagnostic and therapeutic procedures that cannot be performed in the patient's room; 2) when transport is necessary, using appropriate barriers on the patient (e.g., mask, gown, wrapping in sheets or use of impervious dressings to cover the affected area(s) when infectious skin lesions or drainage are present, consistent with the route and risk of transmission; 3) notifying healthcare personnel in the receiving area of the impending arrival of the patient and of the precautions necessary to prevent transmission; and 4) for patients being transported outside the facility, informing the receiving facility and the medi-van or emergency vehicle personnel in advance about the type of Transmission-Based Precautions being used. For tuberculosis, additional precautions may be needed in a small shared air space such as in an ambulance 12 .\n\n# II.I. Environmental measures\nCleaning and disinfecting non-critical surfaces in patient-care areas are part of Standard Precautions. In general, these procedures do not need to be changed for patients on Transmission-Based Precautions. The cleaning and disinfection of all patient-care areas is important for frequently touched surfaces, especially those closest to the patient, that are most likely to be contaminated (e.g., bedrails, bedside tables, commodes, doorknobs, sinks, surfaces and equipment in close proximity to the patient) 11, 72,73,835 . The frequency or intensity of cleaning may need to change based on the patient's level of hygiene and the degree of environmental contamination and for certain for infectious agents whose reservoir is the intestinal tract 54 . This may be especially true in LTCFs and pediatric facilities where patients with stool and urine incontinence are encountered more frequently. Also, increased frequency of cleaning may be needed in a Protective Environment to minimize dust accumulation 11 . Special recommendations for cleaning and disinfecting environmental surfaces in dialysis centers have been published 18 . In all healthcare settings, administrative, staffing and scheduling activities should prioritize the proper cleaning and disinfection of surfaces that could be implicated in transmission. During a suspected or proven outbreak where an environmental reservoir is suspected, routine cleaning procedures should be reviewed, and the need for additional trained cleaning staff should be assessed. Adherence should be monitored and reinforced to promote consistent and correct cleaning is performed.\nEPA-registered disinfectants or detergents/disinfectants that best meet the overall needs of the healthcare facility for routine cleaning and disinfection should be selected 11,836 . In general, use of the existing facility detergent/disinfectant according to the manufacturer's recommendations for amount, dilution, and contact time is sufficient to remove pathogens from surfaces of rooms where colonized or infected individuals were housed. This includes those pathogens that are resistant to multiple classes of antimicrobial agents (e.g., C. difficile, VRE, MRSA, MDR-GNB 11, 24,88,435,746,796,837 ). Most often, environmental reservoirs of pathogens during outbreaks are related to a failure to follow recommended procedures for cleaning and disinfection rather than the specific cleaning and disinfectant agents used . Certain pathogens (e.g., rotavirus, noroviruses, C. difficile) may be resistant to some routinely used hospital disinfectants 275,292, .The role of specific disinfectants in limiting transmission of rotavirus has been demonstrated experimentally 842 . Also, since C. difficile may display increased levels of spore production when exposed to non-chlorine-based cleaning agents, and the spores are more resistant than vegetative cells to commonly used surface disinfectants, some investigators have recommended the use of a 1:10 dilution of 5.25% sodium hypochlorite (household bleach) and water for routine environmental disinfection of rooms of patients with C. difficile when there is continued transmission 844,848 . In one study, the use of a hypochlorite solution was associated with a decrease in rates of C. difficile infections 847 . The need to change disinfectants based on the presence of these organisms can be determined in consultation with the infection control committee 11, 847,848 . Detailed recommendations for disinfection and sterilization of surfaces and medical equipment that have been in contact with prion-containing tissue or high risk body fluids, and for cleaning of blood and body substance spills, are available in the Guidelines for Environmental Infection Control in Health-Care Facilities 11 and in the Guideline for Disinfection and Sterilization 848 .\n\n# II.J. Patient care equipment and instruments/devices\nMedical equipment and instruments/devices must be cleaned and maintained according to the manufacturers' instructions to prevent patient-to-patient transmission of infectious agents 86,87,325,849 . Cleaning to remove organic material must always precede high level disinfection and sterilization of critical and semi-critical instruments and devices because residual proteinacous material reduces the effectiveness of the disinfection and sterilization processes 836,848 . Noncritical equipment, such as commodes, intravenous pumps, and ventilators, must be thoroughly cleaned and disinfected before use on another patient. All such equipment and devices should be handled in a manner that will prevent HCW and environmental contact with potentially infectious material. It is important to include computers and personal digital assistants (PDAs) used in patient care in policies for cleaning and disinfection of non-critical items. The literature on contamination of computers with pathogens has been summarized 850 and two reports have linked computer contamination to colonization and infections in patients 851,852 . Although keyboard covers and washable keyboards that can be easily disinfected are in use, the infection control benefit of those items and optimal management have not been determined.\nIn all healthcare settings, providing patients who are on Transmission-Based Precautions with dedicated noncritical medical equipment (e.g., stethoscope, blood pressure cuff, electronic thermometer) has been beneficial for preventing transmission 74,89,740,853,854 . When this is not possible, disinfection after use is recommended. Consult other guidelines for detailed guidance in developing specific protocols for cleaning and reprocessing medical equipment and patient care items in both routine and special circumstances 11,14,18,20,740,836,848 . In home care, it is preferable to remove visible blood or body fluids from durable medical equipment before it leaves the home. Equipment can be cleaned on-site using a detergent/disinfectant and, when possible, should be placed in a single plastic bag for transport to the reprocessing location 20,739 .\n\n# II.K. Textiles and laundry\nSoiled textiles, including bedding, towels, and patient or resident clothing may be contaminated with pathogenic microorganisms. However, the risk of disease transmission is negligible if they are handled, transported, and laundered in a safe manner 11,855,856 . Key principles for handling soiled laundry are 1) not shaking the items or handling them in any way that may aerosolize infectious agents; 2) avoiding contact of one's body and personal clothing with the soiled items being handled; and 3) containing soiled items in a laundry bag or designated bin. When laundry chutes are used, they must be maintained to minimize dispersion of aerosols from contaminated items 11 . The methods for handling, transporting, and laundering soiled textiles are determined by organizational policy and any applicable regulations 739 ; guidance is provided in the Guidelines for Environmental Infection Control 11 . Rather than rigid rules and regulations, hygienic and common sense storage and processing of clean textiles is recommended 11,857 . When laundering occurs outside of a healthcare facility, the clean items must be packaged or completely covered and placed in an enclosed space during transport to prevent contamination with outside air or construction dust that could contain infectious fungal spores that are a risk for immunocompromised patients 11 .\nInstitutions are required to launder garments used as personal protective equipment and uniforms visibly soiled with blood or infective material 739 . There are few data to determine the safety of home laundering of HCW uniforms, but no increase in infection rates was observed in the one published study 858 and no pathogens were recovered from home-or hospital-laundered scrubs in another study 859 . In the home, textiles and laundry from patients with potentially transmissible infectious pathogens do not require special handling or separate laundering, and may be washed with warm water and detergent 11, 858,859 .\n\n# II.L. Solid waste\nThe management of solid waste emanating from the healthcare environment is subject to federal and state regulations for medical and non-medical waste 860,861 . No additional precautions are needed for non-medical solid waste that is being removed from rooms of patients on Transmission-Based Precautions. Solid waste may be contained in a single bag (as compared to using two bags) of sufficient strength. 862 .\n\n# II.M. Dishware and eating utensils\nThe combination of hot water and detergents used in dishwashers is sufficient to decontaminate dishware and eating utensils. Therefore, no special precautions are needed for dishware (e.g., dishes, glasses, cups) or eating utensils; reusable dishware and utensils may be used for patients requiring Transmission-Based Precautions. In the home and other communal settings, eating utensils and drinking vessels that are being used should not be shared, consistent with principles of good personal hygiene and for the purpose of preventing transmission of respiratory viruses, Herpes simplex virus, and infectious agents that infect the gastrointestinal tract and are transmitted by the fecal/oral route (e.g., hepatitis A virus, noroviruses). If adequate resources for cleaning utensils and dishes are not available, disposable products may be used.\n\n# II.N. Adjunctive measures\nImportant adjunctive measures that are not considered primary components of programs to prevent transmission of infectious agents, but improve the effectiveness of such programs, include 1) antimicrobial management programs; 2) postexposure chemoprophylaxis with antiviral or antibacterial agents; 3) vaccines used both for pre and postexposure prevention; and 4) screening and restricting visitors with signs of transmissible infections. Detailed discussion of judicious use of antimicrobial agents is beyond the scope of this document; however the topic is addressed in the MDRO section (Management of Multidrug-Resistant Organisms in Healthcare Settings 2006. www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf).\n\n# II.N.1. Chemoprophylaxis\nAntimicrobial agents and topical antiseptics may be used to prevent infection and potential outbreaks of selected agents. Infections for which postexposure chemoprophylaxis is recommended under defined conditions include B. pertussis 17,863 , N. meningitidis 864 , B. anthracis after environmental exposure to aeosolizable material 865 , influenza virus 611 , HIV 866 , and group A streptococcus 160 . Orally administered antimicrobials may also be used under defined circumstances for MRSA decolonization of patients or healthcare personnel 867 . Another form of chemoprophylaxis is the use of topical antiseptic agents. For example, triple dye is used routinely on the umbilical cords of term newborns to reduce the risk of colonization, skin infections, and omphalitis caused by S. aureus, including MRSA, and group A streptococcus 868,869 . Extension of the use of triple dye to low birth weight infants in the NICU was one component of a program that controlled one longstanding MRSA outbreak 22 . Topical antiseptics are also used for decolonization of healthcare personnel or selected patients colonized with MRSA, using mupirocin as discussed in the MDRO guideline 870 867, 871-873 .\n\n# II.N.2. Immunoprophylaxis\nCertain immunizations recommended for susceptible healthcare personnel have decreased the risk of infection and the potential for transmission in healthcare facilities 17,874 . The OSHA mandate that requires employers to offer hepatitis B vaccination to HCWs played a substantial role in the sharp decline in incidence of occupational HBV infection 778,875 . The use of varicella vaccine in healthcare personnel has decreased the need to place susceptible HCWs on administrative leave following exposure to patients with varicella 775 . Also, reports of healthcare-associated transmission of rubella in obstetrical clinics 33,876 and measles in acute care settings 34 demonstrate the importance of immunization of susceptible healthcare personnel against childhood diseases. Many states have requirements for HCW vaccination for measles and rubella in the absence of evidence of immunity. Annual influenza vaccine campaigns targeted to patients and healthcare personnel in LTCFs and acute-care settings have been instrumental in preventing or limiting institutional outbreaks and increasing attention is being directed toward improving influenza vaccination rates in healthcare personnel 35 , 611, 690, 877, 878 , 879 . Transmission of B. pertussis in healthcare facilities has been associated with large and costly outbreaks that include both healthcare personnel and patients 17,36,41,100,683,827,880,881 . HCWs who have close contact with infants with pertussis are at particularly high risk because of waning immunity and, until 2005, the absence of a vaccine that could be used in adults. However, two acellular pertussis vaccines were licensed in the United States in 2005, one for use in individuals aged 11-18 and one for use in ages 10-64 years 882 . Provisional ACIP recommendations at the time of publication of this document include adolescents and adults, especially those with contact with infants < 12 months of age and healthcare personnel with direct patient contact 883 884 . Immunization of children and adults will help prevent the introduction of vaccinepreventable diseases into healthcare settings. The recommended immunization schedule for children is published annually in the January issues of the Morbidity Mortality Weekly Report with interim updates as needed 885,886 . An adult immunization schedule also is available for healthy adults and those with special immunization needs due to high risk medical conditions 887 . Some vaccines are also used for postexposure prophylaxis of susceptible individuals, including varicella 888 , influenza 611 , hepatitis B 778 , and smallpox 225 vaccines 17,874 . In the future, administration of a newly developed S. aureus conjugate vaccine (still under investigation) to selected patients may provide a novel method of preventing healthcare-associated S. aureus, including MRSA, infections in high-risk groups (e.g., hemodialysis patients and candidates for selected surgical procedures) 889,890 . Immune globulin preparations also are used for postexposure prophylaxis of certain infectious agents under specified circumstances (e.g., varicella-zoster virus , hepatitis B virus , rabies , measles and hepatitis A virus 17,833,874 ). The RSV monoclonal antibody preparation, Palivizumab, may have contributed to controlling a nosocomial outbreak of RSV in one NICU , but there is insufficient evidence to support a routine recommendation for its use in this setting 891 .\n\n# II.N. 3. Management of visitors\n\n# II.N.3.a. Visitors as sources of infection\nVisitors have been identified as the source of several types of HAIs (e.g., pertussis 40,41 , M. tuberculosis 42,892 , influenza, and other respiratory viruses 24,43,44,373 and SARS 21, ). However, effective methods for visitor screening in healthcare settings have not been studied. Visitor screening is especially important during community outbreaks of infectious diseases and for high risk patient units. Sibling visits are often encouraged in birthing centers, post partum rooms and in pediatric inpatient units, ICUs, and in residential settings for children; in hospital settings, a child visitor should visit only his or her own sibling. Screening of visiting siblings and other children before they are allowed into clinical areas is necessary to prevent the introduction of childhood illnesses and common respiratory infections.\nScreening may be passive through the use of signs to alert family members and visitors with signs and symptoms of communicable diseases not to enter clinical areas. More active screening may include the completion of a screening tool or questionnaire which elicits information related to recent exposures or current symptoms. That information is reviewed by the facility staff and the visitor is either permitted to visit or is excluded 833 . Family and household members visiting pediatric patients with pertussis and tuberculosis may need to be screened for a history of exposure as well as signs and symptoms of current infection. Potentially infectious visitors are excluded until they receive appropriate medical screening, diagnosis, or treatment. If exclusion is not considered to be in the best interest of the patient or family (i.e., primary family members of critically or terminally ill patients), then the symptomatic visitor must wear a mask while in the healthcare facility and remain in the patient's room, avoiding exposure to others, especially in public waiting areas and the cafeteria. Visitor screening is used consistently on HSCT units 15,43 . However, considering the experience during the 2003 SARS outbreaks and the potential for pandemic influenza, developing effective visitor screening systems will be beneficial 9 . Education concerning Respiratory Hygiene/Cough Etiquette is a useful adjunct to visitor screening.\n\n# II.N.3.b. Use of barrier precautions by visitors\nThe use of gowns, gloves, or masks by visitors in healthcare settings has not been addressed specifically in the scientific literature. Some studies included the use of gowns and gloves by visitors in the control of MDRO's, but did not perform a separate analysis to determine whether their use by visitors had a measurable impact . Family members or visitors who are providing care or having very close patient contact (e.g., feeding, holding) may have contact with other patients and could contribute to transmission if barrier precautions are not used correctly. Specific recommendations may vary by facility or by unit and should be determined by the level of interaction.\n\n# Part III: Precautions to Prevent Transmission of Infectious Agents\nThere are two tiers of HICPAC/CDC precautions to prevent transmission of infectious agents, Standard Precautions and Transmission-Based Precautions. Standard Precautions are intended to be applied to the care of all patients in all healthcare settings, regardless of the suspected or confirmed presence of an infectious agent. Implementation of Standard Precautions constitutes the primary strategy for the prevention of healthcare-associated transmission of infectious agents among patients and healthcare personnel. Transmission-Based Precautions are for patients who are known or suspected to be infected or colonized with infectious agents, including certain epidemiologically important pathogens, which require additional control measures to effectively prevent transmission. Since the infecting agent often is not known at the time of admission to a healthcare facility, Transmission-Based Precautions are used empirically, according to the clinical syndrome and the likely etiologic agents at the time, and then modified when the pathogen is identified or a transmissible infectious etiology is ruled out. Examples of this syndromic approach are presented in Table 2. The HICPAC/CDC Guidelines also include recommendations for creating a Protective Environment for allogeneic HSCT patients. The specific elements of Standard and Transmission-Based Precautions are discussed in Part II of this guideline. In Part III, the circumstances in which Standard Precautions, Transmission-Based Precautions, and a Protective Environment are applied are discussed. See Tables 4 and 5 for summaries of the key elements of these sets of precautions III.A. Standard Precautions Standard Precautions combine the major features of Universal Precautions (UP) 780,896 and Body Substance Isolation (BSI) 640 and are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. Standard Precautions include a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which healthcare is delivered (Table 4). These include: hand hygiene; use of gloves, gown, mask, eye protection, or face shield, depending on the anticipated exposure; and safe injection practices. Also, equipment or items in the patient environment likely to have been contaminated with infectious body fluids must be handled in a manner to prevent transmission of infectious agents (e.g. wear gloves for direct contact, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). The application of Standard Precautions during patient care is determined by the nature of the HCW-patient interaction and the extent of anticipated blood, body fluid, or pathogen exposure. For some interactions (e.g., performing venipuncture), only gloves may be needed; during other interactions (e.g., intubation), use of gloves, gown, and face shield or mask and goggles is necessary. Education and training on the principles and rationale for recommended practices are critical elements of Standard Precautions because they facilitate appropriate decision-making and promote adherence when HCWs are faced with new circumstances 655, . An example of the importance of the use of Standard Precautions is intubation, especially under emergency circumstances when infectious agents may not be suspected, but later are identified (e.g., SARS-CoV, N. meningitides). The application of Standard Precautions is described below and summarized in Table 4. Guidance on donning and removing gloves, gowns and other PPE is presented in the Figure . Standard Precautions are also intended to protect patients by ensuring that healthcare personnel do not carry infectious agents to patients on their hands or via equipment used during patient care.\n\n# III.A.1. New Elements of Standard Precautions\nInfection control problems that are identified in the course of outbreak investigations often indicate the need for new recommendations or reinforcement of existing infection control recommendations to protect patients. Because such recommendations are considered a standard of care and may not be included in other guidelines, they are added here to Standard Precautions. Three such areas of practice that have been added are: Respiratory Hygiene/Cough Etiquette, safe injection practices, and use of masks for insertion of catheters or injection of material into spinal or epidural spaces via lumbar puncture procedures (e.g., myelogram, spinal or epidural anesthesia). While most elements of Standard Precautions evolved from Universal Precautions that were developed for protection of healthcare personnel, these new elements of Standard Precautions focus on protection of patients.\n\n# III.A.1.a. Respiratory Hygiene/Cough Etiquette The transmission of SARS-\nCoV in emergency departments by patients and their family members during the widespread SARS outbreaks in 2003 highlighted the need for vigilance and prompt implementation of infection control measures at the first point of encounter within a healthcare setting (e.g., reception and triage areas in emergency departments, outpatient clinics, and physician offices) 21,254,897 . The strategy proposed has been termed Respiratory Hygiene/Cough Etiquette 9,828 and is intended to be incorporated into infection control practices as a new component of Standard Precautions. The strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections, and applies to any person with signs of illness including cough, congestion, rhinorrhea, or increased production of respiratory secretions when entering a healthcare facility 40,41,43 . The term cough etiquette is derived from recommended source control measures for M. tuberculosis 12,126 . The elements of Respiratory Hygiene/Cough Etiquette include 1) education of healthcare facility staff, patients, and visitors; 2) posted signs, in language(s) appropriate to the population served, with instructions to patients and accompanying family members or friends; 3) source control measures (e.g., covering the mouth/nose with a tissue when coughing and prompt disposal of used tissues, using surgical masks on the coughing person when tolerated and appropriate); 4) hand hygiene after contact with respiratory secretions; and 5) spatial separation, ideally >3 feet, of persons with respiratory infections in common waiting areas when possible. Covering sneezes and coughs and placing masks on coughing patients are proven means of source containment that prevent infected persons from dispersing respiratory secretions into the air 107, 145, 898, 899 . Masking may be difficult in some settings, (e.g., pediatrics, in which case, the emphasis by necessity may be on cough etiquette 900 . Physical proximity of <3 feet has been associated with an increased risk for transmission of infections via the droplet route (e.g., N. meningitidis 103 and group A streptococcus 114 and therefore supports the practice of distancing infected persons from others who are not infected. The effectiveness of good hygiene practices, especially hand hygiene, in preventing transmission of viruses and reducing the incidence of respiratory infections both within and outside healthcare settings is summarized in several reviews 559,717,904 . These measures should be effective in decreasing the risk of transmission of pathogens contained in large respiratory droplets (e.g., influenza virus 23 , adenovirus 111 , B. pertussis 827 and Mycoplasma pneumoniae 112 . Although fever will be present in many respiratory infections, patients with pertussis and mild upper respiratory tract infections are often afebrile. Therefore, the absence of fever does not always exclude a respiratory infection. Patients who have asthma, allergic rhinitis, or chronic obstructive lung disease also may be coughing and sneezing. While these patients often are not infectious, cough etiquette measures are prudent. Healthcare personnel are advised to observe Droplet Precautions (i.e., wear a mask) and hand hygiene when examining and caring for patients with signs and symptoms of a respiratory infection. Healthcare personnel who have a respiratory infection are advised to avoid direct patient contact, especially with high risk patients. If this is not possible, then a mask should be worn while providing patient care.\n\n# III.A.1.b. Safe Injection Practices\nThe investigation of four large outbreaks of HBV and HCV among patients in ambulatory care facilities in the United States identified a need to define and reinforce safe injection practices 453 . The four outbreaks occurred in a private medical practice, a pain clinic, an endoscopy clinic, and a hematology/oncology clinic. The primary breaches in infection control practice that contributed to these outbreaks were 1) reinsertion of used needles into a multiple-dose vial or solution container (e.g., saline bag) and 2) use of a single needle/syringe to administer intravenous medication to multiple patients. In one of these outbreaks, preparation of medications in the same workspace where used needle/syringes were dismantled also may have been a contributing factor. These and other outbreaks of viral hepatitis could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications 453,454 . These include the use of a sterile, single-use, disposable needle and syringe for each injection given and prevention of contamination of injection equipment and medication.\nWhenever possible, use of single-dose vials is preferred over multiple-dose vials, especially when medications will be administered to multiple patients. Outbreaks related to unsafe injection practices indicate that some healthcare personnel are unaware of, do not understand, or do not adhere to basic principles of infection control and aseptic technique. A survey of US healthcare workers who provide medication through injection found that 1% to 3% reused the same needle and/or syringe on multiple patients 905 . Among the deficiencies identified in recent outbreaks were a lack of oversight of personnel and failure to follow-up on reported breaches in infection control practices in ambulatory settings. Therefore, to ensure that all healthcare workers understand and adhere to recommended practices, principles of infection control and aseptic technique need to be reinforced in training programs and incorporated into institutional polices that are monitored for adherence 454 .\n\n# III.A.1.c. Infection Control Practices for Special Lumbar Puncture Procedues\nIn 2004, CDC investigated eight cases of post-myelography meningitis that either were reported to CDC or identified through a survey of the Emerging Infections Network of the Infectious Disease Society of America. Blood and/or cerebrospinal fluid of all eight cases yielded streptococcal species consistent with oropharyngeal flora and there were changes in the CSF indices and clinical status indicative of bacterial meningitis. Equipment and products used during these procedures (e.g., contrast media) were excluded as probable sources of contamination. Procedural details available for seven cases determined that antiseptic skin preparations and sterile gloves had been used. However, none of the clinicians wore a face mask, giving rise to the speculation that droplet transmission of oralpharyngeal flora was the most likely explanation for these infections. Bacterial meningitis following myelogram and other spinal procedures (e.g., lumbar puncture, spinal and epidural anesthesia, intrathecal chemotherapy) has been reported previously . As a result, the question of whether face masks should be worn to prevent droplet spread of oral flora during spinal procedures (e.g., myelogram, lumbar puncture, spinal anesthesia) has been debated 916,917 . Face masks are effective in limiting the dispersal of oropharyngeal droplets 918 and are recommended for the placement of central venous catheters 919 . In October 2005, the Healthcare Infection Control Practices Advisory Committee (HICPAC) reviewed the evidence and concluded that there is sufficient experience to warrant the additional protection of a face mask for the individual placing a catheter or injecting material into the spinal or epidural space.\n\n# III.B. Transmission-Based Precautions\nThere are three categories of Transmission-Based Precautions: Contact Precautions, Droplet Precautions, and Airborne Precautions. Transmission-Based Precautions are used when the route(s) of transmission is (are) not completely interrupted using Standard Precautions alone. For some diseases that have multiple routes of transmission (e.g., SARS), more than one Transmission-Based Precautions category may be used. When used either singly or in combination, they are always used in addition to Standard Precautions. See Appendix A for recommended precautions for specific infections. When Transmission-Based Precautions are indicated, efforts must be made to counteract possible adverse effects on patients (i.e., anxiety, depression and other mood disturbances , perceptions of stigma 923 , reduced contact with clinical staff , and increases in preventable adverse events 565 in order to improve acceptance by the patients and adherence by HCWs.\n\n# III.B.1. Contact Precautions\nContact Precautions are intended to prevent transmission of infectious agents, including epidemiologically important microorganisms, which are spread by direct or indirect contact with the patient or the patient's environment as described in I.B.3.a. The specific agents and circumstance for which Contact Precautions are indicated are found in Appendix A. The application of Contact Precautions for patients infected or colonized with MDROs is described in the 2006 HICPAC/CDC MDRO guideline 927 . Contact Precautions also apply where the presence of excessive wound drainage, fecal incontinence, or other discharges from the body suggest an increased potential for extensive environmental contamination and risk of transmission. A singlepatient room is preferred for patients who require Contact Precautions. When a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (e.g., cohorting, keeping the patient with an existing roommate). In multi-patient rooms, >3 feet spatial separation between beds is advised to reduce the opportunities for inadvertent sharing of items between the infected/colonized patient and other patients. Healthcare personnel caring for patients on Contact Precautions wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. Donning PPE upon room entry and discarding before exiting the patient room is done to contain pathogens, especially those that have been implicated in transmission through environmental contamination (e.g., VRE, C. difficile, noroviruses and other intestinal tract pathogens; RSV) 54,72,73,78,274,275,740 .\n\n# III.B.2. Droplet Precautions\nDroplet Precautions are intended to prevent transmission of pathogens spread through close respiratory or mucous membrane contact with respiratory secretions as described in I.B.3.b. Because these pathogens do not remain infectious over long distances in a healthcare facility, special air handling and ventilation are not required to prevent droplet transmission. Infectious agents for which Droplet Precautions are indicated are found in Appendix A and include B. pertussis, influenza virus, adenovirus, rhinovirus, N. meningitides, and group A streptococcus (for the first 24 hours of antimicrobial therapy). A single patient room is preferred for patients who require Droplet Precautions. When a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (e.g., cohorting, keeping the patient with an existing roommate). Spatial separation of > 3 feet and drawing the curtain between patient beds is especially important for patients in multi-bed rooms with infections transmitted by the droplet route. Healthcare personnel wear a mask (a respirator is not necessary) for close contact with infectious patient; the mask is generally donned upon room entry. Patients on Droplet Precautions who must be transported outside of the room should wear a mask if tolerated and follow Respiratory Hygiene/Cough Etiquette.\n\n# III.B.3. Airborne Precautions\nAirborne Precautions prevent transmission of infectious agents that remain infectious over long distances when suspended in the air (e.g., rubeola virus , varicella virus , M. tuberculosis, and possibly SARS-CoV) as described in I.B.3.c and Appendix A. The preferred placement for patients who require Airborne Precautions is in an airborne infection isolation room (AIIR). An AIIR is a single-patient room that is equipped with special air handling and ventilation capacity that meet the American Institute of Architects/Facility Guidelines Institute (AIA/FGI) standards for AIIRs (i.e., monitored negative pressure relative to the surrounding area, 12 air exchanges per hour for new construction and renovation and 6 air exchanges per hour for existing facilities, air exhausted directly to the outside or recirculated through HEPA filtration before return) 12,13 . Some states require the availability of such rooms in hospitals, emergency departments, and nursing homes that care for patients with M. tuberculosis. A respiratory protection program that includes education about use of respirators, fit-testing, and user seal checks is required in any facility with AIIRs. In settings where Airborne Precautions cannot be implemented due to limited engineering resources (e.g., physician offices), masking the patient, placing the patient in a private room (e.g., office examination room) with the door closed, and providing N95 or higher level respirators or masks if respirators are not available for healthcare personnel will reduce the likelihood of airborne transmission until the patient is either transferred to a facility with an AIIR or returned to the home environment, as deemed medically appropriate. Healthcare personnel caring for patients on Airborne Precautions wear a mask or respirator, depending on the disease-specific recommendations (Respiratory Protection II.E.4, Table 2, and Appendix A), that is donned prior to room entry. Whenever possible, non-immune HCWs should not care for patients with vaccine-preventable airborne diseases (e.g., measles, chickenpox, and smallpox).\n\n# III.C. Syndromic and empiric applications of Transmission-Based Precautions Diagnosis of many infections requires laboratory confirmation.\nSince laboratory tests, especially those that depend on culture techniques, often require two or more days for completion, Transmission-Based Precautions must be implemented while test results are pending based on the clinical presentation and likely pathogens. Use of appropriate Transmission-Based Precautions at the time a patient develops symptoms or signs of transmissible infection, or arrives at a healthcare facility for care, reduces transmission opportunities. While it is not possible to identify prospectively all patients needing Transmission-Based Precautions, certain clinical syndromes and conditions carry a sufficiently high risk to warrant their use empirically while confirmatory tests are pending (Table 2). Infection control professionals are encouraged to modify or adapt this table according to local conditions.\n\n# III.D. Discontinuation of Transmission-Based Precautions Transmission-\nBased Precautions remain in effect for limited periods of time (i.e., while the risk for transmission of the infectious agent persists or for the duration of the illness (Appendix A). For most infectious diseases, this duration reflects known patterns of persistence and shedding of infectious agents associated with the natural history of the infectious process and its treatment. For some diseases (e.g., pharyngeal or cutaneous diphtheria, RSV), Transmission-Based Precautions remain in effect until culture or antigen-detection test results document eradication of the pathogen and, for RSV, symptomatic disease is resolved. For other diseases, (e.g., M. tuberculosis) state laws and regulations, and healthcare facility policies, may dictate the duration of precautions 12 ). In immunocompromised patients, viral shedding can persist for prolonged periods of time (many weeks to months) and transmission to others may occur during that time; therefore, the duration of contact and/or droplet precautions may be prolonged for many weeks 500, . The duration of Contact Precautions for patients who are colonized or infected with MDROs remains undefined. MRSA is the only MDRO for which effective decolonization regimens are available 867 . However, carriers of MRSA who have negative nasal cultures after a course of systemic or topical therapy may resume shedding MRSA in the weeks that follow therapy 934,935 . Although early guidelines for VRE suggested discontinuation of Contact Precautions after three stool cultures obtained at weekly intervals proved negative 740 , subsequent experiences have indicated that such screening may fail to detect colonization that can persist for >1 year 27, . Likewise, available data indicate that colonization with VRE, MRSA 939 , and possibly MDR-GNB, can persist for many months, especially in the presence of severe underlying disease, invasive devices, and recurrent courses of antimicrobial agents. It may be prudent to assume that MDRO carriers are colonized permanently and manage them accordingly. Alternatively, an interval free of hospitalizations, antimicrobial therapy, and invasive devices (e.g., 6 or 12 months) before reculturing patients to document clearance of carriage may be used. Determination of the best strategy awaits the results of additional studies. See the 2006 HICPAC/CDC MDRO guideline 927 for discussion of possible criteria to discontinue Contact Precautions for patients colonized or infected with MDROs.\n\n# III.E. Application of Transmission-Based Precautions in ambulatory and home care settings Although Transmission-Based Precautions generally\napply in all healthcare settings, exceptions exist. For example, in home care, AIIRs are not available. Furthermore, family members already exposed to diseases such as varicella and tuberculosis would not use masks or respiratory protection, but visiting HCWs would need to use such protection. Similarly, management of patients colonized or infected with MDROs may necessitate Contact Precautions in acute care hospitals and in some LTCFs when there is continued transmission, but the risk of transmission in ambulatory care and home care, has not been defined. Consistent use of Standard Precautions may suffice in these settings, but more information is needed.\n\n# III.F. Protective Environment\nA Protective Environment is designed for allogeneic HSCT patients to minimize fungal spore counts in the air and reduce the risk of invasive environmental fungal infections (see Table 5 for specifications) 11, . The need for such controls has been demonstrated in studies of aspergillus outbreaks associated with construction 11,14,15,157,158 . As defined by the American Insitute of Architecture 13 and presented in detail in the Guideline for Environmental Infection Control 2003 11,861 , air quality for HSCT patients is improved through a combination of environmental controls that include 1) HEPA filtration of incoming air; 2) directed room air flow; 3) positive room air pressure relative to the corridor; 4) well-sealed rooms (including sealed walls, floors, ceilings, windows, electrical outlets) to prevent flow of air from the outside; 5) ventilation to provide >12 air changes per hour; 6) strategies to minimize dust (e.g., scrubbable surfaces rather than upholstery 940 and carpet 941 , and routinely cleaning crevices and sprinkler heads); and 7) prohibiting dried and fresh flowers and potted plants in the rooms of HSCT patients. The latter is based on molecular typing studies that have found indistinguishable strains of Aspergillus terreus in patients with hematologic malignancies and in potted plants in the vicinity of the patients . The desired quality of air may be achieved without incurring the inconvenience or expense of laminar airflow 15,157 . To prevent inhalation of fungal spores during periods when construction, renovation, or other dust-generating activities that may be ongoing in and around the health-care facility, it has been advised that severely immunocompromised patients wear a high-efficiency respiratory-protection device (e.g., an N95 respirator) when they leave the Protective Environment 11, 14,945 ). The use of masks or respirators by HSCT patients when they are outside of the Protective Environment for prevention of environmental fungal infections in the absence of construction has not been evaluated. A Protective Environment does not include the use of barrier precautions beyond those indicated for Standard and Transmission-Based Precautions. No published reports support the benefit of placing solid organ transplants or other immunocompromised patients in a Protective Environment.\n\n# Part IV:\n\n# Recommendations\nThese recommendations are designed to prevent transmission of infectious agents among patients and healthcare personnel in all settings where healthcare is delivered. As in other CDC/HICPAC guidelines, each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and when possible, economic impact. The CDC/HICPAC system for categorizing recommendations is as follows: Category IA Strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies. Category IB Strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. Category IC Required for implementation, as mandated by federal and/or state regulation or standard. Category II Suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. No recommendation; unresolved issue. Practices for which insufficient evidence or no consensus regarding efficacy exists.\n\n# I. Administrative Responsibilities\nHealthcare organization administrators should ensure the implementation of recommendations in this section. underlying conditions that predispose to serious adverse outcomes) y Analyze data to identify trends that may indicated increased rates of transmission y Feedback information on trends in the incidence and prevalence of HAIs, probable risk factors, and prevention strategies and their impact to the appropriate healthcare providers, organization administrators, and as required by local and state health authorities III.C. Develop and implement strategies to reduce risks for transmission and evaluate effectiveness 566, 673, 684, 970 963 971 . Category IB III.D. When transmission of epidemiologically-important organisms continues despite implementation and documented adherence to infection prevention and control strategies, obtain consultation from persons knowledgeable in infection control and healthcare epidemiology to review the situation and recommend additional measures for control 566 247 687 . Category IB III.E. Review periodically information on community or regional trends in the incidence and prevalence of epidemiologically-important organisms (e.g., influenza, RSV, pertussis, invasive group A streptococcal disease, MRSA, VRE) (including in other healthcare facilities) that may impact transmission of organisms within the facility 398, 687, 972, 973 974 . Category II\n\n# IV.\nStandard Precautions Assume that every person is potentially infected or colonized with an organism that could be transmitted in the healthcare setting and apply the following infection control practices during the delivery of health care. IV.A. Hand Hygiene IV.A.1. During the delivery of healthcare, avoid unnecessary touching of surfaces in close proximity to the patient to prevent both contamination of clean hands from environmental surfaces and transmission of pathogens from contaminated hands to surfaces 72, 73 739, 800, 975{CDC, 2001 #970 . Category IB/IC IV.A.2. When hands are visibly dirty, contaminated with proteinaceous material, or visibly soiled with blood or body fluids, wash hands with either a nonantimicrobial soap and water or an antimicrobial soap and water 559 . Category IA IV.A.3. If hands are not visibly soiled, or after removing visible material with nonantimicrobial soap and water, decontaminate hands in the clinical situations described in IV.A.2.a-f. The preferred method of hand decontamination is with an alcohol-based hand rub 562,978 .\nAlternatively, hands may be washed with an antimicrobial soap and water. Frequent use of alcohol-based hand rub immediately following handwashing with nonantimicrobial soap may increase the frequency of dermatitis 559 . Category IB Perform hand hygiene: IV.A.3.a. Before having direct contact with patients 664,979 . Category IB IV.A.3.b. After contact with blood, body fluids or excretions, mucous membranes, nonintact skin, or wound dressings 664 . Category IA IV.A.3.c. After contact with a patient's intact skin (e.g., when taking a pulse or blood pressure or lifting a patient) 167,976,979,980 . Category IB IV.A.3.d. If hands will be moving from a contaminated-body site to a clean-body site during patient care. Category II IV.A.3.e. After contact with inanimate objects (including medical equipment) in the immediate vicinity of the patient 72, 73, 88, 800, 981 982 . Category II IV.A.3.f. After removing gloves 728,741,742 . Category IB IV.A.4. Wash hands with non-antimicrobial soap and water or with antimicrobial soap and water if contact with spores (e.g., C. difficile or Bacillus anthracis) is likely to have occurred. The physical action of washing and rinsing hands under such circumstances is recommended because alcohols, chlorhexidine, iodophors, and other antiseptic agents have poor activity against spores 559,956,983 .\nCategory II IV.A.5.\nDo not wear artificial fingernails or extenders if duties include direct contact with patients at high risk for infection and associated adverse outcomes (e.g., those in ICUs or operating rooms) 30,31,559, . Category IA IV.A.5.a. Develop an organizational policy on the wearing of non-natural nails by healthcare personnel who have direct contact with patients outside of the groups specified above 984 IV.E.1. Establish policies and procedures for containing, transporting, and handling patient-care equipment and instruments/devices that may be contaminated with blood or body fluids 18,739,975 . Category IB/IC IV.E.2. Remove organic material from critical and semi-critical instrument/devices, using recommended cleaning agents before high level disinfection and sterilization to enable effective disinfection and sterilization processes 836 991, 992 . Category IA IV.E.3. Wear PPE (e.g., gloves, gown), according to the level of anticipated contamination, when handling patient-care equipment and instruments/devices that is visibly soiled or may have been in contact with blood or body fluids 18,739,975 . Category IB/IC IV.F. Care of the environment 11 IV.F.1. Establish policies and procedures for routine and targeted cleaning of environmental surfaces as indicated by the level of patient contact and degree of soiling 11 . Category II IV.F.2.\nClean and disinfect surfaces that are likely to be contaminated with pathogens, including those that are in close proximity to the patient (e.g., bed rails, over bed tables) and frequently-touched surfaces in the patient care environment (e.g., door knobs, surfaces in and surrounding toilets in patients' rooms) on a more frequent schedule compared to that for other surfaces (e.g., horizontal surfaces in waiting rooms) 11 73, 740, 746, 993, 994 72, 800, 835 995 . Category IB IV.F.3.\nUse EPA-registered disinfectants that have microbiocidal (i.e., killing) activity against the pathogens most likely to contaminate the patient-care environment. Use in accordance with manufacturer's instructions 842-844, 956, 996 . Category IB/IC IV.F.3.a. Review the efficacy of in-use disinfectants when evidence of continuing transmission of an infectious agent (e.g., rotavirus, C. difficile, norovirus) may indicate resistance to the in-use product and change to a more effective disinfectant as indicated 275,842,847 . Category II IV.F. 4.\nIn facilities that provide health care to pediatric patients or have waiting areas with child play toys (e.g., obstetric/gynecology offices and clinics), establish policies and procedures for cleaning and disinfecting toys at regular intervals 379 80 . Category IB - Use the following principles in developing this policy and procedures: Category II y Select play toys that can be easily cleaned and disinfected y Do not permit use of stuffed furry toys if they will be shared y Clean and disinfect large stationary toys (e.g., climbing equipment) at least weekly and whenever visibly soiled y If toys are likely to be mouthed, rinse with water after disinfection; alternatively wash in a dishwasher y When a toy requires cleaning and disinfection, do so immediately or store in a designated labeled container separate from toys that are clean and ready for use IV.F.5.\nInclude multi-use electronic equipment in policies and procedures for preventing contamination and for cleaning and disinfection, especially those items that are used by patients, those used during delivery of patient care, and mobile devices that are moved in and out of patient rooms frequently (e.g., daily) 850 851, 852, 997 . Category IB IV.F.5.a. No recommendation for use of removable protective covers or washable keyboards. Unresolved issue IV.G. Textiles and laundry IV.G.1. Handle used textiles and fabrics with minimum agitation to avoid contamination of air, surfaces and persons 739,998,999 . Category IB/IC IV.G.2. If laundry chutes are used, ensure that they are properly designed, maintained, and used in a manner to minimize dispersion of aerosols from contaminated laundry 11, 13, 1000, 1001 . Category IB/IC IV.H. Safe injection practices\nThe following recommendations apply to the use of needles, cannulas that replace needles, and, where applicable intravenous delivery systems 454 IV.H.1. Use aseptic technique to avoid contamination of sterile injection equipment 1002,1003 . Category IA IV.H.2. Do not administer medications from a syringe to multiple patients, even if the needle or cannula on the syringe is changed. Needles, cannulae and syringes are sterile, single-use items; they should not be reused for another patient nor to access a medication or solution that might be used for a subsequent patient 453,919,1004,1005 . Category IA IV.H.3. Use fluid infusion and administration sets (i.e., intravenous bags, tubing and connectors) for one patient only and dispose appropriately after use. Consider a syringe or needle/cannula contaminated once it has been used to enter or connect to a patient's intravenous infusion bag or administration set 453 . Category IB IV.H.4. Use single-dose vials for parenteral medications whenever possible 453 . Category IA IV.H.5. Do not administer medications from single-dose vials or ampules to multiple patients or combine leftover contents for later use 369 453, 1005 . Category IA IV.H.6. If multidose vials must be used, both the needle or cannula and syringe used to access the multidose vial must be sterile 453,1002 . Category IA IV.H.7. Do not keep multidose vials in the immediate patient treatment area and store in accordance with the manufacturer's recommendations; discard if sterility is compromised or questionable 453,1003 . Category IA IV.H.8. Do not use bags or bottles of intravenous solution as a common source of supply for multiple patients 453,1006 . Category IB IV.I. Infection control practices for special lumbar puncture procedures Wear a surgical mask when placing a catheter or injecting material into the spinal canal or subdural space (i.e., during myelograms, lumbar puncture and spinal or epidural anesthesia 906 907-909 910, 911 912-914, 918 1007 . Category IB IV.J. Worker safety Adhere to federal and state requirements for protection of healthcare personnel from exposure to bloodborne pathogens 739 . Category IC\n\n# V. Transmission-Based Precautions\nV.A. General principles V.A.1.\nIn addition to Standard Precautions, use Transmission-Based Precautions for patients with documented or suspected infection or colonization with highly transmissible or epidemiologically-important pathogens for which additional precautions are needed to prevent transmission (see Appendix A) 24,93,126,141,306,806,1008 regarding patient placement on a case-by-case basis, balancing infection risks to other patients in the room, the presence of risk factors that increase the likelihood of transmission, and the potential adverse psychological impact on the infected or colonized patient 920,921 . Category II V.B.2.c. In ambulatory settings, place patients who require Contact Precautions in an examination room or cubicle as soon as possible 20 . Category II V.B.3.\nUse of personal protective equipment V.B.3.a. Gloves Wear gloves whenever touching the patient's intact skin 24,89,134,559,746,837 or surfaces and articles in close proximity to the patient (e.g., medical equipment, bed rails) 72,73,88,837 . Don gloves upon entry into the room or cubicle.\nCategory IB V.B.3.b. Gowns V.B.3.b.i.\nWear a gown whenever anticipating that clothing will have direct contact with the patient or potentially contaminated environmental surfaces or equipment in close proximity to the patient. Don gown upon entry into the room or cubicle. Remove gown and observe hand hygiene before leaving the patient-care environment 24,88,134,745,837 .\nCategory IB V.B.3.b.ii.\nAfter gown removal, ensure that clothing and skin do not contact potentially contaminated environmental surfaces that could result in possible transfer of microorganism to other patients or environmental surfaces 72,73 . Patient-care equipment and instruments/devices V.B.5.a. Handle patient-care equipment and instruments/devices according to Standard Precautions 739,836 . Category IB/IC V.B.5.b. In acute care hospitals and long-term care and other residential settings, use disposable noncritical patient-care equipment (e.g., blood pressure cuffs) or implement patient-dedicated use of such equipment. If common use of equipment for multiple patients is unavoidable, clean and disinfect such equipment before use on another patient 24,88,796,836,837,854,1016 . Category IB V.B.5.c. In home care settings V.B.5.c.i.\nCategory II V.B.\nLimit the amount of non-disposable patient-care equipment brought into the home of patients on Contact Precautions. Whenever possible, leave patient-care equipment in the home until discharge from home care services. Category II V.B.5.c.ii.\nIf noncritical patient-care equipment (e.g., stethoscope) cannot remain in the home, clean and disinfect items before taking them from the home using a low-to intermediate-level disinfectant. Alternatively, place contaminated reusable items in a plastic bag for transport and subsequent cleaning and disinfection. Category II V.B.5.d. In ambulatory settings, place contaminated reusable noncritical patient-care equipment in a plastic bag for transport to a soiled utility area for reprocessing. Category II V.B.6.\nEnvironmental measures Ensure that rooms of patients on Contact Precautions are prioritized for frequent cleaning and disinfection (e.g., at least daily) with a focus on frequently-touched surfaces (e.g., bed rails, overbed table, bedside commode, lavatory surfaces in patient bathrooms, doorknobs) and equipment in the immediate vicinity of the patient 11,24,88,746,837 . Category IB V.B.7.\nDiscontinue Contact Precautions after signs and symptoms of the infection have resolved or according to pathogen-specific recommendations in Appendix A. Category IB V.C. Droplet Precautions V.C.1. Use Droplet Precautions as recommended in Appendix A for patients known or suspected to be infected with pathogens transmitted by respiratory droplets (i.e., large-particle droplets >5µ in size) that are generated by a patient who is coughing, sneezing or talking 14, 23, Steinberg, 196914, 23, Steinberg, #170814, 23, Steinberg, , 41, 95, 103, 111, 112, 755, 756, 989, 1017 .\nCategory IB V.C.2.\nPatient placement V.C.2.a. In acute care hospitals, place patients who require Droplet Precautions in a single-patient room when available Category II When single-patient rooms are in short supply, apply the following principles for making decisions on patient placement: y Prioritize patients who have excessive cough and sputum production for single-patient room placement Category II y Place together in the same room (cohort) patients who are infected the same pathogen and are suitable roommates 814 816 . Category IB y If it becomes necessary to place patients who require Droplet Precautions in a room with a patient who does not have the same infection: y Avoid placing patients on Droplet Precautions in the same room with patients who have conditions that may increase the risk of adverse outcome from infection or that may facilitate transmission (e.g., those who are immunocompromised, have or have anticipated prolonged lengths of stay). Category II y Ensure that patients are physically separated (i.e., >3 feet apart) from each other. Draw the privacy curtain between beds to minimize opportunities for close contact 103, 104 410 .\nCategory IB y Change protective attire and perform hand hygiene between contact with patients in the same room, regardless of whether one patient or both patients are on Droplet Precautions 741-743, 988, 1014, 1015 . Category IB V.C.2.b. In long-term care and other residential settings, make decisions regarding patient placement on a case-by-case basis after considering infection risks to other patients in the room and available alternatives 410 . Category II V.C.2.c. In ambulatory settings, place patients who require Droplet\nPrecautions in an examination room or cubicle as soon as possible. Instruct patients to follow recommendations for Respiratory Hygiene/Cough Etiquette 447, 448 9, 828 . Category II V.C.3.\nUse of personal protective equipment V.C.3.a. Don a mask upon entry into the patient room or cubicle 14,23,41,103,111,113,115,827 . Category IB V.C. Use Airborne Precautions as recommended in Appendix A for patients known or suspected to be infected with infectious agents transmitted person-to-person by the airborne route (e.g., M tuberculosis 12 , measles 34,122,1020 , chickenpox 123,773,1021 , disseminated herpes zoster 1022 . Category IA/IC V.D.2.\nPatient placement V.D.2.a. In acute care hospitals and long-term care settings, place patients who require Airborne Precautions in an AIIR that has been constructed in accordance with current guidelines . Category IA/IC V.D.2.a.i.\nProvide at least six (existing facility) or 12 (new construction/renovation) air changes per hour. V.D.2.a.ii.\nDirect exhaust of air to the outside. If it is not possible to exhaust air from an AIIR directly to the outside, the air may be returned to the air-handling system or adjacent spaces if all air is directed through HEPA filters. V.D.2.a.iii. Whenever an AIIR is in use for a patient on Airborne Precautions, monitor air pressure daily with visual indicators (e.g., smoke tubes, flutter strips), regardless of the presence of differential pressure sensing devices (e.g., manometers) 11, 12, 1023, 1024 . V.D.2.a.iv. Keep the AIIR door closed when not required for entry and exit. V.D.2.b. When an AIIR is not available, transfer the patient to a facility that has an available AIIR 12 . Category II V.D.2.c. In the event of an outbreak or exposure involving large numbers of patients who require Airborne Precautions: y Consult infection control professionals before patient placement to determine the safety of alternative room that do not meet engineering requirements for an AIIR. y Place together (cohort) patients who are presumed to have the same infection( based on clinical presentation and diagnosis when known) in areas of the facility that are away from other patients, especially patients who are at increased risk for infection (e.g., immunocompromised patients). y Use temporary portable solutions (e.g., exhaust fan) to create a negative pressure environment in the converted area of the facility. Discharge air directly to the outside,away from people and air intakes, or direct all the air through HEPA filters before it is introduced to other air spaces 12 Category II V.D. Place the patient in an AIIR as soon as possible. If an AIIR is not available, place a surgical mask on the patient and place him/her in an examination room. Once the patient leaves, the room should remain vacant for the appropriate time, generally one hour, to allow for a full exchange of air 11,12,122 . Category IB/IC V.D.2.d.iii. Instruct patients with a known or suspected airborne infection to wear a surgical mask and observe Respiratory Hygiene/Cough Etiquette. Once in an AIIR, the mask may be removed; the mask should remain on if the patient is not in an AIIR 12,107,145,899 . Category IB/IC V.D.3.\nPersonnel restrictions Restrict susceptible healthcare personnel from entering the rooms of patients known or suspected to have measles (rubeola), varicella (chickenpox), disseminated zoster, or smallpox if other immune healthcare personnel are available 17,775 . Category IB V.D.4.\nUse of PPE V.D.4.a. Wear a fit-tested NIOSH-approved N95 or higher level respirator for respiratory protection when entering the room or home of a patient when the following diseases are suspected or confirmed: y Infectious pulmonary or laryngeal tuberculosis or when infectious tuberculosis skin lesions are present and procedures that would aerosolize viable organisms (e.g., irrigation, incision and drainage, whirlpool treatments) are performed 12,1025,1026 . Category IB y Smallpox (vaccinated and unvaccinated). Respiratory protection is recommended for all healthcare personnel, including those with a documented \"take\" after smallpox vaccination due to the risk of a genetically engineered virus against which the vaccine may not provide protection, or of exposure to a very large viral load (e.g., from high-risk aerosol-generating procedures, immunocompromised patients, hemorrhagic or flat smallpox 108,129 . Category II V.D.4.b. No recommendation is made regarding the use of PPE by healthcare personnel who are presumed to be immune to measles (rubeola) or varicella-zoster based on history of disease, vaccine, or serologic testing when caring for an individual with known or suspected measles, chickenpox or disseminated zoster, due to difficulties in establishing definite immunity 1027,1028 . Unresolved issue V.D.4.c. No recommendation is made regarding the type of personal protective equipment (i.e., surgical mask or respiratory protection with a N95 or higher respirator) to be worn by susceptible healthcare personnel who must have contact with patients with known or suspected measles, chickenpox or disseminated herpes zoster. Unresolved issue V.D.5.\nPatient transport V.D.5.a. In acute care hospitals and long-term care and other residential settings, limit transport and movement of patients outside of the room to medically-necessary purposes. Category II V.D.5.b. If transport or movement outside an AIIR is necessary, instruct patients to wear a surgical mask, if possible, and observe Respiratory Hygiene/Cough Etiquette 12 . Category II V.D.5.c. For patients with skin lesions associated with varicella or smallpox or draining skin lesions caused by M. tuberculosis, cover the affected areas to prevent aerosolization or contact with the infectious agent in skin lesions 108,1025,1026, . Category IB V.D.5.d. Healthcare personnel transporting patients who are on Airborne Precautions do not need to wear a mask or respirator during transport if the patient is wearing a mask and infectious skin lesions are covered. Category II V.D.6.\nExposure management Immunize or provide the appropriate immune globulin to susceptible persons as soon as possible following unprotected contact (i.e., exposed) to a patient with measles, varicella or smallpox: Category IA y Administer measles vaccine to exposed susceptible persons within 72 hours after the exposure or administer immune globulin within six days of the exposure event for high-risk persons in whom vaccine is contraindicated 17, . y Administer varicella vaccine to exposed susceptible persons within 120 hours after the exposure or administer varicella immune globulin (VZIG or alternative product), when available, within 96 hours for high-risk persons in whom vaccine is contraindicated (e.g., immunocompromised patients, pregnant women, newborns whose mother's varicella onset was 12.5 Pa ) 13 . Category IB VI.C.1.c.i.\nMonitor air pressure daily with visual indicators (e.g., smoke tubes, flutter strips) 11, 1024 . Category IA VI.C.1.d. Well-sealed rooms that prevent infiltration of outside air 13 .\nCategory IB VI.C.1.e. At least 12 air changes per hour 13 . Category IB VI.C.2. Lower dust levels by using smooth, nonporous surfaces and finishes that can be scrubbed, rather than textured material (e.g., upholstery). Wet dust horizontal surfaces whenever dust detected and routinely clean crevices and sprinkler heads where dust may accumulate 940,941 . Category II VI.C.3. Avoid carpeting in hallways and patient rooms in areas 941 .\nCategory IB VI.C.4. Prohibit dried and fresh flowers and potted plants . Category II VI.D. Minimize the length of time that patients who require a Protective Environment are outside their rooms for diagnostic procedures and other activities 11,158,945 . Category IB VI.E. During periods of construction, to prevent inhalation of respirable particles that could contain infectious spores, provide respiratory protection (e.g., N95 respirator) to patients who are medically fit to tolerate a respirator when they are required to leave the Protective Environment 945 158 . Barrier precautions, (e.g., masks, gowns, gloves) are not required for healthcare personnel in the absence of suspected or confirmed infection in the patient or if they are not indicated according to Standard Precautions 15 . Category II VI.F.4.\nCategory\nImplement Airborne Precautions for patients who require a Protective Environment room and who also have an airborne infectious disease (e.g., pulmonary or laryngeal tuberculosis, acute varicella-zoster). Category IA VI.F.4.a. Ensure that the Protective Environment is designed to maintain positive pressure 13 . Category IB VI.F.4.b. Use an anteroom to further support the appropriate air-balance relative to the corridor and the Protective Environment; provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct if the return air must be recirculated 13,1041 . Category IB VI.F.4.c. If an anteroom is not available, place the patient in an AIIR and use portable, industrial-grade HEPA filters in the room to enhance filtration of spores 1042 . Category II Preamble The mode(s) and risk of transmission for each specific disease agent included in Appendix A were reviewed. Principle sources consulted for the development of disease-specific recommendations for Appendix A included infectious disease manuals and textbooks 833,1043,1044 . The published literature was searched for evidence of person-to-person transmission in healthcare and non-healthcare settings with a focus on reported outbreaks that would assist in developing recommendations for all settings where healthcare is delivered. Criteria used to assign Transmission-Based Precautions categories follow:\n- A Transmission-Based Precautions category was assigned if there was strong evidence for person-to-person transmission via droplet, contact, or airborne routes in healthcare or non-healthcare settings and/or if patient factors (e.g., diapered infants, diarrhea, draining wounds) increased the risk of transmission - Transmission-Based Precautions category assignments reflect the predominant mode(s) of transmission\n- If there was no evidence for person-to-person transmission by droplet, contact or airborne routes, Standard Precautions were assigned - If there was a low risk for person-to-person transmission and no evidence of healthcare-associated transmission, Standard Precautions were assigned - Standard Precautions were assigned for bloodborne pathogens (e.g., hepatitis B and C viruses, human immunodeficiency virus) as per CDC recommendations for Universal Precautions issued in 1988 780 . Subsequent experience has confirmed the efficacy of Standard Precautions to prevent exposure to infected blood and body fluid 778,779,866 .\nAdditional information relevant to use of precautions was added in the comments column to assist the caregiver in decision-making. Citations were added as needed to support a change in or provide additional evidence for recommendations for a specific disease and for new infectious agents (e.g., SARS-CoV, avian influenza) that have been added to Appendix A. The reader may refer to more detailed discussion concerning modes of transmission and emerging pathogens in the background text and for MDRO control in Appendix B. Use Contact Precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. Persons who clean areas heavily contaminated with feces or vomitus may benefit from wearing masks since virus can be aerosolized from these body substances 142, 147 148 ; ensure consistent environmental cleaning and disinfection with focus on restrooms even when apparently unsoiled 273,1064 ). Hypochlorite solutions may be required when there is continued transmission . Alcohol is less active, but there is no evidence that alcohol antiseptic handrubs are not effective for hand decontamination 294 . Cohorting of affected patients to separate airspaces and toilet facilities may help interrupt transmission during outbreaks. . Install screens in windows and doors in endemic areas. Use DEET-containing mosquito repellants and clothing to cover extremities Marburg virus disease (see viral hemorrhagic fevers) Measles (rubeola) A 4 days after onset of rash; DI in immune compromised Susceptible HCWs should not enter room if immune care providers are available; no recommendation for face protection for immune HCW; no recommendation for type of face protection for susceptible HCWs, i.e., mask or respirator 1027,1028 . For exposed susceptibles, post-exposure vaccine within 72 hrs. or immune globulin within 6 days when available 17,1032,1034 precautions are implemented always, hospitals must have systems in place to evaluate patients routinely according to these criteria as part of their preadmission and admission care. † Patients with the syndromes or conditions listed below may present with atypical signs or symptoms (e.g.neonates and adults with pertussis may not have paroxysmal or severe cough). The clinician's index of suspicion should be guided by the prevalence of specific conditions in the community, as well as clinical judgment. ‡ The organisms listed under the column \"Potential Pathogens\" are not intended to represent the complete, or even most likely, diagnoses, but rather possible etiologic agents that require additional precautions beyond Standard Precautions until they can be ruled out. § These pathogens include enterohemorrhagic Escherichia coli O157:H7, Shigella spp, hepatitis A virus, noroviruses, rotavirus, C. difficile. Cutaneous (contact with spores);RT (inhalation of spores);GIT (ingestion of spores -rare) Comment: Spores can be inhaled into the lower respiratory tract. The infectious dose of B. anthracis in humans by any route is not precisely known. In primates, the LD50 (i.e., the dose required to kill 50% of animals) for an aerosol challenge with B. anthracis is estimated to be 8,000-50,000 spores; the infectious dose may be as low as 1-3 spores\n\n# APPENDIX A 1\n\n# TYPE AND DURATION OF PRECAUTIONS RECOMMENDED FOR SELECTED INFECTIONS AND CONDITIONS\n\n# Rotavirus\n\n# Incubation Period\nCutaneous: 1 to12 days; RT: Usually 1 to 7 days but up to 43 days reported; GIT: 15-72 hours\n\n# Clinical Features\nCutaneous: Painless, reddish papule, which develops a central vesicle or bulla in 1-2 days; over next 3-7 days lesion becomes pustular, and then necrotic, with black eschar; extensive surrounding edema. RT: initial flu-like illness for 1-3 days with headache, fever, malaise, cough; by day 4 severe dyspnea and shock, and is usually fatal (85%-90% if untreated; meningitis in 50% of RT cases. GIT: ; if intestinal form, necrotic, ulcerated edematous lesions develop in intestines with fever, nausea and vomiting, progression to hematemesis and bloody diarrhea; 25 GIT: Ingestion of toxin-containing food, RT: Inhalation of toxin containing aerosol cause disease. Comment: Toxin ingested or potentially delivered by aerosol in bioterrorist incidents. LD 50 for type A is 0.001 μg/ml/kg.\n\n# Incubation Period\n1-5 days.\n\n# Clinical Features\nPtosis, generalized weakness, dizziness, dry mouth and throat, blurred vision, diplopia, dysarthria, dysphonia, and dysphagia followed by symmetrical descending paralysis and respiratory failure.\n\n# Diagnosis\nClinical diagnosis; identification of toxin in stool, serology unless toxin-containing material available for toxin neutralization bioassays.\n\n# Infectivity\nNot transmitted from person to person. Exposure to toxin necessary for disease.\n\n# Recommended Precautions\nStandard Precautions.\n\n# Disease Ebola Hemorrhagic Fever Site(s) of Infection; Transmission Mode\nAs a rule infection develops after exposure of mucous membranes or RT, or through broken skin or percutaneous injury.\n\n# Incubation Period\n2-19 days, usually 5-10 days\n\n# Clinical Features\nFebrile illnesses with malaise, myalgias, headache, vomiting and diarrhea that are rapidly complicated by hypotension, shock, and hemorrhagic features. Massive hemorrhage in < 50% pts.\n\n# Diagnosis\nEtiologic diagnosis can be made using RT-PCR, serologic detection of antibody and antigen, pathologic assessment with immunohistochemistry and viral culture with EM confirmation of morphology,\n\n# Infectivity\nPerson-to-person transmission primarily occurs through unprotected contact with blood and body fluids; percutaneous injuries (e.g., needlestick) associated with a high rate of transmission; transmission in healthcare settings has been reported but is prevented by use of barrier precautions.\n\n# Recommended Precautions\nHemorrhagic fever specific barrier precautions: If disease is believed to be related to intentional release of a bioweapon, epidemiology of transmission is unpredictable pending observation of disease transmission. Until the nature of the pathogen is understood and its transmission pattern confirmed, Standard, Contact and Airborne Precautions should be used. Once the pathogen is characterized, if the epidemiology of transmission is consistent with natural disease, Droplet Precautions can be substituted for Airborne Precautions. Emphasize: 1) use of sharps safety devices and safe work practices, 2) hand hygiene; 3) barrier protection against blood and body fluids upon entry into room (single gloves and fluidresistant or impermeable gown, face/eye protection with masks, goggles or face shields); and 4) appropriate waste handling. Use N95 or higher respirators when performing aerosol-generating procedures. In settings where AIIRs are unavailable or the large numbers of patients cannot be accommodated by existing AIIRs, observe Droplet Precautions (plus Standard Precautions and Contact Precautions) and segregate patients from those not suspected of VHF infection. Limit blooddraws to those essential to care. See text for discussion and Appendix A for recommendations for naturally occurring VHFs.\n\n# Disease\nPlague 2 Site(s) of Infection; Transmission Mode RT: Inhalation of respiratory droplets. Comment: Pneumonic plague most likely to occur if used as a biological weapon, but some cases of bubonic and primary septicemia may also occur. Infective dose 100 to 500 bacteria Incubation Period 1 to 6, usually 2 to 3 days.\n\n# Clinical Features\nPneumonic: fever, chills, headache, cough, dyspnea, rapid progression of weakness, and in a later stage hemoptysis, circulatory collapse, and bleeding diathesis Diagnosis Presumptive diagnosis from Gram stain or Wayson stain of sputum, blood, or lymph node aspirate; definitive diagnosis from cultures of same material, or paired acute/convalescent serology.\n\n# Infectivity\nPerson-to-person transmission occurs via respiratory droplets risk of transmission is low during first 20-24 hours of illness and requires close contact. Respiratory secretions probably are not infectious within a few hours after initiation of appropriate therapy.\n\n# Recommended Precautions\nStandard Precautions, Droplet Precautions until patients have received 48 hours of appropriate therapy. Chemoprophylaxis: Consider antibiotic prophylaxis for HCWs with close contact exposure.\ntransmit the infection when the disease is in the end stage. These persons cough copious amounts of bloody sputum that contains many plague bacteria. Patients in the early stage of primary pneumonic plague (approximately the first 20-24 h) apparently pose little risk . Antibiotic medication rapidly clears the sputum of plague bacilli, so that a patient generally is not infective within hours after initiation of effective antibiotic treatment . This means that in modern times many patients will never reach a stage where they pose a significant risk to others. Even in the end stage of disease, transmission only occurs after close contact. Simple protective measures, such as wearing masks, good hygiene, and avoiding close contact, have been effective to interrupt transmission during many pneumonic plague outbreaks . In the United States, the last known cases of person to person transmission of pneumonic plague occurred in 1925 . Only immune HCWs to care for pts; post-exposure vaccine within 4 days. Vaccinia: HCWs cover vaccination site with gauze and semi-permeable dressing until scab separates (>21 days). Observe hand hygiene. Adverse events with virus-containing lesions: Standard plus Contact Precautions until all lesions crusted b Transmission by the airborne route is a rare event; Airborne Precautions is recommended when possible, but in the event of mass exposures, barrier precautions and containment within a designated area are most important 204,212 . c Vaccinia adverse events with lesions containing infectious virus include inadvertent autoinoculation, ocular lesions (blepharitis, conjunctivitis), generalized vaccinia, progressive vaccinia, eczema vaccinatum; bacterial superinfection also requires addition of contact precautions if exudates cannot be contained 216,217 . Pneumonic: malaise, cough, sputum production, dyspnea; Typhoidal: fever, prostration, weight loss and frequently an associated pneumonia.\n\n# Disease\n\n# Diagnosis\nDiagnosis usually made with serology on acute and convalescent serum specimens; bacterium can be detected by PCR (LRN) or isolated from blood and other body fluids on cysteine-enriched media or mouse inoculation.\n\n# Infectivity\nPerson-to-person spread is rare. Laboratory workers who encounter/handle cultures of this organism are at high risk for disease if exposed.\n\n# Recommended Precautions\nStandard Precautions\n- - During aerosol-generating procedures on patients with suspected or proven infections transmitted by respiratory aerosols (e.g., SARS), wear a fit-tested N95 or higher respirator in addition to gloves, gown,and face/eye protection. (e.g., flutter strips, smoke tubes) or a hand held pressure gauge - Self-closing door on all room exits - Maintain back-up ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for PE areas and take immediate steps to restore the fixed ventilation system - For patients who require both a PE and Airborne Infection Isolation, use an anteroom to ensure proper air balance relationships and provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct. If an anteroom is not available, place patient in an AIIR and use portable ventilation units, industrial-grade HEPA filters to enhance filtration of spores. Bioaerosols. An airborne dispersion of particles containing whole or parts of biological entities, such as bacteria, viruses, dust mites, fungal hyphae, or fungal spores. Such aerosols usually consist of a mixture of mono-dispersed and aggregate cells, spores or viruses, carried by other materials, such as respiratory secretions and/or inert particles. Infectious bioaerosols (i.e., those that contain biological agents capable of causing an infectious disease) can be generated from human sources (e.g., expulsion from the respiratory tract during coughing, sneezing, talking or singing; during suctioning or wound irrigation), wet environmental sources (e.g. HVAC and cooling tower water with Legionella) or dry sources (e.g.,constuction dust with spores produced by Aspergillus spp.). Bioaerosols include large respiratory droplets and small droplet nuclei (Cole EC. AJIC 1998;26: 453-64).\n\n# IV. Surfaces\nCaregivers.. All persons who are not employees of an organization, are not paid, and provide or assist in providing healthcare to a patient (e.g., family member, friend) and acquire technical training as needed based on the tasks that must be performed.\nCohorting. In the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients). During outbreaks, healthcare personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff).\nColonization. Proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression. The presence of a microorganism within a host may occur with varying duration, but may become a source of potential transmission. In many instances, colonization and carriage are synonymous.\nDroplet nuclei. Microscopic particles < 5 µm in size that are the residue of evaporated droplets and are produced when a person coughs, sneezes, shouts, or sings. These particles can remain suspended in the air for prolonged periods of time and can be carried on normal air currents in a room or beyond, to adjacent spaces or areas receiving exhaust air.\n\n# Hand hygiene.\nA general term that applies to any one of the following: 1) handwashing with plain (nonantimicrobial) soap and water); 2) antiseptic handwash (soap containing antiseptic agents and water); 3) antiseptic handrub (waterless antiseptic product, most often alcohol-based, rubbed on all surfaces of hands); or 4) surgical hand antisepsis (antiseptic handwash or antiseptic handrub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora) 559 .\n\n# Healthcare-associated infection (HAI).\nAn infection that develops in a patient who is cared for in any setting where healthcare is delivered (e.g., acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (i.e., was not incubating or present at the time healthcare was provided). In ambulatory and home settings, HAI would apply to any infection that is associated with a medical or surgical intervention. Since the geographic location of infection acquisition is often uncertain, the preferred term is considered to be healthcare-associated rather than healthcare-acquired.\n\n# Hematopoietic stem cell transplantation (HSCT).\nAny transplantation of bloodor bone marrow-derived hematopoietic stem cells, regardless of donor type (e.g., allogeneic or autologous) or cell source (e.g., bone marrow, peripheral blood, or placental/umbilical cord blood); associated with periods of severe immunosuppression that vary with the source of the cells, the intensity of chemotherapy required, and the presence of graft versus host disease (MMWR 2000; 49: RR-10).\nHigh-efficiency particulate air (HEPA) filter. An air filter that removes >99.97% of particles > 0.3µm (the most penetrating particle size) at a specified flow rate of air. HEPA filters may be integrated into the central air handling systems, installed at the point of use above the ceiling of a room, or used as portable units (MMWR 2003; 52: RR-10).\nHome care. A wide-range of medical, nursing, rehabilitation, hospice and social services delivered to patients in their place of residence (e.g., private residence, senior living center, assisted living facility). Home health-care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy.\n\n# Immunocompromised patients.\nThose patients whose immune mechanisms are deficient because of congenital or acquired immunologic disorders (e.g., human immunodeficiency virus infection, congenital immune deficiency syndromes), chronic diseases such as diabetes mellitus, cancer, emphysema, or cardiac failure, ICU care, malnutrition, and immunosuppressive therapy of another disease process ). The type of infections for which an immunocompromised patient has increased susceptibility is determined by the severity of immunosuppression and the specific component(s) of the immune system that is affected. Patients undergoing allogeneic HSCT and those with chronic graft versus host disease are considered the most vulnerable to HAIs.\nImmunocompromised states also make it more difficult to diagnose certain infections (e.g., tuberculosis) and are associated with more severe clinical disease states than persons with the same infection and a normal immune system.\nInfection. The transmission of microorganisms into a host after evading or overcoming defense mechanisms, resulting in the organism's proliferation and invasion within host tissue(s). Host responses to infection may include clinical symptoms or may be subclinical, with manifestations of disease mediated by direct organisms pathogenesis and/or a function of cell-mediated or antibody responses that result in the destruction of host tissues.\n\n# Infection control and prevention professional (ICP).\nA person whose primary training is in either nursing, medical technology, microbiology, or epidemiology and who has acquired special training in infection control. Responsibilities may include collection, analysis, and feedback of infection data and trends to healthcare providers; consultation on infection risk assessment, prevention and control strategies; performance of education and training activities; implementation of evidence-based infection control practices or those mandated by regulatory and licensing agencies; application of epidemiologic principles to improve patient outcomes; participation in planning renovation and construction projects (e.g., to ensure appropriate containment of construction dust); evaluation of new products or procedures on patient outcomes; oversight of employee health services related to infection prevention; implementation of preparedness plans; communication within the healthcare setting, with local and state health departments, and with the community at large concerning infection control issues; and participation in research. Certification in infection control (CIC) is available through the Certification Board of Infection Control and Epidemiology.\n\n# Infection control and prevention program.\nA multidisciplinary program that includes a group of activities to ensure that recommended practices for the prevention of healthcare-associated infections are implemented and followed by HCWs, making the healthcare setting safe from infection for patients and healthcare personnel. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires the following five components of an infection control program for accreditation: 1) surveillance: monitoring patients and healthcare personnel for acquisition of infection and/or colonization; 2) investigation: identification and analysis of infection problems or undesirable trends; 3) prevention: implementation of measures to prevent transmission of infectious agents and to reduce risks for device-and procedure-related infections; 4) control: evaluation and management of outbreaks; and 5) reporting: provision of information to external agencies as required by state and federal law and regulation (www.jcaho.org). The infection control program staff has the ultimate authority to determine infection control policies for a healthcare organization with the approval of the organization's governing body.\n\n# Long-term care facilities (LTCFs\n). An array of residential and outpatient facilities designed to meet the bio-psychosocial needs of persons with sustained self-care deficits. These include skilled nursing facilities, chronic disease hospitals, nursing homes, foster and group homes, institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and longterm psychiatric hospitals.\n\n# Mask.\nA term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks (www.fda.gov/cdrh/ode/guidance/094.html#4).\n\n# Multidrug-resistant organisms (MDROs).\nIn general, bacteria that are resistant to one or more classes of antimicrobial agents and usually are resistant to all but one or two commercially available antimicrobial agents (e.g., MRSA, VRE, extended spectrum beta-lactamase -producing or intrinsically resistant gram-negative bacilli) 176 .\n\n# Nosocomial infection.\nA term that is derived from two Greek words \"nosos\" (disease) and \"komeion\" (to take care of) and refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission.\n\n# Personal protective equipment (PPE).\nA variety of barriers used alone or in combination to protect mucous membranes, skin, and clothing from contact with infectious agents. PPE includes gloves, masks, respirators, goggles, face shields, and gowns.\n\n# Procedure Mask.\nA covering for the nose and mouth that is intended for use in general patient care situations. These masks generally attach to the face with ear loops rather than ties or elastic. Unlike surgical masks, procedure masks are not regulated by the Food and Drug Administration.\nProtective Environment. A specialized patient-care area, usually in a hospital, that has a positive air flow relative to the corridor (i.e., air flows from the room to the outside adjacent space). The combination of high-efficiency particulate air (HEPA) filtration, high numbers (>12) of air changes per hour (ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients with a severely compromised immune system (e.g., those who have received allogeneic hemopoietic stem-cell transplant ) and decrease the risk of exposure to spores produced by environmental fungi. Other components include use of scrubbable surfaces instead of materials such as upholstery or carpeting, cleaning to prevent dust accumulation, and prohibition of fresh flowers or potted plants.\nQuasi-experimental studies. Studies to evaluate interventions but do not use randomization as part of the study design. These studies are also referred to as nonrandomized, pre-post-intervention study designs. These studies aim to demonstrate causality between an intervention and an outcome but cannot achieve the level of confidence concerning attributable benefit obtained through a randomized, controlled trial. In hospitals and public health settings, randomized control trials often cannot be implemented due to ethical, practical and urgency reasons; therefore, quasi-experimental design studies are used commonly. However, even if an intervention appears to be effective statistically, the question can be raised as to the possibility of alternative explanations for the result.. Such study design is used when it is not logistically feasible or ethically possible to conduct a randomized, controlled trial, (e.g., during outbreaks). Within the classification of quasi-experimental study designs, there is a hierarchy of design features that may contribute to validity of results (Harris et al. CID 2004:38: 1586).\n\n# Residential care setting.\nA facility in which people live, minimal medical care is delivered, and the psychosocial needs of the residents are provided for.\n\n# Respirator.\nA personal protective device worn by healthcare personnel to protect them from inhalation exposure to airborne infectious agents that are < 5 μm in size. These include infectious droplet nuclei from patients with M. tuberculosis, variola virus , SARS-CoV), and dust particles that contain infectious particles, such as spores of environmental fungi (e.g., Aspergillus sp.\n\n# Respiratory Hygiene/ Cough Etiquette.\nA combination of measures designed to minimize the transmission of respiratory pathogens via droplet or airborne routes in healthcare settings. The components of Respiratory Hygiene/Cough Etiquette are 1) covering the mouth and nose during coughing and sneezing, 2) using tissues to contain respiratory secretions with prompt disposal into a notouch receptacle, 3) offering a surgical mask to persons who are coughing to decrease contamination of the surrounding environment, and 4) turning the head away from others and maintaining spatial separation, ideally >3 feet, when coughing. These measures are targeted to all patients with symptoms of respiratory infection and their accompanying family members or friends beginning at the point of initial encounter with a healthcare setting (e.g., reception/triage in emergency departments, ambulatory clinics, healthcare provider offices) 126 (Srinivasin A ICHE 2004; 25: 1020; www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm).\nSafety culture/climate. The shared perceptions of workers and management regarding the expectations of safety in the work environment. A hospital safety climate includes the following six organizational components: 1) senior management support for safety programs; 2) absence of workplace barriers to safe work practices; 3) cleanliness and orderliness of the worksite; 4) minimal conflict and good communication among staff members; 5) frequent safetyrelated feedback/training by supervisors; and 6) availability of PPE and engineering controls 620 .\nSource Control. The process of containing an infectious agent either at the portal of exit from the body or within a confined space. The term is applied most frequently to containment of infectious agents transmitted by the respiratory route but could apply to other routes of transmission, (e.g., a draining wound, vesicular or bullous skin lesions). Respiratory Hygiene/Cough Etiquette that encourages individuals to \"cover your cough\" and/or wear a mask is a source control measure. The use of enclosing devices for local exhaust ventilation (e.g., booths for sputum induction or administration of aerosolized medication) is another example of source control.\n\n# Standard Precautions.\nA group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status. Standard Precautions is a combination and expansion of Universal Precautions 780 and Body Substance Isolation 1102 . Standard Precautions is based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. Standard Precautions includes hand hygiene, and depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield. Also, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents, (e.g. wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient).\n\n# Surgical mask.\nA device worn over the mouth and nose by operating room personnel during surgical procedures to protect both surgical patients and operating room personnel from transfer of microorganisms and body fluids. Surgical masks also are used to protect healthcare personnel from contact with large infectious droplets (>5 μm in size). According to draft guidance issued by the Food and Drug Administration on May 15, 2003, surgical masks are evaluated using standardized testing procedures for fluid resistance, bacterial filtration efficiency, differential pressure (air exchange), and flammability in order to mitigate the risks to health associated with the use of surgical masks. These specifications apply to any masks that are labeled surgical, laser, isolation, or dental or medical procedure (www.fda.gov/cdrh/ode/guidance/094.html#4). Surgical masks do not protect against inhalation of small particles or droplet nuclei and should not be confused with particulate respirators that are recommended for protection against selected airborne infectious agents, (e.g., Mycobacterium tuberculosis).\n\n# Appendix A:\n\n# APPENDIX A 1\n\n# TYPE AND DURATION OF PRECAUTIONS RECOMMENDED FOR SELECTED INFECTIONS AND CONDITIONS\n\n# APPENDIX A 1\n\n# TYPE AND DURATION OF PRECAUTIONS RECOMMENDED FOR SELECTED INFECTIONS AND CONDITIONS\n\n# HAND HYGIENE\nPerform hand hygiene immediately after removing all PPE!"},"raw_text":{"kind":"string","value":"The term nosocomial infection is retained to refer only to infections acquired in hospitals. The term healthcare-associated infection (HAI) is used to refer to infections associated with healthcare delivery in any setting (e.g., hospitals, long-term care facilities, ambulatory settings, home care). This term reflects the inability to determine with certainty where the pathogen is acquired since patients may be colonized with or exposed to potential pathogens outside of the healthcare setting, before receiving health care, or may develop infections caused by those pathogens when exposed to the conditions associated with delivery of healthcare. Additionally, patients frequently move among the various settings within a healthcare system 8 . A new addition to the practice recommendations for Standard Precautions is Respiratory Hygiene/Cough Etiquette. While Standard Precautions generally apply to the recommended practices of healthcare personnel during patient care, Respiratory Hygiene/Cough Etiquette applies broadly to all persons who enter a healthcare setting, including healthcare personnel, patients and visitors. These recommendations evolved from observations during the SARS epidemic that failure to implement basic source control measures with patients, visitors, and healthcare personnel with signs and symptoms of respiratory tract infection may have contributed to SARS coronavirus (SARS-CoV) transmission. This concept has been incorporated into CDC planning documents for SARS and pandemic influenza 9, 10 . The term \"Airborne Precautions\" has been supplemented with the term \"Airborne Infection Isolation Room (AIIR)\" for consistency with the Guidelines for Environmental Infection Control in Healthcare Facilities 11 , the Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings 2005 12 and the American Institute of Architects (AIA) guidelines for design and construction of hospitals, 2006 13 A set of prevention measures termed Protective Environment has been added to the precautions used to prevent HAIs. These measures, which have been defined in other guidelines , consist of engineering and design interventions that decrease the risk of exposure to environmental fungi for severely immunocompromised allogeneic hematiopoietic stem cell transplant (HSCT) patients during their highest risk phase, usually the first 100 days post transplant, or longer in the presence of graft-versus-host disease 11,[13][14][15] . Recommendations for a Protective Environment apply only to acute care hospitals that provide care to HSCT patients. Scope This guideline, like its predecessors, focuses primarily on interactions between patients and healthcare providers. The Guidelines for the Prevention of MDRO Infection were published separately in November 2006, and are available online at www.cdc.gov/ncidod/dhqp/index.html. Several other HICPAC# TABLE OF CONTENTS\nExecutive\n# Tables\nTable 1. Recent history of guidelines for prevention of healthcare-associated infections...... Table 2. Clinical syndromes or conditions warranting additional empiric transmissionbased precautions pending confirmation of diagnosis…………………………......... Table 3. Infection control considerations for high-priority (CDC Category A) diseases that Table 4. Recommendations for application of Standard Precautions for the care of all may result from bioterrorist attacks or are considered to be bioterrorist threats .. \n# EXECUTIVE SUMMARY\nThe Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings updates and expands the 1996 Guideline for Isolation Precautions in Hospitals. The following developments led to revision of the 1996 guideline:\n1. The transition of healthcare delivery from primarily acute care hospitals to other healthcare settings (e.g., home care, ambulatory care, free-standing specialty care sites, long-term care) created a need for recommendations that can be applied in all healthcare settings using common principles of infection control practice, yet can be modified to reflect setting-specific needs. Accordingly, the revised guideline addresses the spectrum of healthcare delivery settings. Furthermore, the term \"nosocomial infections\" is replaced by \"healthcareassociated infections\" (HAIs) to reflect the changing patterns in healthcare delivery and difficulty in determining the geographic site of exposure to an infectious agent and/or acquisition of infection. 2. The emergence of new pathogens (e.g., SARS-CoV associated with the severe acute respiratory syndrome [SARS], Avian influenza in humans), renewed concern for evolving known pathogens (e.g., C. difficile, noroviruses, communityassociated MRSA [CA-MRSA]), development of new therapies (e.g., gene therapy), and increasing concern for the threat of bioweapons attacks, established a need to address a broader scope of issues than in previous isolation guidelines. 3. The successful experience with Standard Precautions, first recommended in the 1996 guideline, has led to a reaffirmation of this approach as the foundation for preventing transmission of infectious agents in all healthcare settings. New additions to the recommendations for Standard Precautions are Respiratory Hygiene/Cough Etiquette and safe injection practices, including the use of a mask when performing certain high-risk, prolonged procedures involving spinal canal punctures (e.g., myelography, epidural anesthesia). The need for a recommendation for Respiratory Hygiene/Cough Etiquette grew out of observations during the SARS outbreaks where failure to implement simple source control measures with patients, visitors, and healthcare personnel with respiratory symptoms may have contributed to SARS coronavirus (SARS-CoV) transmission. The recommended practices have a strong evidence base. The continued occurrence of outbreaks of hepatitis B and hepatitis C viruses in ambulatory settings indicated a need to re-iterate safe injection practice recommendations as part of Standard Precautions. The addition of a mask for certain spinal injections grew from recent evidence of an associated risk for developing meningitis caused by respiratory flora. 4. The accumulated evidence that environmental controls decrease the risk of lifethreatening fungal infections in the most severely immunocompromised patients (allogeneic hematopoietic stem-cell transplant patients) led to the update on the components of the Protective Environment (PE). 5. Evidence that organizational characteristics (e.g., nurse staffing levels and composition, establishment of a safety culture) influence healthcare personnel adherence to recommended infection control practices, and therefore are important factors in preventing transmission of infectious agents, led to a new emphasis and recommendations for administrative involvement in the development and support of infection control programs. 6. Continued increase in the incidence of HAIs caused by multidrug-resistant organisms (MDROs) in all healthcare settings and the expanded body of knowledge concerning prevention of transmission of MDROs created a need for more specific recommendations for surveillance and control of these pathogens that would be practical and effective in various types of healthcare settings.\nThis document is intended for use by infection control staff, healthcare epidemiologists, healthcare administrators, nurses, other healthcare providers, and persons responsible for developing, implementing, and evaluating infection control programs for healthcare settings across the continuum of care. The reader is referred to other guidelines and websites for more detailed information and for recommendations concerning specialized infection control problems.\n# Parts I -III: Review of the Scientific Data Regarding Transmission of Infectious\nAgents in Healthcare Settings Part I reviews the relevant scientific literature that supports the recommended prevention and control practices. As with the 1996 guideline, the modes and factors that influence transmission risks are described in detail. New to the section on transmission are discussions of bioaerosols and of how droplet and airborne transmission may contribute to infection transmission. This became a concern during the SARS outbreaks of 2003, when transmission associated with aerosol-generating procedures was observed. Also new is a definition of \"epidemiologically important organisms\" that was developed to assist in the identification of clusters of infections that require investigation (i.e. multidrug-resistant organisms, C. difficile). Several other pathogens that hold special infection control interest (i.e., norovirus, SARS, Category A bioterrorist agents, prions, monkeypox, and the hemorrhagic fever viruses) also are discussed to present new information and infection control lessons learned from experience with these agents. This section of the guideline also presents information on infection risks associated with specific healthcare settings and patient populations.\nPart II updates information on the basic principles of hand hygiene, barrier precautions, safe work practices and isolation practices that were included in previous guidelines. However, new to this guideline, is important information on healthcare system components that influence transmission risks, including those under the influence of healthcare administrators. An important administrative priority that is described is the need for appropriate infection control staffing to meet the ever-expanding role of infection control professionals in the modern, complex healthcare system. Evidence presented also demonstrates another administrative concern, the importance of nurse staffing levels, including numbers of appropriately trained nurses in ICUs for preventing HAIs. The role of the clinical microbiology laboratory in supporting infection control is described to emphasize the need for this service in healthcare facilites. Other factors that influence transmission risks are discussed i.e., healthcare worker adherence to recommended infection control practices, organizational safety culture or climate, education and training Discussed for the first time in an isolation guideline is surveillance of healthcare-associated infections. The information presented will be useful to new infection control professionals as well as persons involved in designing or responding to state programs for public reporting of HAI rates.\nPart III describes each of the categories of precautions developed by the Healthcare Infection Control Practices Advisory Committee (HICPAC) and the Centers for Disease Control and Prevention (CDC) and provides guidance for their application in various healthcare settings. The categories of Transmission-Based Precautions are unchanged from those in the 1996 guideline: Contact, Droplet, and Airborne. One important change is the recommendation to don the indicated personal protective equipment (gowns, gloves, mask) upon entry into the patient's room for patients who are on Contact and/or Droplet Precautions since the nature of the interaction with the patient cannot be predicted with certainty and contaminated environmental surfaces are important sources for transmission of pathogens.\nIn addition, the Protective Environment (PE) for allogeneic hematopoietic stem cell transplant patients, described in previous guidelines, has been updated.\n# Tables, Appendices, and other Information\nThere are several tables that summarize important information: 1) a summary of the evolution of this document; 2) guidance on using empiric isolation precautions according to a clinical syndrome; 3) a summary of infection control recommendations for category A agents of bioterrorism; 4) components of Standard Precautions and recommendations for their application; 5) components of the Protective Environment; and 6) a glossary of definitions used in this guideline. New in this guideline is a figure that shows a recommended sequence for donning and removing personal protective equipment used for isolation precautions to optimize safety and prevent self-contamination during removal.\n# Appendix A: Type and Duration of Precautions Recommended for Selected Infections and Conditions\nAppendix A consists of an updated alphabetical list of most infectious agents and clinical conditions for which isolation precautions are recommended. A preamble to the Appendix provides a rationale for recommending the use of one or more Transmission-Based Precautions, in addition to Standard Precautions, based on a review of the literature and evidence demonstrating a real or potential risk for person-to-person transmission in healthcare settings.The type and duration of recommended precautions are presented with additional comments concerning the use of adjunctive measures or other relevant considerations to prevent transmission of the specific agent. Relevant citations are included.\n# Pre-Publication of the Guideline on Preventing Transmission of MDROs\nNew to this guideline is a comprehensive review and detailed recommendations for prevention of transmission of MDROs. This portion of the guideline was published electronically in October 2006 and updated in November, 2006 (Siegel JD, Rhinehart E, Jackson M, Chiarello L and HICPAC. Management of Multidrug-Resistant Organisms in Healthcare Settings 2006 www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf), and is considered a part of the Guideline for Isolation Precautions. This section provides a detailed review of the complex topic of MDRO control in healthcare settings and is intended to provide a context for evaluation of MDRO at individual healthcare settings. A rationale and institutional requirements for developing an effective MDRO control program are summarized. Although the focus of this guideline is on measures to prevent transmission of MDROs in healthcare settings, information concerning the judicious use of antimicrobial agents is presented since such practices are intricately related to the size of the reservoir of MDROs which in turn influences transmission (e.g. colonization pressure). There are two tables that summarize recommended prevention and control practices using the following seven categories of interventions to control MDROs: administrative measures, education of healthcare personnel, judicious antimicrobial use, surveillance, infection control precautions, environmental measures, and decolonization. Recommendations for each category apply to and are adapted for the various healthcare settings. With the increasing incidence and prevalence of MDROs, all healthcare facilities must prioritize effective control of MDRO transmission. Facilities should identify prevalent MDROs at the facility, implement control measures, assess the effectiveness of control programs, and demonstrate decreasing MDRO rates. A set of intensified MDRO prevention interventions is presented to be added 1) if the incidence of transmission of a target MDRO is NOT decreasing despite implementation of basic MDRO infection control measures, and 2) when the first case(s) of an epidemiologically important MDRO is identified within a healthcare facility.\n# Summary\nThis updated guideline responds to changes in healthcare delivery and addresses new concerns about transmission of infectious agents to patients and healthcare workers in the United States and infection control. The primary objective of the guideline is to improve the safety of the nation's healthcare delivery system by reducing the rates of HAIs. Objectives and methods The objectives of this guideline are to 1) provide infection control recommendations for all components of the healthcare delivery system, including hospitals, long-term care facilities, ambulatory care, home care and hospice; 2) reaffirm Standard Precautions as the foundation for preventing transmission during patient care in all healthcare settings; 3) reaffirm the importance of implementing Transmission-Based Precautions based on the clinical presentation or syndrome and likely pathogens until the infectious etiology has been determined (Table 2); and 4) provide epidemiologically sound and, whenever possible, evidence-based recommendations. This guideline is designed for use by individuals who are charged with administering infection control programs in hospitals and other healthcare settings. The information also will be useful for other healthcare personnel, healthcare administrators, and anyone needing information about infection control measures to prevent transmission of infectious agents. Commonly used abbreviations are provided on page 12 and terms used in the guideline are defined in the Glossary (page 137). Med-line and Pub Med were used to search for relevant studies published in English, focusing on those published since 1996. Much of the evidence cited for preventing transmission of infectious agents in healthcare settings is derived from studies that used \"quasi-experimental designs\", also referred to as nonrandomized, pre-post-intervention study designs 2 . Although these types of studies can provide valuable information regarding the effectiveness of various interventions, several factors decrease the certainty of attributing improved outcome to a specific intervention. These include: difficulties in controlling for important confounding variables; the use of multiple interventions during an outbreak; and results that are explained by the statistical principle of regression to the mean, (e.g., improvement over time without any intervention) 3 . Observational studies remain relevant and have been used to evaluate infection control interventions 4,5 . The quality of studies, consistency of results and correlation with results from randomized, controlled trials when available were considered during the literature review and assignment of evidence-based categories (See Part IV: Recommendations) to the recommendations in this guideline. Several authors have summarized properties to consider when evaluating studies for the purpose of determining if the results should change practice or in designing new studies 2,6,7 .\n# Abbreviations Used in the Guideline\nAIIR\nguidelines to prevent transmission of infectious agents associated with healthcare delivery are cited; e.g., Guideline for Hand Hygiene, Guideline for Environmental Infection Control, Guideline for Prevention of Healthcare-Associated Pneumonia, and Guideline for Infection Control in Healthcare Personnel 11,14,16,17 . In combination, these provide comprehensive guidance on the primary infection control measures for ensuring a safe environment for patients and healthcare personnel.\nThis guideline does not discuss in detail specialized infection control issues in defined populations that are addressed elsewhere, (e.g., Recommendations for Preventing Transmission of Infections among Chronic Hemodialysis Patients ,\n# Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Facilities 2005, Guidelines for Infection Control in Dental Health-Care Settings and Infection Control Recommendations for Patients with Cystic\nFibrosis 12,[18][19][20] . An exception has been made by including abbreviated guidance for a Protective Environment used for allogeneic HSCT recipients because components of the Protective Environment have been more completely defined since publication of the Guidelines for Preventing Opportunistic Infections Among HSCT Recipients in 2000 and the Guideline for Environmental Infection Control in Healthcare Facilities 11, 15 .\n# I.B. Rationale for Standard and Transmission-Based Precautions in healthcare settings\nTransmission of infectious agents within a healthcare setting requires three elements: a source (or reservoir) of infectious agents, a susceptible host with a portal of entry receptive to the agent, and a mode of transmission for the agent. This section describes the interrelationship of these elements in the epidemiology of HAIs.\n# I.B.1. Sources of infectious agents\nInfectious agents transmitted during healthcare derive primarily from human sources but inanimate environmental sources also are implicated in transmission. Human reservoirs include patients [20][21][22][23][24][25][26][27][28] , healthcare personnel 29-35 17, 36-39 , and household members and other visitors [40][41][42][43][44][45] . Such source individuals may have active infections, may be in the asymptomatic and/or incubation period of an infectious disease, or may be transiently or chronically colonized with pathogenic microorganisms, particularly in the respiratory and gastrointestinal tracts. The endogenous flora of patients (e.g., bacteria residing in the respiratory or gastrointestinal tract) also are the source of HAIs [46][47][48][49][50][51][52][53][54] .\n# I.B.2. Susceptible hosts\nInfection is the result of a complex interrelationship between a potential host and an infectious agent. Most of the factors that influence infection and the occurrence and severity of disease are related to the host. However, characteristics of the host-agent interaction as it relates to pathogenicity, virulence and antigenicity are also important, as are the infectious dose, mechanisms of disease production and route of exposure 55 . There is a spectrum of possible outcomes following exposure to an infectious agent. Some persons exposed to pathogenic microorganisms never develop symptomatic disease while others become severely ill and even die. Some individuals are prone to becoming transiently or permanently colonized but remain asymptomatic. Still others progress from colonization to symptomatic disease either immediately following exposure, or after a period of asymptomatic colonization. The immune state at the time of exposure to an infectious agent, interaction between pathogens, and virulence factors intrinsic to the agent are important predictors of an individuals' outcome. Host factors such as extremes of age and underlying disease (e.g. diabetes 56,57 ), human immunodeficiency virus/acquired immune deficiency syndrome [HIV/AIDS] 58,59 , malignancy, and transplants 18,60,61 can increase susceptibility to infection as do a variety of medications that alter the normal flora (e.g., antimicrobial agents, gastric acid suppressants, corticosteroids, antirejection drugs, antineoplastic agents, and immunosuppressive drugs). Surgical procedures and radiation therapy impair defenses of the skin and other involved organ systems. Indwelling devices such as urinary catheters, endotracheal tubes, central venous and arterial catheters [62][63][64] and synthetic implants facilitate development of HAIs by allowing potential pathogens to bypass local defenses that would ordinarily impede their invasion and by providing surfaces for development of bioflms that may facilitate adherence of microorganisms and protect from antimicrobial activity 65 . Some infections associated with invasive procedures result from transmission within the healthcare facility; others arise from the patient's endogenous flora [46][47][48][49][50] . High-risk patient populations with noteworthy risk factors for infection are discussed further in Sections I.D, I.E., and I.F.\n# I.B.3. Modes of transmission\nSeveral classes of pathogens can cause infection, including bacteria, viruses, fungi, parasites, and prions. The modes of transmission vary by type of organism and some infectious agents may be transmitted by more than one route: some are transmitted primarily by direct or indirect contact, (e.g., Herpes simplex virus [HSV], respiratory syncytial virus, Staphylococcus aureus), others by the droplet, (e.g., influenza virus, B. pertussis) or airborne routes (e.g., M. tuberculosis). Other infectious agents, such as bloodborne viruses (e.g., hepatitis B and C viruses [HBV, HCV] and HIV are transmitted rarely in healthcare settings, via percutaneous or mucous membrane exposure. Importantly, not all infectious agents are transmitted from person to person. These are distinguished in Appendix A. The three principal routes of transmission are summarized below.\n# I.B.3.a. Contact transmission\nThe most common mode of transmission, contact transmission is divided into two subgroups: direct contact and indirect contact.\n# I.B.3.a.i. Direct contact transmission\nDirect transmission occurs when microorganisms are transferred from one infected person to another person without a contaminated intermediate object or person. Opportunities for direct contact transmission between patients and healthcare personnel have been summarized in the Guideline for Infection Control in Healthcare Personnel, 1998 17 and include:\n• blood or other blood-containing body fluids from a patient directly enters a caregiver's body through contact with a mucous membrane 66 or breaks (i.e., cuts, abrasions) in the skin 67 . • mites from a scabies-infested patient are transferred to the skin of a caregiver while he/she is having direct ungloved contact with the patient's skin 68,69 . • a healthcare provider develops herpetic whitlow on a finger after contact with HSV when providing oral care to a patient without using gloves or HSV is transmitted to a patient from a herpetic whitlow on an ungloved hand of a healthcare worker (HCW) 70,71 .\n# I.B.3.a.ii. Indirect contact transmission\nIndirect transmission involves the transfer of an infectious agent through a contaminated intermediate object or person. In the absence of a point-source outbreak, it is difficult to determine how indirect transmission occurs. However, extensive evidence cited in the Guideline for Hand Hygiene in Health-Care Settings suggests that the contaminated hands of healthcare personnel are important contributors to indirect contact transmission 16 . Examples of opportunities for indirect contact transmission include:\n• Hands of healthcare personnel may transmit pathogens after touching an infected or colonized body site on one patient or a contaminated inanimate object, if hand hygiene is not performed before touching another patient. 72,73 . • Patient-care devices (e.g., electronic thermometers, glucose monitoring devices) may transmit pathogens if devices contaminated with blood or body fluids are shared between patients without cleaning and disinfecting between patients 74 75-77 . • Shared toys may become a vehicle for transmitting respiratory viruses (e.g., respiratory syncytial virus 24,78,79 or pathogenic bacteria (e.g., Pseudomonas aeruginosa 80 ) among pediatric patients. • Instruments that are inadequately cleaned between patients before disinfection or sterilization (e.g., endoscopes or surgical instruments) [81][82][83][84][85] or that have manufacturing defects that interfere with the effectiveness of reprocessing 86,87 may transmit bacterial and viral pathogens. Clothing, uniforms, laboratory coats, or isolation gowns used as personal protective equipment (PPE), may become contaminated with potential pathogens after care of a patient colonized or infected with an infectious agent, (e.g., MRSA 88 , VRE 89 , and C. difficile 90 . Although contaminated clothing has not been implicated directly in transmission, the potential exists for soiled garments to transfer infectious agents to successive patients.\n# I.B.3.b. Droplet transmission\nDroplet transmission is, technically, a form of contact transmission, and some infectious agents transmitted by the droplet route also may be transmitted by the direct and indirect contact routes. However, in contrast to contact transmission, respiratory droplets carrying infectious pathogens transmit infection when they travel directly from the respiratory tract of the infectious individual to susceptible mucosal surfaces of the recipient, generally over short distances, necessitating facial protection. Respiratory droplets are generated when an infected person coughs, sneezes, or talks 91,92 or during procedures such as suctioning, endotracheal intubation, [93][94][95][96] , cough induction by chest physiotherapy 97 and cardiopulmonary resuscitation 98,99 . Evidence for droplet transmission comes from epidemiological studies of disease outbreaks [100][101][102][103] , experimental studies 104 and from information on aerosol dynamics 91,105 . Studies have shown that the nasal mucosa, conjunctivae and less frequently the mouth, are susceptible portals of entry for respiratory viruses 106 . The maximum distance for droplet transmission is currently unresolved, although pathogens transmitted by the droplet route have not been transmitted through the air over long distances, in contrast to the airborne pathogens discussed below. Historically, the area of defined risk has been a distance of <3 feet around the patient and is based on epidemiologic and simulated studies of selected infections 103,104 . Using this distance for donning masks has been effective in preventing transmission of infectious agents via the droplet route. However, experimental studies with smallpox 107,108 and investigations during the global SARS outbreaks of 2003 101 suggest that droplets from patients with these two infections could reach persons located 6 feet or more from their source. It is likely that the distance droplets travel depends on the velocity and mechanism by which respiratory droplets are propelled from the source, the density of respiratory secretions, environmental factors such as temperature and humidity, and the ability of the pathogen to maintain infectivity over that distance 105 . Thus, a distance of <3 feet around the patient is best viewed as an example of what is meant by \"a short distance from a patient\" and should not be used as the sole criterion for deciding when a mask should be donned to protect from droplet exposure. Based on these considerations, it may be prudent to don a mask when within 6 to 10 feet of the patient or upon entry into the patient's room, especially when exposure to emerging or highly virulent pathogens is likely. More studies are needed to improve understanding of droplet transmission under various circumstances.\nDroplet size is another variable under discussion. Droplets traditionally have been defined as being >5 µm in size. Droplet nuclei, particles arising from desiccation of suspended droplets, have been associated with airborne transmission and defined as <5 µm in size 105 , a reflection of the pathogenesis of pulmonary tuberculosis which is not generalizeable to other organisms. Observations of particle dynamics have demonstrated that a range of droplet sizes, including those with diameters of 30µm or greater, can remain suspended in the air 109 . The behavior of droplets and droplet nuclei affect recommendations for preventing transmission. Whereas fine airborne particles containing pathogens that are able to remain infective may transmit infections over long distances, requiring AIIR to prevent its dissemination within a facility; organisms transmitted by the droplet route do not remain infective over long distances, and therefore do not require special air handling and ventilation. Examples of infectious agents that are transmitted via the droplet route include Bordetella pertussis 110 , influenza virus 23 , adenovirus 111 , rhinovirus 104 , Mycoplasma pneumoniae 112 , SARS-associated coronavirus (SARS-CoV) 21,96,113 , group A streptococcus 114 , and Neisseria meningitidis 95,103,115 . Although respiratory syncytial virus may be transmitted by the droplet route, direct contact with infected respiratory secretions is the most important determinant of transmission and consistent adherence to Standard plus Contact Precautions prevents transmission in healthcare settings 24,116,117 .\nRarely, pathogens that are not transmitted routinely by the droplet route are dispersed into the air over short distances. For example, although S. aureus is transmitted most frequently by the contact route, viral upper respiratory tract infection has been associated with increased dispersal of S. aureus from the nose into the air for a distance of 4 feet under both outbreak and experimental conditions and is known as the \"cloud baby\" and \"cloud adult\" phenomenon [118][119][120] .\n# I.B.3.c. Airborne transmission\nAirborne transmission occurs by dissemination of either airborne droplet nuclei or small particles in the respirable size range containing infectious agents that remain infective over time and distance (e.g., spores of Aspergillus spp, and Mycobacterium tuberculosis). Microorganisms carried in this manner may be dispersed over long distances by air currents and may be inhaled by susceptible individuals who have not had face-to-face contact with (or been in the same room with) the infectious individual [121][122][123][124] . Preventing the spread of pathogens that are transmitted by the airborne route requires the use of special air handling and ventilation systems (e.g., AIIRs) to contain and then safely remove the infectious agent 11,12 . Infectious agents to which this applies include Mycobacterium tuberculosis [124][125][126][127] , rubeola virus (measles) 122 , and varicella-zoster virus (chickenpox) 123 . In addition, published data suggest the possibility that variola virus (smallpox) may be transmitted over long distances through the air under unusual circumstances and AIIRs are recommended for this agent as well; however, droplet and contact routes are the more frequent routes of transmission for smallpox 108,128,129 . In addition to AIIRs, respiratory protection with NIOSH certified N95 or higher level respirator is recommended for healthcare personnel entering the AIIR to prevent acquisition of airborne infectious agents such as M. tuberculosis 12 .\nFor certain other respiratory infectious agents, such as influenza 130,131 and rhinovirus 104 , and even some gastrointestinal viruses (e.g., norovirus 132 and rotavirus 133 ) there is some evidence that the pathogen may be transmitted via small-particle aerosols, under natural and experimental conditions. Such transmission has occurred over distances longer than 3 feet but within a defined airspace (e.g., patient room), suggesting that it is unlikely that these agents remain viable on air currents that travel long distances. AIIRs are not required routinely to prevent transmission of these agents. Additional issues concerning examples of small particle aerosol transmission of agents that are most frequently transmitted by the droplet route are discussed below.\n# I.B.3.d. Emerging issues concerning airborne transmission of infectious agents.\n\n# I.B.3.d.i. Transmission from patients\nThe emergence of SARS in 2002, the importation of monkeypox into the United States in 2003, and the emergence of avian influenza present challenges to the assignment of isolation categories because of conflicting information and uncertainty about possible routes of transmission. Although SARS-CoV is transmitted primarily by contact and/or droplet routes, airborne transmission over a limited distance (e.g. within a room), has been suggested, though not proven [134][135][136][137][138][139][140][141] . This is true of other infectious agents such as influenza virus 130 and noroviruses 132,142,143 . Influenza viruses are transmitted primarily by close contact with respiratory droplets 23,102 and acquisition by healthcare personnel has been prevented by Droplet Precautions, even when positive pressure rooms were used in one center 144 However, inhalational transmission could not be excluded in an outbreak of influenza in the passengers and crew of a single aircraft 130 . Observations of a protective effect of UV lights in preventing influenza among patients with tuberculosis during the influenza pandemic of 1957-'58 have been used to suggest airborne transmission 145,146 . In contrast to the strict interpretation of an airborne route for transmission (i.e., long distances beyond the patient room environment), short distance transmission by small particle aerosols generated under specific circumstances (e.g., during endotracheal intubation) to persons in the immediate area near the patient has been demonstrated. Also, aerosolized particles <100 μm can remain suspended in air when room air current velocities exceed the terminal settling velocities of the particles 109 . SARS-CoV transmission has been associated with endotracheal intubation, noninvasive positive pressure ventilation, and cardiopulmonary resuscitation 93,94,96,98,141 . Although the most frequent routes of transmission of noroviruses are contact and food and waterborne routes, several reports suggest that noroviruses may be transmitted through aerosolization of infectious particles from vomitus or fecal material 142,143,147,148 . It is hypothesized that the aerosolized particles are inhaled and subsequently swallowed.\nRoy and Milton proposed a new classification for aerosol transmission when evaluating routes of SARS transmission: 1) obligate: under natural conditions, disease occurs following transmission of the agent only through inhalation of small particle aerosols (e.g., tuberculosis); 2) preferential: natural infection results from transmission through multiple routes, but small particle aerosols are the predominant route (e.g. measles, varicella); and 3) opportunistic: agents that naturally cause disease through other routes, but under special circumstances may be transmitted via fine particle aerosols 149 . This conceptual framework can explain rare occurrences of airborne transmission of agents that are transmitted most frequently by other routes (e.g., smallpox, SARS, influenza, noroviruses). Concerns about unknown or possible routes of transmission of agents associated with severe disease and no known treatment often result in more extreme prevention strategies than may be necessary; therefore, recommended precautions could change as the epidemiology of an emerging infection is defined and controversial issues are resolved.\n# I.B.3.d.ii.\nTransmission from the environment Some airborne infectious agents are derived from the environment and do not usually involve person-toperson transmission. For example, anthrax spores present in a finely milled powdered preparation can be aerosolized from contaminated environmental surfaces and inhaled into the respiratory tract 150,151 . Spores of environmental fungi (e.g., Aspergillus spp.) are ubiquitous in the environment and may cause disease in immunocompromised patients who inhale aerosolized (e.g., via construction dust) spores 152,153 . As a rule, neither of these organisms is subsequently transmitted from infected patients. However, there is one welldocumented report of person-to-person transmission of Aspergillus sp. in the ICU setting that was most likey due to the aerosolization of spores during wound debridement 154 . A Protective Environment refers to isolation practices designed to decrease the risk of exposure to environmental fungal agents in allogeneic HSCT patients 11,14,15,[155][156][157][158] . Environmental sources of respiratory pathogens (eg. Legionella) transmitted to humans through a common aerosol source is distinct from direct patient-topatient transmission.\n# I.B.3.e. Other sources of infection\nTransmission of infection from sources other than infectious individuals include those associated with common environmental sources or vehicles (e.g. contaminated food, water, or medications (e.g. intravenous fluids). Although Aspergillus spp. have been recovered from hospital water systems 159 , the role of water as a reservoir for immunosuppressed patients remains uncertain. Vectorborne transmission of infectious agents from mosquitoes, flies, rats, and other vermin also can occur in healthcare settings. Prevention of vector borne transmission is not addressed in this document.\n# I.C. Infectious agents of special infection control interest for healthcare settings\nSeveral infectious agents with important infection control implications that either were not discussed extensively in previous isolation guidelines or have emerged recently are discussed below. These are epidemiologically important organisms (e.g., C. difficile), agents of bioterrorism, prions, SARS-CoV, monkeypox, noroviruses, and the hemorrhagic fever viruses. Experience with these agents has broadened the understanding of modes of transmission and effective preventive measures. These agents are included for purposes of information and, for some (i.e., SARS-CoV, monkeypox), because of the lessons that have been learned about preparedness planning and responding effectively to new infectious agents.\n# I.C.1. Epidemiologically important organisms\nAny infectious agents transmitted in healthcare settings may, under defined conditions, become targeted for control because they are epidemiologically important. C. difficile is specifically discussed below because of wide recognition of its current importance in U.S. healthcare facilities. In determining what constitutes an \"epidemiologically important organism\", the following characteristics apply:\n• A propensity for transmission within healthcare facilities based on published reports and the occurrence of temporal or geographic clusters of > 2 patients, (e.g., C..difficile, norovirus, respiratory syncytial virus (RSV), influenza, rotavirus, Enterobacter spp; Serratia spp., group A streptococcus). A single case of healthcare-associated invasive disease caused by certain pathogens (e.g., group A streptococcus post-operatively 14, 163 160 , in burn units 161 , or in a LTCF 162 ; Legionella sp. , Aspergillus sp. 164 ) is generally considered a trigger for investigation and enhanced control measures because of the risk of additional cases and severity of illness associated with these infections. Antimicrobial resistance • Resistance to first-line therapies (e.g., MRSA, VISA, VRSA, VRE, ESBLproducing organisms). • Common and uncommon microorganisms with unusual patterns of resistance within a facility (e.g., the first isolate of Burkholderia cepacia complex or Ralstonia spp. in non-CF patients or a quinolone-resistant strain of Pseudomonas aeruginosa in a facility). • Difficult to treat because of innate or acquired resistance to multiple classes of antimicrobial agents (e.g., Stenotrophomonas maltophilia, Acinetobacter spp.). • Association with serious clinical disease, increased morbidity and mortality (e.g., MRSA and MSSA, group A streptococcus) • A newly discovered or reemerging pathogen I.C.1.a. C.difficile C. difficile is a spore-forming gram positive anaerobic bacillus that was first isolated from stools of neonates in 1935 165 and identified as the most commonly identified causative agent of antibiotic-associated diarrhea and pseudomembranous colitis in 1977 166 . This pathogen is a major cause of healthcare-associated diarrhea and has been responsible for many large outbreaks in healthcare settings that were extremely difficult to control. Important factors that contribute to healthcare-associated outbreaks include environmental contamination, persistence of spores for prolonged periods of time, resistance of spores to routinely used disinfectants and antiseptics, hand carriage by healthcare personnel to other patients, and exposure of patients to frequent courses of antimicrobial agents 167 . Antimicrobials most frequently associated with increased risk of C. difficile include third generation cephalosporins, clindamycin, vancomycin, and fluoroquinolones.\nSince 2001, outbreaks and sporadic cases of C. difficile with increased morbidity and mortality have been observed in several U.S. states, Canada, England and the Netherlands [168][169][170][171][172] . The same strain of C. difficile has been implicated in these outbreaks 173 . This strain, toxinotype III, North American PFGE type 1, and PCR-ribotype 027 (NAP1/027). has been found to hyperproduce toxin A (16 fold increase) and toxin B (23 fold increase) compared with isolates from 12 different pulsed-field gel electrophoresisPFGE types. A recent survey of U.S. infectious disease physicians found that 40% perceived recent increases in the incidence and severity of C. difficile disease 174 . Standardization of testing methodology and surveillance definitions is needed for accurate comparisons of trends in rates among hospitals 175 . It is hypothesized that the incidence of disease and apparent heightened transmissibility of this new strain may be due, at least in part, to the greater production of toxins A and B, increasing the severity of diarrhea and resulting in more environmental contamination. Considering the greater morbidity, mortality, length of stay, and costs associated with C. difficile disease in both acute care and long term care facilities, control of this pathogen is now even more important than previously. Prevention of transmission focuses on syndromic application of Contact Precautions for patients with diarrhea, accurate identification of patients, environmental measures (e.g., rigorous cleaning of patient rooms) and consistent hand hygiene. Use of soap and water, rather than alcohol based handrubs, for mechanical removal of spores from hands, and a bleach-containing disinfectant (5000 ppm) for environmental disinfection, may be valuable when there is transmission in a healthcare facility. See Appendix A for specific recommendations.\n# I.C.1. b. Multidrug-Resistant Organisms (MDROs)\nIn general, MDROs are defined as microorganisms -predominantly bacteria -that are resistant to one or more classes of antimicrobial agents 176 . Although the names of certain MDROs suggest resistance to only one agent (e.g., methicillin-resistant Staphylococcus aureus [MRSA], vancomycin resistant enterococcus [VRE]), these pathogens are usually resistant to all but a few commercially available antimicrobial agents. This latter feature defines MDROs that are considered to be epidemiologically important and deserve special attention in healthcare facilities 177 . Other MDROs of current concern include multidrug-resistant Streptococcus pneumoniae (MDRSP) which is resistant to penicillin and other broad-spectrum agents such as macrolides and fluroquinolones, multidrug-resistant gram-negative bacilli (MDR-GNB), especially those producing extended spectrum beta-lactamases (ESBLs); and strains of S. aureus that are intermediate or resistant to vancomycin (i.e., VISA and VRSA) 178-197 198 .\nMDROs are transmitted by the same routes as antimicrobial susceptible infectious agents. Patient-to-patient transmission in healthcare settings, usually via hands of HCWs, has been a major factor accounting for the increase in MDRO incidence and prevalence, especially for MRSA and VRE in acute care facilities [199][200][201] . Preventing the emergence and transmission of these pathogens requires a comprehensive approach that includes administrative involvement and measures (e.g., nurse staffing, communication systems, performance improvement processes to ensure adherence to recommended infection control measures), education and training of medical and other healthcare personnel, judicious antibiotic use, comprehensive surveillance for targeted MDROs, application of infection control precautions during patient care, environmental measures (e.g., cleaning and disinfection of the patient care environment and equipment, dedicated single-patient-use of non-critical equipment), and decolonization therapy when appropriate.\nThe prevention and control of MDROs is a national priority -one that requires that all healthcare facilities and agencies assume responsibility and participate in community-wide control programs 176,177 . A detailed discussion of this topic and recommendations for prevention was published in 2006 may be found at http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf I.C.2. Agents of bioterrorism CDC has designated the agents that cause anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulism as Category A (high priority) because these agents can be easily disseminated environmentally and/or transmitted from person to person; can cause high mortality and have the potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness 202 . General information relevant to infection control in healthcare settings for Category A agents of bioterrorism is summarized in Table 3. Consult www.bt.cdc.gov for additional, updated Category A agent information as well as information concerning Category B and C agents of bioterrorism and updates. Category B and C agents are important but are not as readily disseminated and cause less morbidity and mortality than Category A agents.\nHealthcare facilities confront a different set of issues when dealing with a suspected bioterrorism event as compared with other communicable diseases. An understanding of the epidemiology, modes of transmission, and clinical course of each disease, as well as carefully drafted plans that provide an approach and relevant websites and other resources for disease-specific guidance to healthcare, administrative, and support personnel, are essential for responding to and managing a bioterrorism event. Infection control issues to be addressed include: 1) identifying persons who may be exposed or infected; 2) preventing transmission among patients, healthcare personnel, and visitors; 3) providing treatment, chemoprophylaxis or vaccine to potentially large numbers of people; 4) protecting the environment including the logistical aspects of securing sufficient numbers of AIIRs or designating areas for patient cohorts when there are an insufficient number of AIIRs available;5) providing adequate quantities of appropriate personal protective equipment; and 6) identifying appropriate staff to care for potentially infectious patients (e.g., vaccinated healthcare personnel for care of patients with smallpox). The response is likely to differ for exposures resulting from an intentional release compared with naturally occurring disease because of the large number persons that can be exposed at the same time and possible differences in pathogenicity.\nA variety of sources offer guidance for the management of persons exposed to the most likely agents of bioterrorism. Federal agency websites (e.g., www.usamriid.army.mil/publications/index.html , www.bt.cdc.gov ) and state and county health department web sites should be consulted for the most up-to-date information. Sources of information on specific agents include: anthrax 203 ; smallpox [204][205][206] ; plague 207,208 ; botulinum toxin 209 ; tularemia 210 ; and hemorrhagic fever viruses: 211,212 .\n# I.C.2.a.\nPre-event administration of smallpox (vaccinia) vaccine to healthcare personnel Vaccination of personnel in preparation for a possible smallpox exposure has important infection control implications [213][214][215] . These include the need for meticulous screening for vaccine contraindications in persons who are at increased risk for adverse vaccinia events; containment and monitoring of the vaccination site to prevent transmission in the healthcare setting and at home; and the management of patients with vaccinia-related adverse events 216,217 . The pre-event U.S. smallpox vaccination program of 2003 is an example of the effectiveness of carefully developed recommendations for both screening potential vaccinees for contraindications and vaccination site care and monitoring. Approximately 760,000 individuals were vaccinated in the Department of Defense and 40,000 in the civilian or public health populations from December 2002 to February 2005, including approximately 70,000 who worked in healthcare settings. There were no cases of eczema vaccinatum, progressive vaccinia, fetal vaccinia, or contact transfer of vaccinia in healthcare settings or in military workplaces 218,219 . Outside the healthcare setting, there were 53 cases of contact transfer from military vaccinees to close personal contacts (e.g., bed partners or contacts during participation in sports such as wrestling 220 ). All contact transfers were from individuals who were not following recommendations to cover their vaccination sites. Vaccinia virus was confirmed by culture or PCR in 30 cases, and two of the confirmed cases resulted from tertiary transfer. All recipients, including one breast-fed infant, recovered without complication. Subsequent studies using viral culture and PCR techniques have confirmed the effectiveness of semipermeable dressings to contain vaccinia [221][222][223][224] . This experience emphasizes the importance of ensuring that newly vaccinated healthcare personnel adhere to recommended vaccination-site care, especially if they are to care for high-risk patients. Recommendations for preevent smallpox vaccination of healthcare personnel and vaccinia-related infection control recommendations are published in the MMWR 216,225 with updates posted on the CDC bioterrorism web site 205 .\n# I.C.3. Prions\nCreutzfeldt-Jakob disease (CJD) is a rapidly progressive, degenerative, neurologic disorder of humans with an incidence in the United States of approximately 1 person/million population/year 226,227 (www.cdc.gov/ncidod/diseases/cjd/cjd.htm). CJD is believed to be caused by a transmissible proteinaceous infectious agent termed a prion. Infectious prions are isoforms of a host-encoded glycoprotein known as the prion protein. The incubation period (i.e., time between exposure and and onset of symptoms) varies from two years to many decades. However, death typically occurs within 1 year of the onset of symptoms. Approximately 85% of CJD cases occur sporadically with no known environmental source of infection and 10% are familial. Iatrogenic transmission has occurred with most resulting from treatment with human cadaveric pituitary-derived growth hormone or gonadotropin 228,229 , from implantation of contaminated human dura mater grafts 230 or from corneal transplants 231 ). Transmission has been linked to the use of contaminated neurosurgical instruments or stereotactic electroencephalogram electrodes 232, 233 , 234 , 235 .\nPrion diseases in animals include scrapie in sheep and goats, bovine spongiform encephalopathy (BSE, or \"mad cow disease\") in cattle, and chronic wasting disease in deer and elk 236 . BSE, first recognized in the United Kingdom (UK) in 1986, was associated with a major epidemic among cattle that had consumed contaminated meat and bone meal.\nThe possible transmission of BSE to humans causing variant CJD (vCJD) was first described in 1996 and subsequently found to be associated with consumption of BSE-contaminated cattle products primarily in the United Kingdom. There is strong epidemiologic and laboratory evidence for a causal association between the causative agent of BSE and vCJD 237 . Although most cases of vCJD have been reported from the UK, a few cases also have been reported from Europe, Japan, Canada, and the United States. Most vCJD cases worldwide lived in or visited the UK during the years of a large outbreak of BSE (1980-96) and may have consumed contaminated cattle products during that time (www.cdc.gov/ncidod/diseases/cjd/cjd.htm). Although there has been no indigenously acquired vCJD in the United States, the sporadic occurrence of BSE in cattle in North America has heightened awareness of the possibility that such infections could occur and have led to increased surveillance activities. Updated information may be found on the following website: www.cdc.gov/ncidod/diseases/cjd/cjd.htm. The public health impact of prion diseases has been reviewed 238 .\nvCJD in humans has different clinical and pathologic characteristics from sporadic or classic CJD 239 , including the following: 1) younger median age at death: 28 (range 16-48) vs. 68 years; 2) longer duration of illness: median 14 months vs. 4-6 months; 3) increased frequency of sensory symptoms and early psychiatric symptoms with delayed onset of frank neurologic signs; and 4) detection of prions in tonsillar and other lymphoid tissues from vCJD patients but not from sporadic CJD patients 240 . Similar to sporadic CJD, there have been no reported cases of direct human-to-human transmission of vCJD by casual or environmental contact, droplet, or airborne routes. Ongoing blood safety surveillance in the U.S. has not detected sporadic CJD transmission through blood transfusion [241][242][243] . However, bloodborne transmission of vCJD is believed to have occurred in two UK patients 244,245 . The following FDA websites provide information on steps that are being taken in the US to protect the blood supply from CJD and vCJD: http://www.fda.gov/cber/gdlns/cjdvcjd.htm; http://www.fda.gov/cber/gdlns/cjdvcjdq&a.htm.\nStandard Precautions are used when caring for patients with suspected or confirmed CJD or vCJD. However, special precautions are recommended for tissue handling in the histology laboratory and for conducting an autopsy, embalming, and for contact with a body that has undergone autopsy 246 . Recommendations for reprocessing surgical instruments to prevent transmission of CJD in healthcare settings have been published by the World Health Organization (WHO) and are currently under review at CDC. Questions concerning notification of patients potentially exposed to CJD or vCJD through contaminated instruments and blood products from patients with CJD or vCJD or at risk of having vCJD may arise. The risk of transmission associated with such exposures is believed to be extremely low but may vary based on the specific circumstance. Therefore consultation on appropriate options is advised. The United Kingdom has developed several documents that clinicians and patients in the US may find useful (http://www.hpa.org.uk/infections/topics_az/cjd/information_documents.htm).\n# I.C.4. Severe Acute Respiratory Syndrome (SARS)\nSARS is a newly discovered respiratory disease that emerged in China late in 2002 and spread to several countries 135,140 ; Mainland China, Hong Kong, Hanoi, Singapore, and Toronto were affected significantly. SARS is caused by SARS CoV, a previously unrecognized member of the coronavirus family 247,248 . The incubation period from exposure to the onset of symptoms is 2 to 7 days but can be as long as 10 days and uncommonly even longer 249 . The illness is initially difficult to distinguish from other common respiratory infections. Signs and symptoms usually include fever >38.0 o C and chills and rigors, sometimes accompanied by headache, myalgia, and mild to severe respiratory symptoms. Radiographic finding of atypical pneumonia is an important clinical indicator of possible SARS. Compared with adults, children have been affected less frequently, have milder disease, and are less likely to transmit SARS-CoV 135,[249][250][251] . The overall case fatality rate is approximately 6.0%; underlying disease and advanced age increase the risk of mortality (www.who.int/csr/sarsarchive/2003_05_07a/en/).\nOutbreaks in healthcare settings, with transmission to large numbers of healthcare personnel and patients have been a striking feature of SARS; undiagnosed, infectious patients and visitors were important initiators of these outbreaks 21,[252][253][254] . The relative contribution of potential modes of transmission is not precisely known. There is ample evidence for droplet and contact transmission 96,101,113 ; however, opportunistic airborne transmission cannot be excluded 101, 135-139, 149, 255 . For example, exposure to aerosol-generating procedures (e.g., endotracheal intubation, suctioning) was associated with transmission of infection to large numbers of healthcare personnel outside of the United States 93,94,96,98,253 .Therefore, aerosolization of small infectious particles generated during these and other similar procedures could be a risk factor for transmission to others within a multi-bed room or shared airspace. A review of the infection control literature generated from the SARS outbreaks of 2003 concluded that the greatest risk of transmission is to those who have close contact, are not properly trained in use of protective infection control procedures, do not consistently use PPE; and that N95 or higher respirators may offer additional protection to those exposed to aerosol-generating procedures and high risk activities 256,257 . Organizational and individual factors that affected adherence to infection control practices for SARS also were identified 257 .\nControl of SARS requires a coordinated, dynamic response by multiple disciplines in a healthcare setting 9 . Early detection of cases is accomplished by screening persons with symptoms of a respiratory infection for history of travel to areas experiencing community transmission or contact with SARS patients, followed by implementation of Respiratory Hygiene/Cough Etiquette (i.e., placing a mask over the patient's nose and mouth) and physical separation from other patients in common waiting areas.The precise combination of precautions to protect healthcare personnel has not been determined. At the time of this publication, CDC recommends Standard Precautions, with emphasis on the use of hand hygiene, Contact Precautions with emphasis on environmental cleaning due to the detection of SARS CoV RNA by PCR on surfaces in rooms occupied by SARS patients 138,254,258 , Airborne Precautions, including use of fit-tested NIOSH-approved N95 or higher level respirators, and eye protection 259 . In Hong Kong, the use of Droplet and Contact Precautions, which included use of a mask but not a respirator, was effective in protecting healthcare personnel 113 . However, in Toronto, consistent use of an N95 respirator was slightly more protective than a mask 93 . It is noteworthy that there was no transmission of SARS-CoV to public hospital workers in Vietnam despite inconsistent use of infection control measures, including use of PPE, which suggests other factors (e.g., severity of disease, frequency of high risk procedures or events, environmental features) may influence opportunities for transmission 260 . SARS-CoV also has been transmitted in the laboratory setting through breaches in recommended laboratory practices. Research laboratories where SARS-CoV was under investigation were the source of most cases reported after the first series of outbreaks in the winter and spring of 2003 261,262 . Studies of the SARS outbreaks of 2003 and transmissions that occurred in the laboratory re-affirm the effectiveness of recommended infection control precautions and highlight the importance of consistent adherence to these measures.\nLessons from the SARS outbreaks are useful for planning to respond to future public health crises, such as pandemic influenza and bioterrorism events. Surveillance for cases among patients and healthcare personnel, ensuring availability of adequate supplies and staffing, and limiting access to healthcare facilities were important factors in the response to SARS that have been summarized 9 . Guidance for infection control precautions in various settings is available at www.cdc.gov/ncidod/sars. I.C.5. Monkeypox Monkeypox is a rare viral disease found mostly in the rain forest countries of Central and West Africa. The disease is caused by an orthopoxvirus that is similar in appearance to smallpox but causes a milder disease. The only recognized outbreak of human monkeypox in the United States was detected in June 2003 after several people became ill following contact with sick pet prairie dogs. Infection in the prairie dogs was subsequently traced to their contact with a shipment of animals from Africa, including giant Gambian rats 263 . This outbreak demonstrates the importance of recognition and prompt reporting of unusual disease presentations by clinicians to enable prompt identification of the etiology; and the potential of epizootic diseases to spread from animal reservoirs to humans through personal and occupational exposure 264 .\nLimited data on transmission of monkeypox are available. Transmission from infected animals and humans is believed to occur primarily through direct contact with lesions and respiratory secretions; airborne transmission from animals to humans is unlikely but cannot be excluded, and may have occurred in veterinary practices (e.g., during administration of nebulized medications to ill prairie dogs 265 ). Among humans, four instances of monkeypox transmission within hospitals have been reported in Africa among children, usually related to sharing the same ward or bed 266,267 . Additional recent literature documents transmission of Congo Basin monkeypox in a hospital compound for an extended number of generations 268 .\nThere has been no evidence of airborne or any other person-to-person transmission of monkeypox in the United States, and no new cases of monkeypox have been identified since the outbreak in June 2003 269 . The outbreak strain is a clade of monkeypox distinct from the Congo Basin clade and may have different epidemiologic properties (including human-to-human transmission potential) from monkeypox strains of the Congo Basin 270 ; this awaits further study. Smallpox vaccine is 85% protective against Congo Basin monkeypox 271 . Since there is an associated case fatality rate of <10%, administration of smallpox vaccine within 4 days to individuals who have had direct exposure to patients or animals with monkeypox is a reasonable consideration 272 . For the most current information on monkeypox, see www.cdc.gov/ncidod/monkeypox/clinicians.htm. I.C.6. Noroviruses Noroviruses, formerly referred to as Norwalk-like viruses, are members of the Caliciviridae family. These agents are transmitted via contaminated food or water and from person-to-person, causing explosive outbreaks of gastrointestinal disease 273 . Environmental contamination also has been documented as a contributing factor in ongoing transmission during outbreaks 274,275 . Although noroviruses cannot be propagated in cell culture, DNA detection by molecular diagnostic techniques has facilitated a greater appreciation of their role in outbreaks of gastrointestinal disease 276 . Reported outbreaks in hospitals 132,142,277 , nursing homes 275,[278][279][280][281][282][283] , cruise ships 284,285 , hotels 143,147 , schools 148 , and large crowded shelters established for hurricane evacuees 286 , demonstrate their highly contagious nature, the disruptive impact they have in healthcare facilities and the community, and the difficulty of controlling outbreaks in settings where people share common facilites and space. Of note, there is nearly a 5 fold increase in the risk to patients in outbreaks where a patient is the index case compared with exposure of patients during outbreaks where a staff member is the index case 287 .\nThe average incubation period for gastroenteritis caused by noroviruses is 12-48 hours and the clinical course lasts 12-60 hours 273 . Illness is characterized by acute onset of nausea, vomiting, abdominal cramps, and/or diarrhea. The disease is largely self-limited; rarely, death caused by severe dehydration can occur, particularly among the elderly with debilitating health conditions.\nThe epidemiology of norovirus outbreaks shows that even though primary cases may result from exposure to a fecally-contaminated food or water, secondary and tertiary cases often result from person-to-person transmission that is facilitated by contamination of fomites 273,288 and dissemination of infectious particles, especially during the process of vomiting 132,142,143,147,148,273,279,280 . Widespread, persistent and inapparent contamination of the environment and fomites can make outbreaks extremely difficult to control 147,275,284 .These clinical observations and the detection of norovirus DNA on horizontal surfaces 5 feet above the level that might be touched normally suggest that, under certain circumstances, aerosolized particles may travel distances beyond 3 feet 147 . It is hypothesized that infectious particles may be aerosolized from vomitus, inhaled, and swallowed. In addition, individuals who are responsible for cleaning the environment may be at increased risk of infection. Development of disease and transmission may be facilitated by the low infectious dose (i.e., <100 viral particles) 289 and the resistance of these viruses to the usual cleaning and disinfection agents (i.e., may survive < 10 ppm chlorine) [290][291][292] . An alternate phenolic agent that was shown to be effective against feline calicivirus was used for environmental cleaning in one outbreak 275,293 . There are insufficient data to determine the efficacy of alcohol-based hand rubs against noroviruses when the hands are not visibly soiled 294 . Absence of disease in certain individuals during an outbreak may be explained by protection from infection conferred by the B histo-blood group antigen 295 . Consultation on outbreaks of gastroenteritis is available through CDC's Division of Viral and Rickettsial Diseases 296 .\n# I.C.7. Hemorrhagic fever viruses (HFV)\nThe hemorrhagic fever viruses are a mixed group of viruses that cause serious disease with high fever, skin rash, bleeding diathesis, and in some cases, high mortality; the disease caused is referred to as viral hemorrhagic fever (VHF). Among the more commonly known HFVs are Ebola and Marburg viruses (Filoviridae), Lassa virus (Arenaviridae), Crimean-Congo hemorrhagic fever and Rift Valley Fever virus (Bunyaviridae), and Dengue and Yellow fever viruses (Flaviviridae) 212,297 . These viruses are transmitted to humans via contact with infected animals or via arthropod vectors. While none of these viruses is endemic in the United States, outbreaks in affected countries provide potential opportunities for importation by infected humans and animals. Furthermore, there are concerns that some of these agents could be used as bioweapons 212 . Person-to-person transmission is documented for Ebola, Marburg, Lassa and Crimean-Congo hemorrhagic fever viruses. In resource-limited healthcare settings, transmission of these agents to healthcare personnel, patients and visitors has been described and in some outbreaks has accounted for a large proportion of cases [298][299][300] . Transmissions within households also have occurred among individuals who had direct contact with ill persons or their body fluids, but not to those who did not have such contact 301 .\nEvidence concerning the transmission of HFVs has been summarized 212,302 . Person-to-person transmission is associated primarily with direct blood and body fluid contact. Percutaneous exposure to contaminated blood carries a particularly high risk for transmission and increased mortality 303,304 . The finding of large numbers of Ebola viral particles in the skin and the lumina of sweat glands has raised concern that transmission could occur from direct contact with intact skin though epidemiologic evidence to support this is lacking 305 . Postmortem handling of infected bodies is an important risk for transmission 301,306,307 . In rare situations, cases in which the mode of transmission was unexplained among individuals with no known direct contact , have led to speculation that airborne transmission could have occurred 298 . However, airborne transmission of naturally occurring HFVs in humans has not been seen. In one study of airplane passengers exposed to an in-flight index case of Lassa fever, there was no transmission to any passengers 308 .\nIn the laboratory setting, animals have been infected experimentally with Marburg or Ebola viruses via direct inoculation of the nose, mouth and/or conjunctiva 309,310 and by using mechanically generated virus-containing aerosols 311,312 . Transmission of Ebola virus among laboratory primates in an animal facility has been described 313 . Secondarily infected animals were in individual cages and separated by approximately 3 meters. Although the possibility of airborne transmission was suggested, the authors were not able to exclude droplet or indirect contact transmission in this incidental observation.\nGuidance on infection control precautions for HVFs that are transmitted personto-person have been published by CDC 1, 211 and by the Johns Hopkins Center for Civilian Biodefense Strategies 212 . The most recent recommendations at the time of publication of this document were posted on the CDC website on 5/19/05 314 . Inconsistencies among the various recommendations have raised questions about the appropriate precautions to use in U.S. hospitals. In less developed countries, outbreaks of HFVs have been controlled with basic hygiene, barrier precautions, safe injection practices, and safe burial practices 299,306 . The preponderance of evidence on HFV transmission indicates that Standard, Contact and Droplet Precautions with eye protection are effective in protecting healthcare personnel and visitors who may attend an infected patient. Single gloves are adequate for routine patient care; double-gloving is advised during invasive procedures (e.g., surgery) that pose an increased risk for blood exposure. Routine eye protection (i.e. goggles or face shield) is particularly important. Fluid-resistant gowns should be worn for all patient contact. Airborne Precautions are not required for routine patient care; however, use of AIIRs is prudent when procedures that could generate infectious aerosols are performed (e.g., endotracheal intubation, bronchoscopy, suctioning, autopsy procedures involving oscillating saws). N95 or higher level respirators may provide added protection for individuals in a room during aerosol-generating procedures (Table 3, Appendix A). When a patient with a syndrome consistent with hemorrhagic fever also has a history of travel to an endemic area, precautions are initiated upon presentation and then modified as more information is obtained (Table 2). Patients with hemorrhagic fever syndrome in the setting of a suspected bioweapon attack should be managed using Airborne Precautions, including AIIRs, since the epidemiology of a potentially weaponized hemorrhagic fever virus is unpredictable.\n# I.D. Transmission risks associated with specific types of healthcare settings\nNumerous factors influence differences in transmission risks among the various healthcare settings. These include the population characteristics (e.g., increased susceptibility to infections, type and prevalence of indwelling devices), intensity of care, exposure to environmental sources, length of stay, and frequency of interaction between patients/residents with each other and with HCWs. These factors, as well as organizational priorities, goals, and resources, influence how different healthcare settings adapt transmission prevention guidelines to meet their specific needs 315,316 . Infection control management decisions are informed by data regarding institutional experience/epidemiology, trends in community and institutional HAIs, local, regional, and national epidemiology, and emerging infectious disease threats.\n# I.D.1. Hospitals\nInfection transmission risks are present in all hospital settings. However, certain hospital settings and patient populations have unique conditions that predispose patients to infection and merit special mention. These are often sentinel sites for the emergence of new transmission risks that may be unique to that setting or present opportunities for transmission to other settings in the hospital.\n# I.D.1.a. Intensive Care Units\nIntensive care units (ICUs) serve patients who are immunocompromised by disease state and/or by treatment modalities, as well as patients with major trauma, respiratory failure and other life-threatening conditions (e.g., myocardial infarction, congestive heart failure, overdoses, strokes, gastrointestinal bleeding, renal failure, hepatic failure, multi-organ system failure, and the extremes of age). Although ICUs account for a relatively small proportion of hospitalized patients, infections acquired in these units accounted for >20% of all HAIs 317 . In the National Nosocomial Infection Surveillance (NNIS) system, 26.6% of HAIs were reported from ICU and high risk nursery (NICU) patients in 2002 (NNIS, unpublished data). This patient population has increased susceptibility to colonization and infection, especially with MDROs and Candida sp. 318,319 , because of underlying diseases and conditions, the invasive medical devices and technology used in their care (e.g. central venous catheters and other intravascular devices, mechanical ventilators, extracorporeal membrane oxygenation (ECMO), hemodialysis/-filtration, pacemakers, implantable left ventricular assist devices), the frequency of contact with healthcare personnel, prolonged length of stay, and prolonged exposure to antimicrobial agents [320][321][322][323][324][325][326][327][328][329][330][331] . Furthermore, adverse patient outcomes in this setting are more severe and are associated with a higher mortality 332 . Outbreaks associated with a variety of bacterial, fungal and viral pathogens due to commonsource and person-to-person transmissions are frequent in adult and pediatric ICUs 31, 333-336, 337 , 338 .\n# I.D.1.b. Burn Units\nBurn wounds can provide optimal conditions for colonization, infection, and transmission of pathogens; infection acquired by burn patients is a frequent cause of morbidity and mortality 320,339,340 . In patients with a burn injury involving >30% of the total body surface area (TBSA), the risk of invasive burn wound infection is particularly high 341,342 . Infections that occur in patients with burn injury involving <30% TBSA are usually associated with the use of invasive devices. Methicillin-susceptible Staphylococcus aureus, MRSA, enterococci, including VRE, gram-negative bacteria, and candida are prevalent pathogens in burn infections 53,340,[343][344][345][346][347][348][349][350] and outbreaks of these organisms have been reported [351][352][353][354] . Shifts over time in the predominance of pathogens causing infections among burn patients often lead to changes in burn care practices 343,[355][356][357][358] . Burn wound infections caused by Aspergillus sp. or other environmental molds may result from exposure to supplies contaminated during construction 359 or to dust generated during construction or other environmental disruption 360 .\nHydrotherapy equipment is an important environmental reservoir of gramnegative organisms. Its use for burn care is discouraged based on demonstrated associations between use of contaminated hydrotherapy equipment and infections. Burn wound infections and colonization, as well as bloodstream infections, caused by multidrug-resistant P. aeruginosa 361 , A. baumannii 362 , and MRSA 352 have been associated with hydrotherapy; excision of burn wounds in operating rooms is preferred.\nAdvances in burn care, specifically early excision and grafting of the burn wound, use of topical antimicrobial agents, and institution of early enteral feeding, have led to decreased infectious complications. Other advances have included prophylactic antimicrobial usage, selective digestive decontamination (SDD), and use of antimicrobial-coated catheters (ACC), but few epidemiologic studies and no efficacy studies have been performed to show the relative benefit of these 357 measures .\nThere is no consensus on the most effective infection control practices to prevent transmission of infections to and from patients with serious burns (e.g., singlebed rooms 358 , laminar flow 363 and high efficiency particulate air filtration [HEPA] 360 or maintaining burn patients in a separate unit without exposure to patients or equipment from other units 364 ). There also is controversy regarding the need for and type of barrier precautions for routine care of burn patients. One retrospective study demonstrated efficacy and cost effectiveness of a simplified barrier isolation protocol for wound colonization, emphasizing handwashing and use of gloves, caps, masks and plastic impermeable aprons (rather than isolation gowns) for direct patient contact 365 . However, there have been no studies that define the most effective combination of infection control precautions for use in burn settings. Prospective studies in this area are needed.\n# I.D.1.c. Pediatrics\nStudies of the epidemiology of HAIs in children have identified unique infection control issues in this population 63,64,[366][367][368][369][370] . Pediatric intensive care unit (PICU) patients and the lowest birthweight babies in the highrisk nursery (HRN) monitored in the NNIS system have had high rates of central venous catheter-associated bloodstream infections 64,320,[369][370][371][372] . Additionally, there is a high prevalence of community-acquired infections among hospitalized infants and young children who have not yet become immune either by vaccination or by natural infection. The result is more patients and their sibling visitors with transmissible infections present in pediatric healthcare settings, especially during seasonal epidemics (e.g., pertussis 36,40,41 , respiratory viral infections including those caused by RSV 24 , influenza viruses 373 , parainfluenza virus 374 , human metapneumovirus 375 , and adenoviruses 376 ; rubeola [measles] 34 , varicella [chickenpox] 377 , and rotavirus 38,378 ).\nClose physical contact between healthcare personnel and infants and young children (eg. cuddling, feeding, playing, changing soiled diapers, and cleaning copious uncontrolled respiratory secretions) provides abundant opportunities for transmission of infectious material. Practices and behaviors such as congregation of children in play areas where toys and bodily secretions are easily shared and family members rooming-in with pediatric patients can further increase the risk of transmission. Pathogenic bacteria have been recovered from toys used by hospitalized patients 379 ; contaminated bath toys were implicated in an outbreak of multidrug-resistant P. aeruginosa on a pediatric oncology unit 80 . In addition, several patient factors increase the likelihood that infection will result from exposure to pathogens in healthcare settings (e.g., immaturity of the neonatal immune system, lack of previous natural infection and resulting immunity, prevalence of patients with congenital or acquired immune deficiencies, congenital anatomic anomalies, and use of life-saving invasive devices in neontal and pediatric intensive care units) 63 . There are theoretical concerns that infection risk will increase in association with innovative practices used in the NICU for the purpose of improving developmental outcomes, Such factors include co-bedding 380 and kangaroo care 381 that may increase opportunity for skin-to-skin exposure of multiple gestation infants to each other and to their mothers, respectively; although infection risk smay actually be reduced among infants receiving kangaroo care 382 . Children who attend child care centers 383,384 and pediatric rehabilitation units 385 may increase the overall burden of antimicrobial resistance (eg. by contributing to the reservoir of community-associated MRSA [CA-MRSA]) [386][387][388][389][390][391] . Patients in chronic care facilities may have increased rates of colonization with resistant GNBs and may be sources of introduction of resistant organisms to acute care settings 50 .\n# I.D.2. Nonacute healthcare settings\nHealthcare is provided in various settings outside of hospitals including facilities, such as long-term care facilities (LTCF) (e.g. nursing homes), homes for the developmentally disabled, settings where behavioral health services are provided, rehabilitation centers and hospices 392 . In addition, healthcare may be provided in nonhealthcare settings such as workplaces with occupational health clinics, adult day care centers, assisted living facilities, homeless shelters, jails and prisons, school clinics and infirmaries. Each of these settings has unique circumstances and population risks to consider when designing and implementing an infection control program. Several of the most common settings and their particular challenges are discussed below. While this Guideline does not address each setting, the principles and strategies provided may be adapted and applied as appropriate.\n# I.D.2.a. Long-term care\nThe designation LTCF applies to a diverse group of residential settings, ranging from institutions for the developmentally disabled to nursing homes for the elderly and pediatric chronic-care facilities [393][394][395] . Nursing homes for the elderly predominate numerically and frequently represent longterm care as a group of facilities. Approximately 1.8 million Americans reside in the nation's 16,500 nursing homes 396 . Estimates of HAI rates of 1.8 to 13.5 per 1000 resident-care days have been reported with a range of 3 to 7 per 1000 resident-care days in the more rigorous studies [397][398][399][400][401] . The infrastructure described in the Department of Veterans Affairs nursing home care units is a promising example for the development of a nationwide HAI surveillance system for LTCFs 402 .\nLCTFs are different from other healthcare settings in that elderly patients at increased risk for infection are brought together in one setting and remain in the facility for extended periods of time; for most residents, it is their home. An atmosphere of community is fostered and residents share common eating and living areas, and participate in various facility-sponsored activities 403,404 . Since able residents interact freely with each other, controlling transmission of infection in this setting is challenging 405 . Residents who are colonized or infected with certain microorganisms are, in some cases, restricted to their room. However, because of the psychosocial risks associated with such restriction, it has been recommended that psychosocial needs be balanced with infection control needs in the LTCF setting [406][407][408][409] . Documented LTCF outbreaks have been caused by various viruses (e.g., influenza virus 35,[410][411][412] , rhinovirus 413 , adenovirus (conjunctivitis) 414 , norovirus 278, 279 275, 281 ) and bacteria, including group A streptococcus 162 , B. pertussis 415 , non-susceptible S. pneumoniae 197,198 , other MDROs, and Clostridium difficile 416 ) These pathogens can lead to substantial morbidity and mortality, and increased medical costs; prompt detection and implementation of effective control measures are required.\nRisk factors for infection are prevalent among LTCF residents 395,417,418 . Agerelated declines in immunity may affect responses to immunizations for influenza and other infectious agents, and increase susceptibility to tuberculosis. Immobility, incontinence, dysphagia, underlying chronic diseases, poor functional status, and age-related skin changes increase susceptibility to urinary, respiratory and cutaneous and soft tissue infections, while malnutrition can impair wound healing [419][420][421][422][423] . Medications (e.g., drugs that affect level of consciousness, immune function, gastric acid secretions, and normal flora, including antimicrobial therapy) and invasive devices (e.g., urinary catheters and feeding tubes) heighten susceptibility to infection and colonization in LTCF residents [424][425][426] . Finally, limited functional status and total dependence on healthcare personnel for activities of daily living have been identified as independent risk factors for infection 401,417,427 and for colonization with MRSA 428,429 and ESBL-producing K. pneumoniae 430 . Several position papers and review articles have been published that provide guidance on various aspects of infection control and antimicrobial resistance in LTCFs [406][407][408][431][432][433][434][435][436] . The Centers for Medicare and Medicaid Services (CMS) have established regulations for the prevention of infection in LTCFs 437 .\nBecause residents of LTCFs are hospitalized frequently, they can transfer pathogens between LTCFs and healthcare facilities in which they receive care 8,[438][439][440][441] . This is also true for pediatric long-term care populations. Pediatric chronic care facilities have been associated with importing extended-spectrum cephalosporin-resistant, gram-negative bacilli into one PICU 50 . Children from pediatric rehabilitation units may contribute to the reservoir of communityassociated MRSA 385,[389][390][391] .\n# I.D.2.b. Ambulatory Care\nIn the past decade, healthcare delivery in the United States has shifted from the acute, inpatient hospital to a variety of ambulatory and community-based settings, including the home. Ambulatory care is provided in hospital-based outpatient clinics, nonhospital-based clinics and physician offices, public health clinics, free-standing dialysis centers, ambulatory surgical centers, urgent care centers, and many others. In 2000, there were 83 million visits to hospital outpatient clinics and more than 823 million visits to physician offices 442 ; ambulatory care now accounts for most patient encounters with the health care system 443 . In these settings, adapting transmission prevention guidelines is challenging because patients remain in common areas for prolonged periods waiting to be seen by a healthcare provider or awaiting admission to the hospital, examination or treatment rooms are turned around quickly with limited cleaning, and infectious patients may not be recognized immediately. Furthermore, immunocompromised patients often receive chemotherapy in infusion rooms where they stay for extended periods of time along with other types of patients.\nThere are few data on the risk of HAIs in ambulatory care settings, with the exception of hemodialysis centers 18 , 444, 445 . Transmission of infections in outpatient settings has been reviewed in three publications [446][447][448] . Goodman and Solomon summarized 53 clusters of infections associated with the outpatient setting from 1961-1990 446 . Overall, 29 clusters were associated with common source transmission from contaminated solutions or equipment, 14 with personto-person transmission from or involving healthcare personnel and ten associated with airborne or droplet transmission among patients and healthcare workers. Transmission of bloodborne pathogens (i.e., hepatitis B and C viruses and, rarely, HIV) in outbreaks, sometimes involving hundreds of patients, continues to occur in ambulatory settings. These outbreaks often are related to common source exposures, usually a contaminated medical device, multi-dose vial, or intravenous solution 82,[449][450][451][452][453] . In all cases, transmission has been attributed to failure to adhere to fundamental infection control principles, including safe injection practices and aseptic technique.This subject has been reviewed and recommended infection control and safe injection practices summarized 454 .\nAirborne transmission of M.tuberculosis and measles in ambulatory settings, most frequently emergency departments, has been reported 34,127,446,448,[455][456][457] . Measles virus was transmitted in physician offices and other outpatient settings during an era when immunization rates were low and measles outbreaks in the community were occurring regularly 34,122,458 . Rubella has been transmitted in the outpatient obstetric setting 33 ; there are no published reports of varicella transmission in the outpatient setting. In the ophthalmology setting, adenovirus type 8 epidemic keratoconjunctivitis has been transmitted via incompletely disinfected ophthalmology equipment and/or from healthcare workers to patients, presumably by contaminated hands 17,446,448,[459][460][461][462] .\nIf transmission in outpatient settings is to be prevented, screening for potentially infectious symptomatic and asymptomatic individuals, especially those who may be at risk for transmitting airborne infectious agents (e.g., M. tuberculosis, varicella-zoster virus, rubeola [measles]), is necessary at the start of the initial patient encounter. Upon identification of a potentially infectious patient, implementation of prevention measures, including prompt separation of potentially infectious patients and implementation of appropriate control measures (e.g., Respiratory Hygiene/Cough Etiquette and Transmission-Based Precautions) can decrease transmission risks 9,12 . Transmission of MRSA and VRE in outpatient settings has not been reported, but the association of CA-MRSA in healthcare personnel working in an outpatient HIV clinic with environmental CA-MRSA contamination in that clinic, suggests the possibility of transmission in that setting 463 . Patient-to-patient transmission of Burkholderia species and Pseudomonas aeruginosa in outpatient clinics for adults and children with cystic fibrosis has been confirmed 464,465 .\n# I.D.2.c. Home Care Home care in the United\nStates is delivered by over 20,000 provider agencies that include home health agencies, hospices, durable medical equipment providers, home infusion therapy services, and personal care and support services providers. Home care is provided to patients of all ages with both acute and chronic conditions. The scope of services ranges from assistance with activities of daily living and physical and occupational therapy to the care of wounds, infusion therapy, and chronic ambulatory peritoneal dialysis (CAPD).\nThe incidence of infection in home care patients, other than those associated with infusion therapy is not well studied [466][467][468][469][470][471] . However, data collection and calculation of infection rates have been accomplished for central venous catheter-associated bloodstream infections in patients receiving home infusion therapy [470][471][472][473][474] and for the risk of blood contact through percutaneous or mucosal exposures, demonstrating that surveillance can be performed in this setting 475 . Draft definitions for home care associated infections have been developed 476 .\nTransmission risks during home care are presumed to be minimal. The main transmission risks to home care patients are from an infectious healthcare provider or contaminated equipment; providers also can be exposed to an infectious patient during home visits. Since home care involves patient care by a limited number of personnel in settings without multiple patients or shared equipment, the potential reservoir of pathogens is reduced. Infections of home care providers, that could pose a risk to home care patients include infections transmitted by the airborne or droplet routes (e.g., chickenpox, tuberculosis, influenza), and skin infestations (e.g., scabies 69 and lice) and infections (e.g.,impetigo) transmitted by direct or indirect contact. There are no published data on indirect transmission of MDROs from one home care patient to another, although this is theoretically possible if contaminated equipment is transported from an infected or colonized patient and used on another patient. Of note, investigation of the first case of VISA in homecare 186 and the first 2 reported cases of VRSA 178,180,181,183 found no evidence of transmission of VISA or VRSA to other home care recipients. Home health care also may contribute to antimicrobial resistance; a review of outpatient vancomycin use found 39% of recipients did not receive the antibiotic according to recommended guidelines 477 .\nAlthough most home care agencies implement policies and procedures to prevent transmission of organisms, the current approach is based on the adaptation of the 1996 Guideline for Isolation Precautions in Hospitals 1 as well as other professional guidance 478,479 . This issue has been very challenging in the home care industry and practice has been inconsistent and frequently not evidence-based. For example, many home health agencies continue to observe \"nursing bag technique,\" a practice that prescribes the use of barriers between the nursing bag and environmental surfaces in the home 480 . While the home environment may not always appear clean, the use of barriers between two noncritical surfaces has been questioned 481,482 . Opportunites exist to conduct research in home care related to infection transmission risks 483 .\n# I.D.2.d. Other sites of healthcare delivery\nFacilities that are not primarily healthcare settings but in which healthcare is delivered include clinics in correctional facilities and shelters. Both settings can have suboptimal features, such as crowded conditions and poor ventilation. Economically disadvantaged individuals who may have chronic illnesses and healthcare problems related to alcoholism, injection drug use, poor nutrition, and/or inadequate shelter often receive their primary healthcare at sites such as these 484 . Infectious diseases of special concern for transmission include tuberculosis, scabies, respiratory infections (e.g., N. meningitides, S. pneumoniae), sexually transmitted and bloodborne diseases (e.g.,HIV, HBV, HCV, syphilis, gonorrhea), hepatitis A virus (HAV), diarrheal agents such as norovirus, and foodborne diseases 286,[485][486][487][488] . A high index of suspicion for tuberculosis and CA-MRSA in these populations is needed as outbreaks in these settings or among the populations they serve have been reported [489][490][491][492][493][494][495][496][497] .\nPatient encounters in these types of facilities provide an opportunity to deliver recommended immunizations and screen for M. tuberculosis infection in addition to diagnosing and treating acute illnesses 498 . Recommended infection control measures in these non-traditional areas designated for healthcare delivery are the same as for other ambulatory care settings. Therefore, these settings must be equipped to observe Standard Precautions and, when indicated, Transmission-based Precautions.\n# I.E. Transmission risks associated with special patient populations\nAs new treatments emerge for complex diseases, unique infection control challenges associated with special patient populations need to be addressed.\n# I.E.1. Immunocompromised patients\nPatients who have congenital primary immune deficiencies or acquired disease (eg. treatment-induced immune deficiencies) are at increased risk for numerous types of infections while receiving healthcare and may be located throughout the healthcare facility. The specific defects of the immune system determine the types of infections that are most likely to be acquired (e.g., viral infections are associated with T-cell defects and fungal and bacterial infections occur in patients who are neutropenic). As a general group, immunocompromised patients can be cared for in the same environment as other patients; however, it is always advisable to minimize exposure to other patients with transmissible infections such as influenza and other respiratory viruses 499,500 . The use of more intense chemotherapy regimens for treatment of childhood leukemia may be associated with prolonged periods of neutropenia and suppression of other components of the immune system, extending the period of infection risk and raising the concern that additional precautions may be indicated for select groups 501,502 . With the application of newer and more intense immunosuppressive therapies for a variety of medical conditions (e.g., rheumatologic disease 503,504 , inflammatory bowel disease 505 ), immunosuppressed patients are likely to be more widely distributed throughout a healthcare facility rather than localized to single patient units (e.g. hematology-oncology). Guidelines for preventing infections in certain groups of immunocompromised patients have been published 15,506,507 .\nPublished data provide evidence to support placing allogeneic HSCT patients in a Protective Environment 15,157,158 . Also, three guidelines have been developed that address the special requirements of these immunocompromised patients, including use of antimicrobial prophylaxis and engineering controls to create a Protective Environment for the prevention of infections caused by Aspergillus spp. and other environmental fungi 11,14,15 . As more intense chemotherapy regimens associated with prolonged periods of neutropenia or graft-versus-host disease are implemented, the period of risk and duration of environmental protection may need to be prolonged beyond the traditional 100 days 508 .\n# I.E.2. Cystic fibrosis patients\nPatients with cystic fibrosis (CF) require special consideration when developing infection control guidelines. Compared to other patients, CF patients require additional protection to prevent transmission from contaminated respiratory therapy equipment [509][510][511][512][513] . Infectious agents such as Burkholderia cepacia complex and P. aeruginosa 464,465,514,515 have unique clinical and prognostic significance. In CF patients, B. cepacia infection has been associated with increased morbidity and mortality [516][517][518] , while delayed acquisition of chronic P.aeruginosa infection may be associated with an improved long-term clinical outcome 519,520 .\nPerson-to-person transmission of B. cepacia complex has been demonstrated among children 517 and adults 521 with CF in healthcare settings 464,522 , during various social contacts 523 , most notably attendance at camps for patients with CF 524 , and among siblings with CF 525 . Successful infection control measures used to prevent transmission of respiratory secretions include segregation of CF patients from each other in ambulatory and hospital settings (including use of private rooms with separate showers), environmental decontamination of surfaces and equipment contaminated with respiratory secretions, elimination of group chest physiotherapy sessions, and disbanding of CF camps 97,526 . The Cystic Fibrosis Foundation published a consensus document with evidencebased recommendations for infection control practices for CF patients 20 .\n# I.F. New therapies associated with potentially transmissible infectious agents\nI.F.1. Gene therapy Gene therapy has has been attempted using a number of different viral vectors, including nonreplicating retroviruses, adenoviruses, adenoassociated viruses, and replication-competent strains of poxviruses. Unexpected adverse events have restricted the prevalence of gene therapy protocols.\nThe infectious hazards of gene therapy are theoretical at this time, but require meticulous surveillance due to the possible occurrence of in vivo recombination and the subsequent emergence of a transmissible genetically altered pathogen. Greatest concern attends the use of replication-competent viruses, especially vaccinia. As of the time of publication, no reports have described transmission of a vector virus from a gene therapy recipient to another individual, but surveillance is ongoing. Recommendations for monitoring infection control issues throughout the course of gene therapy trials have been published [527][528][529] .\n# I.F.2. Infections transmitted through blood, organs and other tissues\nThe potential hazard of transmitting infectious pathogens through biologic products is a small but ever present risk, despite donor screening. Reported infections transmitted by transfusion or transplantation include West Nile Virus infection 530 cytomegalovirus infection 531 , Creutzfeldt-Jacob disease 230 , hepatitis C 532 , infections with Clostridium spp. 533 and group A streptococcus 534 , malaria 535 , babesiosis 536 , Chagas disease 537 , lymphocytic choriomeningitis 538 , and rabies 539, 540 . Therefore, it is important to consider receipt of biologic products when evaluating patients for potential sources of infection.\n# I.F.3. Xenotransplantation\nThe transplantation of nonhuman cells, tissues, and organs into humans potentially exposes patients to zoonotic pathogens. Transmission of known zoonotic infections (e.g., trichinosis from porcine tissue), constitutes one concern, but also of concern is the possibility that transplantation of nonhuman cells, tissues, or organs may transmit previously unknown zoonotic infections (xenozoonoses) to immunosuppressed human recipients. Potential infections that might accompany transplantation of porcine organs have been described 541 . Guidelines from the U.S. Public Health Service address many infectious diseases and infection control issues that surround the developing field of xenotransplantation 542 ); work in this area is ongoing.\n# Part II:\nFundamental elements needed to prevent transmission of infectious agents in healthcare settings II.A. Healthcare system components that influence the effectiveness of precautions to prevent transmission II.A.1. Administrative measures Healthcare organizations can demonstrate a commitment to preventing transmission of infectious agents by incorporating infection control into the objectives of the organization's patient and occupational safety programs [543][544][545][546][547] . An infrastructure to guide, support, and monitor adherence to Standard and Transmission-Based Precautions 434,548,549 will facilitate fulfillment of the organization's mission and achievement of the Joint Commission on Accreditation of Healthcare Organization's patient safety goal to decrease HAIs 550 . Policies and procedures that explain how Standard and Transmission-Based Precautions are applied, including systems used to identify and communicate information about patients with potentially transmissible infectious agents, are essential to ensure the success of these measures and may vary according to the characteristics of the organization.\nA key administrative measure is provision of fiscal and human resources for maintaining infection control and occupational health programs that are responsive to emerging needs. Specific components include bedside nurse 551 and infection prevention and control professional (ICP) staffing levels 552 , inclusion of ICPs in facility construction and design decisions 11 , clinical microbiology laboratory support 553,554 , adequate supplies and equipment including facility ventilation systems 11 , adherence monitoring 555 , assessment and correction of system failures that contribute to transmission 556,557 , and provision of feedback to healthcare personnel and senior administrators 434,548,549,558 . The positive influence of institutional leadership has been demonstrated repeatedly in studies of HCW adherence to recommended hand hygiene practices 176,177,434,548,549,[559][560][561][562][563][564] . Healthcare administrator involvement in infection control processes can improve administrators' awareness of the rationale and resource requirements for following recommended infection control practices.\nSeveral administrative factors may affect the transmission of infectious agents in healthcare settings: institutional culture, individual worker behavior, and the work environment. Each of these areas is suitable for performance improvement monitoring and incorporation into the organization's patient safety goals 543,544,546,565 .\n# II.A.1.a.Scope of work and staffing needs for infection control professionals\nThe effectiveness of infection surveillance and control programs in preventing nosocomial infections in United States hospitals was assessed by the CDC through the Study on the Efficacy of Nosocomial Infection Control (SENIC Project) conducted 1970-76 566 . In a representative sample of US general hospitals, those with a trained infection control physician or microbiologist involved in an infection control program, and at least one infection control nurse per 250 beds, were associated with a 32% lower rate of four infections studied (CVC-associated bloodstream infections, ventilator-associated pneumonias, catheter-related urinary tract infections, and surgical site infections).\nSince that landmark study was published, responsibilities of ICPs have expanded commensurate with the growing complexity of the healthcare system, the patient populations served, and the increasing numbers of medical procedures and devices used in all types of healthcare settings. The scope of work of ICPs was first assessed in 1982 [567][568][569] by the Certification Board of Infection Control (CBIC), and has been re-assessed every five years since that time 558, [570][571][572] . The findings of these task analyses have been used to develop and update the Infection Control Certification Examination, offered for the first time in 1983. With each survey, it is apparent that the role of the ICP is growing in complexity and scope, beyond traditional infection control activities in acute care hospitals. Activities currently assigned to ICPs in response to emerging challenges include: 1) surveillance and infection prevention at facilities other than acute care hospitals e.g., ambulatory clinics, day surgery centers, long term care facilities, rehabilitation centers, home care; 2) oversight of employee health services related to infection prevention, e.g. assessment of risk and administration of recommended treatment following exposure to infectious agents, tuberculosis screening, influenza vaccination, respiratory protection fit testing, and administration of other vaccines as indicated, such as smallpox vaccine in 2003; 3) preparedness planning for annual influenza outbreaks, pandemic influenza, SARS, bioweapons attacks; 4) adherence monitoring for selected infection control practices; 5) oversight of risk assessment and implementation of prevention measures associated with construction and renovation; 6) prevention of transmission of MDROs; 7) evaluation of new medical products that could be associated with increased infection risk. e.g.,intravenous infusion materials; 9) communication with the public, facility staff, and state and local health departments concerning infection control-related issues; and 10) participation in local and multi-center research projects 434,549,552,558,573,574 .\nNone of the CBIC job analyses addressed specific staffing requirements for the identified tasks, although the surveys did include information about hours worked; the 2001 survey included the number of ICPs assigned to the responding facilities 558 . There is agreement in the literature that 1 ICP per 250 acute care beds is no longer adequate to meet current infection control needs; a Delphi project that assessed staffing needs of infection control programs in the 21 st century concluded that a ratio of 0.8 to 1.0 ICP per 100 occupied acute care beds is an appropriate level of staffing 552 . A survey of participants in the National Nosocomial Infections Surveillance (NNIS) system found the average daily census per ICP was 115 316 . Results of other studies have been similar: 3 per 500 beds for large acute care hospitals, 1 per 150-250 beds in long term care facilities, and 1.56 per 250 in small rural hospitals 573,575 . The foregoing demonstrates that infection control staffing can no longer be based on patient census alone, but rather must be determined by the scope of the program, characteristics of the patient population, complexity of the healthcare system, tools available to assist personnel to perform essential tasks (e.g., electronic tracking and laboratory support for surveillance), and unique or urgent needs of the institution and community 552 . Furthermore, appropriate training is required to optimize the quality of work performed 558, 572, 576 .\n# II.A.1.a.i. Infection Control Nurse Liaison\nDesignating a bedside nurse on a patient care unit as an infection control liaison or \"link nurse\" is reported to be an effective adjunct to enhance infection control at the unit level [577][578][579][580][581][582] . Such individuals receive training in basic infection control and have frequent communication with the ICPs, but maintain their primary role as bedside caregiver on their units. The infection control nurse liaison increases the awareness of infection control at the unit level. He or she is especially effective in implementation of new policies or control interventions because of the rapport with individuals on the unit, an understanding of unit-specific challenges, and ability to promote strategies that are most likely to be successful in that unit. This position is an adjunct to, not a replacement for, fully trained ICPs. Furthermore, the infection control liaison nurses should not be counted when considering ICP staffing.\n# II.A.1.b. Bedside nurse staffing\nThere is increasing evidence that the level of bedside nurse-staffing influences the quality of patient care 583,584 . If there are adequate nursing staff, it is more likely that infection control practices, including hand hygiene and Standard and Transmission-Based Precautions, will be given appropriate attention and applied correctly and consistently 552 . A national multicenter study reported strong and consistent inverse relationships between nurse staffing and five adverse outcomes in medical patients, two of which were HAIs: urinary tract infections and pneumonia 583 . The association of nursing staff shortages with increased rates of HAIs has been demonstrated in several outbreaks in hospitals and long term care settings, and with increased transmission of hepatitis C virus in dialysis units 22,418,551,[585][586][587][588][589][590][591][592][593][594][595][596][597] . In most cases, when staffing improved as part of a comprehensive control intervention, the outbreak ended or the HAI rate declined. In two studies 590,596 , the composition of the nursing staff (\"pool\" or \"float\" vs. regular staff nurses) influenced the rate of primary bloodstream infections, with an increased infection rate occurring when the proportion of regular nurses decreased and pool nurses increased.\n# II.A.1.c. Clinical microbiology laboratory support\nThe critical role of the clinical microbiology laboratory in infection control and healthcare epidemiology is described well 553,554,[598][599][600] and is supported by the Infectious Disease Society of America policy statement on consolidation of clinical microbiology laboratories published in 2001 553 . The clinical microbiology laboratory contributes to preventing transmission of infectious diseases in healthcare settings by promptly detecting and reporting epidemiologically important organisms, identifying emerging patterns of antimicrobial resistance, and assisting in assessment of the effectiveness of recommended precautions to limit transmission during outbreaks 598 . Outbreaks of infections may be recognized first by laboratorians 162 . Healthcare organizations need to ensure the availability of the recommended scope and quality of laboratory services, a sufficient number of appropriately trained laboratory staff members, and systems to promptly communicate epidemiologically important results to those who will take action (e.g., providers of clinical care, infection control staff, healthcare epidemiologists, and infectious disease consultants) 601 . As concerns about emerging pathogens and bioterrorism grow, the role of the clinical microbiology laboratory takes on even greater importance. For healthcare organizations that outsource microbiology laboratory services (e.g., ambulatory care, home care, LTCFs, smaller acute care hospitals), it is important to specify by contract the types of services (e.g., periodic institution-specific aggregate susceptibility reports) required to support infection control.\nSeveral key functions of the clinical microbiology laboratory are relevant to this guideline:\n• Antimicrobial susceptibility by testing and interpretation in accordance with current guidelines developed by the National Committee for Clinical Laboratory Standards (NCCLS), known as the Clinical and Laboratory Standards Institute (CLSI) since 2005 602 , for the detection of emerging resistance patterns 603,604 , and for the preparation, analysis, and distribution of periodic cumulative antimicrobial susceptibility summary reports [605][606][607] . While not required, clinical laboratories ideally should have access to rapid genotypic identification of bacteria and their antibiotic resistance genes 608 . • Performance of surveillance cultures when appropriate (including retention of isolates for analysis) to assess patterns of infection transmission and effectiveness of infection control interventions at the facility or organization. Microbiologists assist in decisions concerning the indications for initiating and discontinuing active surveillance programs and optimize the use of laboratory resources. • Molecular typing, on-site or outsourced, in order to investigate and control healthcare-associated outbreaks 609 . • Application of rapid diagnostic tests to support clinical decisions involving patient treatment, room selection, and implementation of control measures including barrier precautions and use of vaccine or chemoprophylaxis agents (e.g., influenza [610][611][612] , B. pertussis 613 , RSV 614,615 , and enteroviruses 616 ). The microbiologist provides guidance to limit rapid testing to clinical situations in which rapid results influence patient management decisions, as well as providing oversight of point-of-care testing performed by non-laboratory healthcare workers 617 . • Detection and rapid reporting of epidemiologically important organisms, including those that are reportable to public health agencies. • Implementation of a quality control program that ensures testing services are appropriate for the population served, and stringently evaluated for sensitivity, specificity, applicability, and feasibility. • Participation in a multidisciplinary team to develop and maintain an effective institutional program for the judicious use of antimicrobial agents 618, 619 .\n# II.A.2. Institutional safety culture and organizational characteristics\nSafety culture (or safety climate) refers to a work environment where a shared commitment to safety on the part of management and the workforce is understood and followed 557,620,621 . The authors of the Institute of Medicine Report, To Err is Human 543 , acknowledge that causes of medical error are multifaceted but emphasize repeatedly the pivotal role of system failures and the benefits of a safety culture. A safety culture is created through 1) the actions management takes to improve patient and worker safety; 2) worker participation in safety planning; 3) the availability of appropriate protective equipment; 4) influence of group norms regarding acceptable safety practices; and 5) the organization's socialization process for new personnel. Safety and patient outcomes can be enhanced by improving or creating organizational characteristics within patient care units as demonstrated by studies of surgical ICUs 622, 623 . Each of these factors has a direct bearing on adherence to transmission prevention recommendations 257 . Measurement of an institutional culture of safety is useful for designing improvements in healthcare 624,625 . Several hospital-based studies have linked measures of safety culture with both employee adherence to safe practices and reduced exposures to blood and body fluids [626][627][628][629][630][631][632] . One study of hand hygiene practices concluded that improved adherence requires integration of infection control into the organization's safety culture 561 . Several hospitals that are part of the Veterans Administration Healthcare System have taken specific steps toward improving the safety culture, including error reporting mechanisms, performing root cause analysis on problems identified, providing safety incentives, and employee education. [633][634][635] .\n# II.A.3. Adherence of healthcare personnel to recommended guidelines\nAdherence to recommended infection control practices decreases transmission of infectious agents in healthcare settings 116,562,[636][637][638][639][640] . However, several observational studies have shown limited adherence to recommended practices by healthcare personnel 559,[640][641][642][643][644][645][646][647][648][649][650][651][652][653][654][655][656][657] . Observed adherence to universal precautions ranged from 43% to 89% 641,642,649,651,652 . However, the degree of adherence depended frequently on the practice that was assessed and, for glove use, the circumstance in which they were used. Appropriate glove use has ranged from a low of 15% 645 to a high of 82% 650 . However, 92% and 98% adherence with glove use have been reported during arterial blood gas collection and resuscitation, respectively, procedures where there may be considerable blood contact 643,656 . Differences in observed adherence have been reported among occupational groups in the same healthcare facility 641 and between experienced and nonexperienced professionals 645 . In surveys of healthcare personnel, selfreported adherence was generally higher than that reported in observational studies. Furthermore, where an observational component was included with a self-reported survey, self-perceived adherence was often greater than observed adherence 657 . Among nurses and physicians, increasing years of experience is a negative predictor of adherence 645,651 . Education to improve adherence is the primary intervention that has been studied. While positive changes in knowledge and attitude have been demonstrated, 640,658 , there often has been limited or no accompanying change in behavior 642,644 . Self-reported adherence is higher in groups that have received an educational intervention 630,659 . Educational interventions that incorporated videotaping and performance feedback were successful in improving adherence during the period of study; the long-term effect of these interventions is not known 654 .The use of videotape also served to identify system problems (e.g., communication and access to personal protective equipment) that otherwise may not have been recognized. Use of engineering controls and facility design concepts for improving adherence is gaining interest. While introduction of automated sinks had a negative impact on consistent adherence to hand washing 660 , use of electronic monitoring and voice prompts to remind healthcare workers to perform hand hygiene, and improving accessibility to hand hygiene products, increased adherence and contributed to a decrease in HAIs in one study 661 . More information is needed regarding how technology might improve adherence. Improving adherence to infection control practices requires a multifaceted approach that incorporates continuous assessment of both the individual and the work environment 559,561 . Using several behavioral theories, Kretzer and Larson concluded that a single intervention (e.g., a handwashing campaign or putting up new posters about transmission precautions) would likely be ineffective in improving healthcare personnel adherence 662 . Improvement requires that the organizational leadership make prevention an institutional priority and integrate infection control practices into the organization's safety culture 561 . A recent review of the literature concluded that variations in organizational factors (e.g., safety climate, policies and procedures, education and training) and individual factors (e.g., knowledge, perceptions of risk, past experience) were determinants of adherence to infection control guidelines for protection against SARS and other respiratory pathogens 257 .\n# II.B. Surveillance for healthcare-associated infections (HAIs)\nSurveillance is an essential tool for case-finding of single patients or clusters of patients who are infected or colonized with epidemiologically important organisms (e.g., susceptible bacteria such as S. aureus, S. pyogenes [Group A streptococcus] or Enterobacter-Klebsiella spp; MRSA, VRE, and other MDROs; C. difficile; RSV; influenza virus) for which transmission-based precautions may be required. Surveillance is defined as the ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health 663 . The work of Ignaz Semmelweis that described the role of person-to-person transmission in puerperal sepsis is the earliest example of the use of surveillance data to reduce transmission of infectious agents 664 . Surveillance of both process measures and the infection rates to which they are linked are important for evaluating the effectiveness of infection prevention efforts and identifying indications for change 555,[665][666][667][668] .\nThe Study on the Efficacy of Nosocomial Infection Control (SENIC) found that different combinations of infection control practices resulted in reduced rates of nosocomial surgical site infections, pneumonia, urinary tract infections, and bacteremia in acute care hospitals 566 ; however, surveillance was the only component essential for reducing all four types of HAIs. Although a similar study has not been conducted in other healthcare settings, a role for surveillance and the need for novel strategies have been described in LTCFs 398,434,669,670 and in home care [470][471][472][473] . The essential elements of a surveillance system are: 1) standardized definitions; 2) identification of patient populations at risk for infection; 3) statistical analysis (e.g. risk-adjustment, calculation of rates using appropriate denominators, trend analysis using methods such as statistical process control charts); and 4) feedback of results to the primary caregivers [671][672][673][674][675][676] . Data gathered through surveillance of high-risk populations, device use, procedures, and/or facility locations (e.g., ICUs) are useful for detecting transmission trends [671][672][673] . Identification of clusters of infections should be followed by a systematic epidemiologic investigation to determine commonalities in persons, places, and time; and guide implementation of interventions and evaluation of the effectiveness of those interventions.\nTargeted surveillance based on the highest risk areas or patients has been preferred over facility-wide surveillance for the most effective use of resources 673, 676 . However, surveillance for certain epidemiologically important organisms may need to be facility-wide. Surveillance methods will continue to evolve as healthcare delivery systems change 392,677 and user-friendly electronic tools become more widely available for electronic tracking and trend analysis 674,678,679 . Individuals with experience in healthcare epidemiology and infection control should be involved in selecting software packages for data aggregation and analysis to assure that the need for efficient and accurate HAI surveillance will be met. Effective surveillance is increasingly important as legislation requiring public reporting of HAI rates is passed and states work to develop effective systems to support such legislation 680 .\n# II.C. Education of HCWs, patients, and families\nEducation and training of healthcare personnel are a prerequisite for ensuring that policies and procedures for Standard and Transmission-Based Precautions are understood and practiced. Understanding the scientific rationale for the precautions will allow HCWs to apply procedures correctly, as well as safely modify precautions based on changing requirements, resources, or healthcare settings 14,655,[681][682][683][684][685][686][687][688] . In one study, the likelihood of HCWs developing SARS was strongly associated with less than 2 hours of infection control training and lack of understanding of infection control procedures 689 . Education about the important role of vaccines (e.g., influenza, measles, varicella, pertussis, pneumococcal) in protecting healthcare personnel, their patients, and family members can help improve vaccination rates [690][691][692][693] . Patients, family members, and visitors can be partners in preventing transmission of infections in healthcare settings 9,42,[709][710][711] . Information about Standard Precautions, especially hand hygiene, Respiratory Hygiene/Cough Etiquette, vaccination (especially against influenza) and other routine infection prevention strategies may be incorporated into patient information materials that are provided upon admission to the healthcare facility. Additional information about Transmission-Based Precautions is best provided at the time they are initiated. Fact sheets, pamphlets, and other printed material may include information on the rationale for the additional precautions, risks to household members, room assignment for Transmission-Based Precautions purposes, explanation about the use of personal protective equipment by HCWs, and directions for use of such equipment by family members and visitors. Such information may be particularly helpful in the home environment where household members often have primary responsibility for adherence to recommended infection control practices. Healthcare personnel must be available and prepared to explain this material and answer questions as needed.\n# II.D. Hand hygiene\nHand hygiene has been cited frequently as the single most important practice to reduce the transmission of infectious agents in healthcare settings 559,712,713 and is an essential element of Standard Precautions. The term \"hand hygiene\" includes both handwashing with either plain or antiseptic-containing soap and water, and use of alcohol-based products (gels, rinses, foams) that do not require the use of water. In the absence of visible soiling of hands, approved alcoholbased products for hand disinfection are preferred over antimicrobial or plain soap and water because of their superior microbiocidal activity, reduced drying of the skin, and convenience 559 . Improved hand hygiene practices have been associated with a sustained decrease in the incidence of MRSA and VRE infections primarily in the ICU 561,562,[714][715][716][717] . The scientific rationale, indications, methods, and products for hand hygiene are summarized in other publications 559, 717 .\nThe effectiveness of hand hygiene can be reduced by the type and length of fingernails 559,718,719 . Individuals wearing artifical nails have been shown to harbor more pathogenic organisms, especially gram negative bacilli and yeasts, on the nails and in the subungual area than those with native nails 720,721 . In 2002, CDC/HICPAC recommended (Category IA) that artificial fingernails and extenders not be worn by healthcare personnel who have contact with high-risk patients (e.g., those in ICUs, ORs) due to the association with outbreaks of gramnegative bacillus and candidal infections as confirmed by molecular typing of isolates 30,31,559,[722][723][724][725] .The need to restrict the wearing of artificial fingernails by all healthcare personnel who provide direct patient care or by healthcare personnel who have contact with other high risk groups (e.g., oncology, cystic fibrosis patients), has not been studied, but has been recommended by some experts 20 . At this time such decisions are at the discretion of an individual facility's infection control program. There is less evidence that jewelry affects the quality of hand hygiene. Although hand contamination with potential pathogens is increased with ring-wearing 559,726 , no studies have related this practice to HCW-to-patient transmission of pathogens.\n# II.E. Personal protective equipment (PPE) for healthcare personnel\nPPE refers to a variety of barriers and respirators used alone or in combination to protect mucous membranes, airways, skin, and clothing from contact with infectious agents. The selection of PPE is based on the nature of the patient interaction and/or the likely mode(s) of transmission. Guidance on the use of PPE is discussed in Part III. A suggested procedure for donning and removing PPE that will prevent skin or clothing contamination is presented in the Figure.\nDesignated containers for used disposable or reusable PPE should be placed in a location that is convenient to the site of removal to facilitate disposal and containment of contaminated materials. Hand hygiene is always the final step after removing and disposing of PPE. The following sections highlight the primary uses and methods for selecting this equipment.\n# II.E.1. Gloves\nGloves are used to prevent contamination of healthcare personnel hands when 1) anticipating direct contact with blood or body fluids, mucous membranes, nonintact skin and other potentially infectious material; 2) having direct contact with patients who are colonized or infected with pathogens transmitted by the contact route e.g., VRE, MRSA, RSV 559,727,728 ; or 3) handling or touching visibly or potentially contaminated patient care equipment and environmental surfaces 72,73,559 . Gloves can protect both patients and healthcare personnel from exposure to infectious material that may be carried on hands 73 . The extent to which gloves will protect healthcare personnel from transmission of bloodborne pathogens (e.g., HIV, HBV, HCV) following a needlestick or other pucture that penetrates the glove barrier has not been determined. Although gloves may reduce the volume of blood on the external surface of a sharp by 46-86% 729 , the residual blood in the lumen of a hollowbore needle would not be affected; therefore, the effect on transmission risk is unknown. Gloves manufactured for healthcare purposes are subject to FDA evaluation and clearance 730 . Nonsterile disposable medical gloves made of a variety of materials (e.g., latex, vinyl, nitrile) are available for routine patient care 731 . The selection of glove type for non-surgical use is based on a number of factors, including the task that is to be performed, anticipated contact with chemicals and chemotherapeutic agents, latex sensitivity, sizing, and facility policies for creating a latex-free environment 17,[732][733][734] . For contact with blood and body fluids during non-surgical patient care, a single pair of gloves generally provides adequate barrier protection 734 . However, there is considerable variability among gloves; both the quality of the manufacturing process and type of material influence their barrier effectiveness 735 . While there is little difference in the barrier properties of unused intact gloves 736 , studies have shown repeatedly that vinyl gloves have higher failure rates than latex or nitrile gloves when tested under simulated and actual clinical conditions 731,[735][736][737][738] . For this reason either latex or nitrile gloves are preferable for clinical procedures that require manual dexterity and/or will involve more than brief patient contact. It may be necessary to stock gloves in several sizes. Heavier, reusable utility gloves are indicated for non-patient care activities, such as handling or cleaning contaminated equipment or surfaces 11, 14, . During patient care, transmission of infectious organisms can be reduced by adhering to the principles of working from \"clean\" to \"dirty\", and confining or limiting contamination to surfaces that are directly needed for patient care. It may be necessary to change gloves during the care of a single patient to prevent cross-contamination of body sites 559,740 . It also may be necessary to change gloves if the patient interaction also involves touching portable computer keyboards or other mobile equipment that is transported from room to room. Discarding gloves between patients is necessary to prevent transmission of infectious material. Gloves must not be washed for subsequent reuse because microorganisms cannot be removed reliably from glove surfaces and continued glove integrity cannot be ensured. Furthermore, glove reuse has been associated with transmission of MRSA and gram-negative bacilli [741][742][743] . When gloves are worn in combination with other PPE, they are put on last. Gloves that fit snugly around the wrist are preferred for use with an isolation gown because they will cover the gown cuff and provide a more reliable continuous barrier for the arms, wrists, and hands. Gloves that are removed properly will prevent hand contamination (Figure). Hand hygiene following glove removal further ensures that the hands will not carry potentially infectious material that might have penetrated through unrecognized tears or that could contaminate the hands during glove removal 559,728,741 .\n# II.E.2. Isolation gowns\nIsolation gowns are used as specified by Standard and Transmission-Based Precautions, to protect the HCW's arms and exposed body areas and prevent contamination of clothing with blood, body fluids, and other potentially infectious material 24,88,262,[744][745][746] . The need for and type of isolation gown selected is based on the nature of the patient interaction, including the anticipated degree of contact with infectious material and potential for blood and body fluid penetration of the barrier. The wearing of isolation gowns and other protective apparel is mandated by the OSHA Bloodborne Pathogens Standard 739 . Clinical and laboratory coats or jackets worn over personal clothing for comfort and/or purposes of identity are not considered PPE. When applying Standard Precautions, an isolation gown is worn only if contact with blood or body fluid is anticipated. However, when Contact Precautions are used (i.e., to prevent transmission of an infectious agent that is not interrupted by Standard Precautions alone and that is associated with environmental contamination), donning of both gown and gloves upon room entry is indicated to address unintentional contact with contaminated environmental surfaces 54,72,73,88 . The routine donning of isolation gowns upon entry into an intensive care unit or other high-risk area does not prevent or influence potential colonization or infection of patients in those areas 365,[747][748][749][750] .\nIsolation gowns are always worn in combination with gloves, and with other PPE when indicated. Gowns are usually the first piece of PPE to be donned. Full coverage of the arms and body front, from neck to the mid-thigh or below will ensure that clothing and exposed upper body areas are protected. Several gown sizes should be available in a healthcare facility to ensure appropriate coverage for staff members. Isolation gowns should be removed before leaving the patient care area to prevent possible contamination of the environment outside the patient's room. Isolation gowns should be removed in a manner that prevents contamination of clothing or skin (Figure). The outer, \"contaminated\", side of the gown is turned inward and rolled into a bundle, and then discarded into a designated container for waste or linen to contain contamination.\n# II.E.3. Face protection: masks, goggles, face shields\nII.E.3.a. Masks Masks are used for three primary purposes in healthcare settings: 1) placed on healthcare personnel to protect them from contact with infectious material from patients e.g., respiratory secretions and sprays of blood or body fluids, consistent with Standard Precautions and Droplet Precautions; 2) placed on healthcare personnel when engaged in procedures requiring sterile technique to protect patients from exposure to infectious agents carried in a healthcare worker's mouth or nose, and 3) placed on coughing patients to limit potential dissemination of infectious respiratory secretions from the patient to others (i.e., Respiratory Hygiene/Cough Etiquette). Masks may be used in combination with goggles to protect the mouth, nose and eyes, or a face shield may be used instead of a mask and goggles, to provide more complete protection for the face, as discussed below. Masks should not be confused with particulate respirators that are used to prevent inhalation of small particles that may contain infectious agents transmitted via the airborne route as described below. The mucous membranes of the mouth, nose, and eyes are susceptible portals of entry for infectious agents, as can be other skin surfaces if skin integrity is compromised (e.g., by acne, dermatitis) 66,[751][752][753][754] . Therefore, use of PPE to protect these body sites is an important component of Standard Precautions. The protective effect of masks for exposed healthcare personnel has been demonstrated 93,113,755,756 . Procedures that generate splashes or sprays of blood, body fluids, secretions, or excretions (e.g., endotracheal suctioning, bronchoscopy, invasive vascular procedures) require either a face shield (disposable or reusable) or mask and goggles 93-95, 96 , 113, 115, 262, 739, 757 .The wearing of masks, eye protection, and face shields in specified circumstances when blood or body fluid exposures are likely to occur is mandated by the OSHA Bloodborne Pathogens Standard 739 . Appropriate PPE should be selected based on the anticipated level of exposure. Two mask types are available for use in healthcare settings: surgical masks that are cleared by the FDA and required to have fluid-resistant properties, and procedure or isolation masks 758 #2688 . No studies have been published that compare mask types to determine whether one mask type provides better protection than another. Since procedure/isolation masks are not regulated by the FDA, there may be more variability in quality and performance than with surgical masks. Masks come in various shapes (e.g., molded and non-molded), sizes, filtration efficiency, and method of attachment (e.g., ties, elastic, ear loops). Healthcare facilities may find that different types of masks are needed to meet individual healthcare personnel needs.\n# II.E.3.b. Goggles, face shields\nGuidance on eye protection for infection control has been published 759 . The eye protection chosen for specific work situations (e.g., goggles or face shield) depends upon the circumstances of exposure, other PPE used, and personal vision needs. Personal eyeglasses and contact lenses are NOT considered adequate eye protection (www.cdc.gov/niosh/topics/eye/eye-infectious.html). NIOSH states that, eye protection must be comfortable, allow for sufficient peripheral vision, and must be adjustable to ensure a secure fit. It may be necessary to provide several different types, styles, and sizes of protective equipment. Indirectly-vented goggles with a manufacturer's anti-fog coating may provide the most reliable practical eye protection from splashes, sprays, and respiratory droplets from multiple angles. Newer styles of goggles may provide better indirect airflow properties to reduce fogging, as well as better peripheral vision and more size options for fitting goggles to different workers. Many styles of goggles fit adequately over prescription glasses with minimal gaps. While effective as eye protection, goggles do not provide splash or spray protection to other parts of the face. The role of goggles, in addition to a mask, in preventing exposure to infectious agents transmitted via respiratory droplets has been studied only for RSV. Reports published in the mid-1980s demonstrated that eye protection reduced occupational transmission of RSV 760,761 . Whether this was due to preventing hand-eye contact or respiratory droplet-eye contact has not been determined. However, subsequent studies demonstrated that RSV transmission is effectively prevented by adherence to Standard plus Contact Precations and that for this virus routine use of goggles is not necessary 24,116,117,684,762 . It is important to remind healthcare personnel that even if Droplet Precautions are not recommended for a specific respiratory tract pathogen, protection for the eyes, nose and mouth by using a mask and goggles, or face shield alone, is necessary when it is likely that there will be a splash or spray of any respiratory secretions or other body fluids as defined in Standard Precautions Disposable or non-disposable face shields may be used as an alternative to goggles 759 . As compared with goggles, a face shield can provide protection to other facial areas in addition to the eyes. Face shields extending from chin to crown provide better face and eye protection from splashes and sprays; face shields that wrap around the sides may reduce splashes around the edge of the shield. Removal of a face shield, goggles and mask can be performed safely after gloves have been removed, and hand hygiene performed. The ties, ear pieces and/or headband used to secure the equipment to the head are considered \"clean\" and therefore safe to touch with bare hands. The front of a mask, goggles and face shield are considered contaminated (Figure ).\n# II.E.4. Respiratory protection\nThe subject of respiratory protection as it applies to preventing transmission of airborne infectious agents, including the need for and frequency of fit-testing is under scientific review and was the subject of a CDC workshop in 2004 763 . Respiratory protection currently requires the use of a respirator with N95 or higher filtration to prevent inhalation of infectious particles. Information about respirators and respiratory protection programs is summarized in the Guideline for Preventing Transmission of Mycobacterium tuberculosis in Health-care Settings, 2005 (CDC.MMWR 2005; 54: RR-17 12 ). Respiratory protection is broadly regulated by OSHA under the general industry standard for respiratory protection (29CFR1910.134) 764 which requires that U.S. employers in all employment settings implement a program to protect employees from inhalation of toxic materials. OSHA program components include medical clearance to wear a respirator; provision and use of appropriate respirators, including fit-tested NIOSH-certified N95 and higher particulate filtering respirators; education on respirator use and periodic re-evaluation of the respiratory protection program. When selecting particulate respirators, models with inherently good fit characteristics (i.e., those expected to provide protection factors of 10 or more to 95% of wearers) are preferred and could theoretically relieve the need for fit testing 765,766 . Issues pertaining to respiratory protection remain the subject of ongoing debate. Information on various types of respirators may be found at www.cdc.gov/niosh/npptl/respirators/respsars.html and in published studies 765,767,768 . A user-seal check (formerly called a \"fit check\") should be performed by the wearer of a respirator each time a respirator is donned to minimize air leakage around the facepiece 769 . The optimal frequency of fit-testng has not been determined; re-testing may be indicated if there is a change in facial features of the wearer, onset of a medical condition that would affect respiratory function in the wearer, or a change in the model or size of the initially assigned respirator 12 . Respiratory protection was first recommended for protection of preventing U.S. healthcare personnel from exposure to M. tuberculosis in 1989. That recommendation has been maintained in two successive revisions of the Guidelines for Prevention of Transmission of Tuberculosis in Hospitals and other Healthcare Settings 12,126 . The incremental benefit from respirator use, in addition to administrative and engineering controls (i.e., AIIRs, early recognition of patients likely to have tuberculosis and prompt placement in an AIIR, and maintenance of a patient with suspected tuberculosis in an AIIR until no longer infectious), for preventing transmission of airborne infectious agents (e.g., M. tuberculosis) is undetermined. Although some studies have demonstrated effective prevention of M. tuberculosis transmission in hospitals where surgical masks, instead of respirators, were used in conjunction with other administrative and engineering controls 637,770,771 , CDC currently recommends N95 or higher level respirators for personnel exposed to patients with suspected or confirmed tuberculosis. Currently this is also true for other diseases that could be transmitted through the airborne route, including SARS 262 and smallpox 108,129,772 , until inhalational transmission is better defined or healthcare-specific protective equipment more suitable for for preventing infection are developed. Respirators are also currently recommended to be worn during the performance of aerosol-generating procedures (e.g., intubation, bronchoscopy, suctioning) on patients withSARS Co-V infection, avian influenza and pandemic influenza (See Appendix A). Although Airborne Precautions are recommended for preventing airborne transmission of measles and varicella-zoster viruses, there are no data upon which to base a recommendation for respiratory protection to protect susceptible personnel against these two infections; transmission of varicella-zoster virus has been prevented among pediatric patients using negative pressure isolation alone 773 . Whether respiratory protection (i.e., wearing a particulate respirator) would enhance protection from these viruses has not been studied. Since the majority of healthcare personnel have natural or acquired immunity to these viruses, only immune personnel generally care for patients with these infections [774][775][776][777] . Although there is no evidence to suggest that masks are not adequate to protect healthcare personnel in these settings, for purposes of consistency and simplicity, or because of difficulties in ascertaining immunity, some facilities may require the use of respirators for entry into all AIIRs, regardless of the specific infectious agent.\nProcedures for safe removal of respirators are provided (Figure). In some healthcare settings, particulate respirators used to provide care for patients with M. tuberculosis are reused by the same HCW. This is an acceptable practice providing the respirator is not damaged or soiled, the fit is not compromised by change in shape, and the respirator has not been contaminated with blood or body fluids. There are no data on which to base a recommendation for the length of time a respirator may be reused.\n# II.F. Safe work practices to prevent HCW exposure to bloodborne pathogens\n\n# II.F.1. Prevention of needlesticks and other sharps-related injuries\nInjuries due to needles and other sharps have been associated with transmission of HBV, HCV and HIV to healthcare personnel 778,779 . The prevention of sharps injuries has always been an essential element of Universal and now Standard Precautions 1, 780 . These include measures to handle needles and other sharp devices in a manner that will prevent injury to the user and to others who may encounter the device during or after a procedure. These measures apply to routine patient care and do not address the prevention of sharps injuries and other blood exposures during surgical and other invasive procedures that are addressed elsewhere [781][782][783][784][785] .\nSince 1991, when OSHA first issued its Bloodborne Pathogens Standard to protect healthcare personnel from blood exposure, the focus of regulatory and legislative activity has been on implementing a hierarchy of control measures. This has included focusing attention on removing sharps hazards through the development and use of engineering controls. The federal Needlestick Safety and Prevention Act signed into law in November, 2000 authorized OSHA's revision of its Bloodborne Pathogens Standard to more explicitly require the use of safety-engineered sharp devices 786 . CDC has provided guidance on sharps injury prevention 787,788 , including for the design, implementation and evaluation of a comprehensive sharps injury prevention 789 program .\n# II.F.2. Prevention of mucous membrane contact\nExposure of mucous membranes of the eyes, nose and mouth to blood and body fluids has been associated with the transmission of bloodborne viruses and other infectious agents to healthcare personnel 66,752,754,779 . The prevention of mucous membrane exposures has always been an element of Universal and now Standard Precautions for routine patient care 1, 753 and is subject to OSHA bloodborne pathogen regulations. Safe work practices, in addition to wearing PPE, are used to protect mucous membranes and non-intact skin from contact with potentially infectious material. These include keeping gloved and ungloved hands that are contaminated from touching the mouth, nose, eyes, or face; and positioning patients to direct sprays and splatter away from the face of the caregiver. Careful placement of PPE before patient contact will help avoid the need to make PPE adjustments and possible face or mucous membrane contamination during use. In areas where the need for resuscitation is unpredictable, mouthpieces, pocket resuscitation masks with one-way valves, and other ventilation devices provide an alternative to mouth-to-mouth resuscitation, preventing exposure of the caregiver's nose and mouth to oral and respiratory fluids during the procedure.\n# II.F.2.a. Precautions during aerosol-generating procedures\nThe performance of procedures that can generate small particle aerosols (aerosol-generating procedures), such as bronchoscopy, endotracheal intubation, and open suctioning of the respiratory tract, have been associated with transmission of infectious agents to healthcare personnel, including M. tuberculosis 790 , SARS-CoV 93,94,98 and N. meningitidis 95 . Protection of the eyes, nose and mouth, in addition to gown and gloves, is recommended during performance of these procedures in accordance with Standard Precautions. Use of a particulate respirator is recommended during aerosol-generating procedures when the aerosol is likely to contain M. tuberculosis, SARS-CoV, or avian or pandemic influenza viruses.\n# II.G. Patient placement\n\n# II.G.1. Hospitals and long-term care settings\nOptions for patient placement include single patient rooms, two patient rooms, and multi-bed wards. Of these, single patient rooms are prefered when there is a concern about transmission of an infectious agent. Although some studies have failed to demonstrate the efficacy of single patient rooms to prevent HAIs 791 , other published studies, including one commissioned by the American Institute of Architects and the Facility Guidelines Institute, have documented a beneficial relationship between private rooms and reduction in infectious and noninfectious adverse patient outcomes 792,793 . The AIA notes that private rooms are the trend in hospital planning and design. However, most hospitals and long-term care facilities have multi-bed rooms and must consider many competing priorities when determining the appropriate room placement for patients (e.g., reason for admission; patient characteristics, such as age, gender, mental status; staffing needs; family requests; psychosocial factors; reimbursement concerns). In the absence of obvious infectious diseases that require specified airborne infection isolation rooms (e.g., tuberculosis, SARS, chickenpox), the risk of transmission of infectious agents is not always considered when making placement decisions. When there are only a limited number of single-patient rooms, it is prudent to prioritize them for those patients who have conditions that facilitate transmission of infectious material to other patients (e.g., draining wounds, stool incontinence, uncontained secretions) and for those who are at increased risk of acquisition and adverse outcomes resulting from HAI (e.g., immunosuppression, open wounds, indwelling catheters, anticipated prolonged length of stay, total dependence on HCWs for activities of daily living) 15,24,43,430,794,795 . Single-patient rooms are always indicated for patients placed on Airborne Precautions and in a Protective Environment and are preferred for patients who require Contact or Droplet Precautions 23,24,410,435,796,797 . During a suspected or proven outbreak caused by a pathogen whose reservoir is the gastrointestinal tract, use of single patient rooms with private bathrooms limits opportunities for transmission, especially when the colonized or infected patient has poor personal hygiene habits, fecal incontinence, or cannot be expected to assist in maintaining procedures that prevent transmission of microorganisms (e.g., infants, children, and patients with altered mental status or developmental delay). In the absence of continued transmission, it is not necessary to provide a private bathroom for patients colonized or infected with enteric pathogens as long as personal hygiene practices and Standard Precautions, especially hand hygiene and appropriate environmental cleaning, are maintained. Assignment of a dedicated commode to a patient,and cleaning and disinfecting fixtures and equipment that may have fecal contamination (e.g., bathrooms, commodes 798 , scales used for weighing diapers) and the adjacent surfaces with appropriate agents may be especially important when a single-patient room can not be used since environmental contamination with intestinal tract pathogens is likely from both continent and incontinent patients 54,799 . Results of several studies to determine the benefit of a single-patient room to prevent transmission of Clostridium difficile are inconclusive 167,[800][801][802] . Some studies have shown that being in the same room with a colonized or infected patient is not necessarily a risk factor for transmission 791,[803][804][805] . However, for children, the risk of healthcare-associated diarrhea is increased with the increased number of patients per room 806 . Thus, patient factors are important determinants of infection transmission risks, and the need for a single-patient room and/or private bathroom for any patient is best determined on a case-by-case basis. Cohorting is the practice of grouping together patients who are colonized or infected with the same organism to confine their care to one area and prevent contact with other patients. Cohorts are created based on clinical diagnosis, microbiologic confirmation when available, epidemiology, and mode of transmission of the infectious agent. It is generally preferred not to place severely immunosuppressed patients in rooms with other patients. Cohorting has been used extensively for managing outbreaks of MDROs including MRSA 22,807 811 ; RSV 812,813 ; adenovirus keratoconjunctivitis 814 ; rotavirus 815 ; and SARS 816 . Modeling studies provide additional support for cohorting patients to control outbreaks Talon [817][818][819] . However, cohorting often is implemented only after routine infection control measures have failed to control an outbreak. Assigning or cohorting healthcare personnel to care only for patients infected or colonized with a single target pathogen limits further transmission of the target pathogen to uninfected patients 740,819 but is difficult to achieve in the face of current staffing shortages in hospitals 583 and residential healthcare sites [820][821][822] . However, when continued transmission is occurring after implementing routine infection control measures and creating patient cohorts, cohorting of healthcare personnel may be beneficial.\nDuring the seasons when RSV, human metapneumovirus 823 , parainfluenza, influenza, other respiratory viruses 824 , and rotavirus are circulating in the community, cohorting based on the presenting clinical syndrome is often a priority in facilities that care for infants and young children 825 . For example, during the respiratory virus season, infants may be cohorted based soley on the clinical diagnosis of bronchiolitis due to the logistical difficulties and costs associated with requiring microbiologic confirmation prior to room placement, and the predominance of RSV during most of the season. However, when available, single patient rooms are always preferred since a common clinical presentation (e.g., bronchiolitis), can be caused by more than one infectious agent 823,824,826 . Furthermore, the inability of infants and children to contain body fluids, and the close physical contact that occurs during their care, increases infection transmission risks for patients and personnel in this setting 24,795 .\n# II.G.2. Ambulatory settings\nPatients actively infected with or incubating transmissible infectious diseases are seen frequently in ambulatory settings (e.g., outpatient clinics, physicians' offices, emergency departments) and potentially expose healthcare personnel and other patients, family members and visitors 21,34,127,135,142,827 . In response to the global outbreak of SARS in 2003 and in preparation for pandemic influenza, healthcare providers working in outpatient settings are urged to implement source containment measures (e.g., asking couging patients to wear a surgical mask or cover their coughs with tissues) to prevent transmission of respiratory infections, beginning at the point of initial patient encounter 9, 262, 828 as described below in section III.A.1.a. Signs can be posted at the entrance to facilities or at the reception or registration desk requesting that the patient or individuals accompanying the patient promptly inform the receptionist if there are symptoms of a respiratory infection (e.g., cough, flu-like illness, increased production of respiratory secretions). The presence of diarrhea, skin rash, or known or suspected exposure to a transmissible disease (e.g., measles, pertussis, chickenpox, tuberculosis) also could be added. Placement of potentially infectious patients without delay in an examination room limits the number of exposed individuals, e.g., in the common waiting area.\nIn waiting areas, maintaining a distance between symptomatic and nonsymptomatic patients (e.g., >3 feet), in addition to source control measures, may limit exposures. However, infections transmitted via the airborne route (e.g., M tuberculosis, measles, chickenpox) require additional precautions 12,125,829 . Patients suspected of having such an infection can wear a surgical mask for source containment, if tolerated, and should be placed in an examination room, preferably an AIIR, as soon as possible. If this is not possible, having the patient wear a mask and segregate him/herself from other patients in the waiting area will reduce opportunities to expose others. Since the person(s) accompanying the patient also may be infectious, application of the same infection control precautions may need to be extended to these persons if they are symptomatic 21, 252, 830 . For example, family members accompanying children admitted with suspected M. tuberculosis have been found to have unsuspected pulmonary tuberculosis with cavitary lesions, even when asymptomatic 42,831 . Patients with underlying conditions that increase their susceptibility to infection (e.g., those who are immunocompromised 43,44 or have cystic fibrosis 20 ) require special efforts to protect them from exposures to infected patients in common waiting areas. By informing the receptionist of their infection risk upon arrival, appropriate steps may be taken to further protect them from infection. In some cystic fibrosis clinics, in order to avoid exposure to other patients who could be colonized with B. cepacia, patients have been given beepers upon registration so that they may leave the area and receive notification to return when an examination room becomes available 832 .\n# II.G.3. Home care\nIn home care, the patient placement concerns focus on protecting others in the home from exposure to an infectious household member. For individuals who are especially vulnerable to adverse outcomes associated with certain infections, it may be beneficial to either remove them from the home or segregate them within the home. Persons who are not part of the household may need to be prohibited from visiting during the period of infectivity. For example, if a patient with pulmonary tuberculosis is contagious and being cared for at home, very young children (<4 years of age) 833 and immunocompromised persons who have not yet been infected should be removed or excluded from the household. During the SARS outbreak of 2003, segregation of infected persons during the communicable phase of the illness was beneficial in preventing household transmission 249,834 .\n# II.H. Transport of patients\nSeveral principles are used to guide transport of patients requiring Transmission-Based Precautions. In the inpatient and residential settings these include 1) limiting transport of such patients to essential purposes, such as diagnostic and therapeutic procedures that cannot be performed in the patient's room; 2) when transport is necessary, using appropriate barriers on the patient (e.g., mask, gown, wrapping in sheets or use of impervious dressings to cover the affected area(s) when infectious skin lesions or drainage are present, consistent with the route and risk of transmission; 3) notifying healthcare personnel in the receiving area of the impending arrival of the patient and of the precautions necessary to prevent transmission; and 4) for patients being transported outside the facility, informing the receiving facility and the medi-van or emergency vehicle personnel in advance about the type of Transmission-Based Precautions being used. For tuberculosis, additional precautions may be needed in a small shared air space such as in an ambulance 12 .\n# II.I. Environmental measures\nCleaning and disinfecting non-critical surfaces in patient-care areas are part of Standard Precautions. In general, these procedures do not need to be changed for patients on Transmission-Based Precautions. The cleaning and disinfection of all patient-care areas is important for frequently touched surfaces, especially those closest to the patient, that are most likely to be contaminated (e.g., bedrails, bedside tables, commodes, doorknobs, sinks, surfaces and equipment in close proximity to the patient) 11, 72,73,835 . The frequency or intensity of cleaning may need to change based on the patient's level of hygiene and the degree of environmental contamination and for certain for infectious agents whose reservoir is the intestinal tract 54 . This may be especially true in LTCFs and pediatric facilities where patients with stool and urine incontinence are encountered more frequently. Also, increased frequency of cleaning may be needed in a Protective Environment to minimize dust accumulation 11 . Special recommendations for cleaning and disinfecting environmental surfaces in dialysis centers have been published 18 . In all healthcare settings, administrative, staffing and scheduling activities should prioritize the proper cleaning and disinfection of surfaces that could be implicated in transmission. During a suspected or proven outbreak where an environmental reservoir is suspected, routine cleaning procedures should be reviewed, and the need for additional trained cleaning staff should be assessed. Adherence should be monitored and reinforced to promote consistent and correct cleaning is performed.\nEPA-registered disinfectants or detergents/disinfectants that best meet the overall needs of the healthcare facility for routine cleaning and disinfection should be selected 11,836 . In general, use of the existing facility detergent/disinfectant according to the manufacturer's recommendations for amount, dilution, and contact time is sufficient to remove pathogens from surfaces of rooms where colonized or infected individuals were housed. This includes those pathogens that are resistant to multiple classes of antimicrobial agents (e.g., C. difficile, VRE, MRSA, MDR-GNB 11, 24,88,435,746,796,837 ). Most often, environmental reservoirs of pathogens during outbreaks are related to a failure to follow recommended procedures for cleaning and disinfection rather than the specific cleaning and disinfectant agents used [838][839][840][841] . Certain pathogens (e.g., rotavirus, noroviruses, C. difficile) may be resistant to some routinely used hospital disinfectants 275,292,[842][843][844][845][846][847] .The role of specific disinfectants in limiting transmission of rotavirus has been demonstrated experimentally 842 . Also, since C. difficile may display increased levels of spore production when exposed to non-chlorine-based cleaning agents, and the spores are more resistant than vegetative cells to commonly used surface disinfectants, some investigators have recommended the use of a 1:10 dilution of 5.25% sodium hypochlorite (household bleach) and water for routine environmental disinfection of rooms of patients with C. difficile when there is continued transmission 844,848 . In one study, the use of a hypochlorite solution was associated with a decrease in rates of C. difficile infections 847 . The need to change disinfectants based on the presence of these organisms can be determined in consultation with the infection control committee 11, 847,848 . Detailed recommendations for disinfection and sterilization of surfaces and medical equipment that have been in contact with prion-containing tissue or high risk body fluids, and for cleaning of blood and body substance spills, are available in the Guidelines for Environmental Infection Control in Health-Care Facilities 11 and in the Guideline for Disinfection and Sterilization 848 .\n# II.J. Patient care equipment and instruments/devices\nMedical equipment and instruments/devices must be cleaned and maintained according to the manufacturers' instructions to prevent patient-to-patient transmission of infectious agents 86,87,325,849 . Cleaning to remove organic material must always precede high level disinfection and sterilization of critical and semi-critical instruments and devices because residual proteinacous material reduces the effectiveness of the disinfection and sterilization processes 836,848 . Noncritical equipment, such as commodes, intravenous pumps, and ventilators, must be thoroughly cleaned and disinfected before use on another patient. All such equipment and devices should be handled in a manner that will prevent HCW and environmental contact with potentially infectious material. It is important to include computers and personal digital assistants (PDAs) used in patient care in policies for cleaning and disinfection of non-critical items. The literature on contamination of computers with pathogens has been summarized 850 and two reports have linked computer contamination to colonization and infections in patients 851,852 . Although keyboard covers and washable keyboards that can be easily disinfected are in use, the infection control benefit of those items and optimal management have not been determined.\nIn all healthcare settings, providing patients who are on Transmission-Based Precautions with dedicated noncritical medical equipment (e.g., stethoscope, blood pressure cuff, electronic thermometer) has been beneficial for preventing transmission 74,89,740,853,854 . When this is not possible, disinfection after use is recommended. Consult other guidelines for detailed guidance in developing specific protocols for cleaning and reprocessing medical equipment and patient care items in both routine and special circumstances 11,14,18,20,740,836,848 . In home care, it is preferable to remove visible blood or body fluids from durable medical equipment before it leaves the home. Equipment can be cleaned on-site using a detergent/disinfectant and, when possible, should be placed in a single plastic bag for transport to the reprocessing location 20,739 .\n# II.K. Textiles and laundry\nSoiled textiles, including bedding, towels, and patient or resident clothing may be contaminated with pathogenic microorganisms. However, the risk of disease transmission is negligible if they are handled, transported, and laundered in a safe manner 11,855,856 . Key principles for handling soiled laundry are 1) not shaking the items or handling them in any way that may aerosolize infectious agents; 2) avoiding contact of one's body and personal clothing with the soiled items being handled; and 3) containing soiled items in a laundry bag or designated bin. When laundry chutes are used, they must be maintained to minimize dispersion of aerosols from contaminated items 11 . The methods for handling, transporting, and laundering soiled textiles are determined by organizational policy and any applicable regulations 739 ; guidance is provided in the Guidelines for Environmental Infection Control 11 . Rather than rigid rules and regulations, hygienic and common sense storage and processing of clean textiles is recommended 11,857 . When laundering occurs outside of a healthcare facility, the clean items must be packaged or completely covered and placed in an enclosed space during transport to prevent contamination with outside air or construction dust that could contain infectious fungal spores that are a risk for immunocompromised patients 11 .\nInstitutions are required to launder garments used as personal protective equipment and uniforms visibly soiled with blood or infective material 739 . There are few data to determine the safety of home laundering of HCW uniforms, but no increase in infection rates was observed in the one published study 858 and no pathogens were recovered from home-or hospital-laundered scrubs in another study 859 . In the home, textiles and laundry from patients with potentially transmissible infectious pathogens do not require special handling or separate laundering, and may be washed with warm water and detergent 11, 858,859 .\n# II.L. Solid waste\nThe management of solid waste emanating from the healthcare environment is subject to federal and state regulations for medical and non-medical waste 860,861 . No additional precautions are needed for non-medical solid waste that is being removed from rooms of patients on Transmission-Based Precautions. Solid waste may be contained in a single bag (as compared to using two bags) of sufficient strength. 862 .\n# II.M. Dishware and eating utensils\nThe combination of hot water and detergents used in dishwashers is sufficient to decontaminate dishware and eating utensils. Therefore, no special precautions are needed for dishware (e.g., dishes, glasses, cups) or eating utensils; reusable dishware and utensils may be used for patients requiring Transmission-Based Precautions. In the home and other communal settings, eating utensils and drinking vessels that are being used should not be shared, consistent with principles of good personal hygiene and for the purpose of preventing transmission of respiratory viruses, Herpes simplex virus, and infectious agents that infect the gastrointestinal tract and are transmitted by the fecal/oral route (e.g., hepatitis A virus, noroviruses). If adequate resources for cleaning utensils and dishes are not available, disposable products may be used.\n# II.N. Adjunctive measures\nImportant adjunctive measures that are not considered primary components of programs to prevent transmission of infectious agents, but improve the effectiveness of such programs, include 1) antimicrobial management programs; 2) postexposure chemoprophylaxis with antiviral or antibacterial agents; 3) vaccines used both for pre and postexposure prevention; and 4) screening and restricting visitors with signs of transmissible infections. Detailed discussion of judicious use of antimicrobial agents is beyond the scope of this document; however the topic is addressed in the MDRO section (Management of Multidrug-Resistant Organisms in Healthcare Settings 2006. www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf).\n# II.N.1. Chemoprophylaxis\nAntimicrobial agents and topical antiseptics may be used to prevent infection and potential outbreaks of selected agents. Infections for which postexposure chemoprophylaxis is recommended under defined conditions include B. pertussis 17,863 , N. meningitidis 864 , B. anthracis after environmental exposure to aeosolizable material 865 , influenza virus 611 , HIV 866 , and group A streptococcus 160 . Orally administered antimicrobials may also be used under defined circumstances for MRSA decolonization of patients or healthcare personnel 867 . Another form of chemoprophylaxis is the use of topical antiseptic agents. For example, triple dye is used routinely on the umbilical cords of term newborns to reduce the risk of colonization, skin infections, and omphalitis caused by S. aureus, including MRSA, and group A streptococcus 868,869 . Extension of the use of triple dye to low birth weight infants in the NICU was one component of a program that controlled one longstanding MRSA outbreak 22 . Topical antiseptics are also used for decolonization of healthcare personnel or selected patients colonized with MRSA, using mupirocin as discussed in the MDRO guideline 870 867, 871-873 .\n# II.N.2. Immunoprophylaxis\nCertain immunizations recommended for susceptible healthcare personnel have decreased the risk of infection and the potential for transmission in healthcare facilities 17,874 . The OSHA mandate that requires employers to offer hepatitis B vaccination to HCWs played a substantial role in the sharp decline in incidence of occupational HBV infection 778,875 . The use of varicella vaccine in healthcare personnel has decreased the need to place susceptible HCWs on administrative leave following exposure to patients with varicella 775 . Also, reports of healthcare-associated transmission of rubella in obstetrical clinics 33,876 and measles in acute care settings 34 demonstrate the importance of immunization of susceptible healthcare personnel against childhood diseases. Many states have requirements for HCW vaccination for measles and rubella in the absence of evidence of immunity. Annual influenza vaccine campaigns targeted to patients and healthcare personnel in LTCFs and acute-care settings have been instrumental in preventing or limiting institutional outbreaks and increasing attention is being directed toward improving influenza vaccination rates in healthcare personnel 35 , 611, 690, 877, 878 , 879 . Transmission of B. pertussis in healthcare facilities has been associated with large and costly outbreaks that include both healthcare personnel and patients 17,36,41,100,683,827,880,881 . HCWs who have close contact with infants with pertussis are at particularly high risk because of waning immunity and, until 2005, the absence of a vaccine that could be used in adults. However, two acellular pertussis vaccines were licensed in the United States in 2005, one for use in individuals aged 11-18 and one for use in ages 10-64 years 882 . Provisional ACIP recommendations at the time of publication of this document include adolescents and adults, especially those with contact with infants < 12 months of age and healthcare personnel with direct patient contact 883 884 . Immunization of children and adults will help prevent the introduction of vaccinepreventable diseases into healthcare settings. The recommended immunization schedule for children is published annually in the January issues of the Morbidity Mortality Weekly Report with interim updates as needed 885,886 . An adult immunization schedule also is available for healthy adults and those with special immunization needs due to high risk medical conditions 887 . Some vaccines are also used for postexposure prophylaxis of susceptible individuals, including varicella 888 , influenza 611 , hepatitis B 778 , and smallpox 225 vaccines 17,874 . In the future, administration of a newly developed S. aureus conjugate vaccine (still under investigation) to selected patients may provide a novel method of preventing healthcare-associated S. aureus, including MRSA, infections in high-risk groups (e.g., hemodialysis patients and candidates for selected surgical procedures) 889,890 . Immune globulin preparations also are used for postexposure prophylaxis of certain infectious agents under specified circumstances (e.g., varicella-zoster virus [VZIG], hepatitis B virus [HBIG], rabies [RIG], measles and hepatitis A virus [IG] 17,833,874 ). The RSV monoclonal antibody preparation, Palivizumab, may have contributed to controlling a nosocomial outbreak of RSV in one NICU , but there is insufficient evidence to support a routine recommendation for its use in this setting 891 .\n# II.N. 3. Management of visitors\n\n# II.N.3.a. Visitors as sources of infection\nVisitors have been identified as the source of several types of HAIs (e.g., pertussis 40,41 , M. tuberculosis 42,892 , influenza, and other respiratory viruses 24,43,44,373 and SARS 21,[252][253][254] ). However, effective methods for visitor screening in healthcare settings have not been studied. Visitor screening is especially important during community outbreaks of infectious diseases and for high risk patient units. Sibling visits are often encouraged in birthing centers, post partum rooms and in pediatric inpatient units, ICUs, and in residential settings for children; in hospital settings, a child visitor should visit only his or her own sibling. Screening of visiting siblings and other children before they are allowed into clinical areas is necessary to prevent the introduction of childhood illnesses and common respiratory infections.\nScreening may be passive through the use of signs to alert family members and visitors with signs and symptoms of communicable diseases not to enter clinical areas. More active screening may include the completion of a screening tool or questionnaire which elicits information related to recent exposures or current symptoms. That information is reviewed by the facility staff and the visitor is either permitted to visit or is excluded 833 . Family and household members visiting pediatric patients with pertussis and tuberculosis may need to be screened for a history of exposure as well as signs and symptoms of current infection. Potentially infectious visitors are excluded until they receive appropriate medical screening, diagnosis, or treatment. If exclusion is not considered to be in the best interest of the patient or family (i.e., primary family members of critically or terminally ill patients), then the symptomatic visitor must wear a mask while in the healthcare facility and remain in the patient's room, avoiding exposure to others, especially in public waiting areas and the cafeteria. Visitor screening is used consistently on HSCT units 15,43 . However, considering the experience during the 2003 SARS outbreaks and the potential for pandemic influenza, developing effective visitor screening systems will be beneficial 9 . Education concerning Respiratory Hygiene/Cough Etiquette is a useful adjunct to visitor screening.\n# II.N.3.b. Use of barrier precautions by visitors\nThe use of gowns, gloves, or masks by visitors in healthcare settings has not been addressed specifically in the scientific literature. Some studies included the use of gowns and gloves by visitors in the control of MDRO's, but did not perform a separate analysis to determine whether their use by visitors had a measurable impact [893][894][895] . Family members or visitors who are providing care or having very close patient contact (e.g., feeding, holding) may have contact with other patients and could contribute to transmission if barrier precautions are not used correctly. Specific recommendations may vary by facility or by unit and should be determined by the level of interaction.\n# Part III: Precautions to Prevent Transmission of Infectious Agents\nThere are two tiers of HICPAC/CDC precautions to prevent transmission of infectious agents, Standard Precautions and Transmission-Based Precautions. Standard Precautions are intended to be applied to the care of all patients in all healthcare settings, regardless of the suspected or confirmed presence of an infectious agent. Implementation of Standard Precautions constitutes the primary strategy for the prevention of healthcare-associated transmission of infectious agents among patients and healthcare personnel. Transmission-Based Precautions are for patients who are known or suspected to be infected or colonized with infectious agents, including certain epidemiologically important pathogens, which require additional control measures to effectively prevent transmission. Since the infecting agent often is not known at the time of admission to a healthcare facility, Transmission-Based Precautions are used empirically, according to the clinical syndrome and the likely etiologic agents at the time, and then modified when the pathogen is identified or a transmissible infectious etiology is ruled out. Examples of this syndromic approach are presented in Table 2. The HICPAC/CDC Guidelines also include recommendations for creating a Protective Environment for allogeneic HSCT patients. The specific elements of Standard and Transmission-Based Precautions are discussed in Part II of this guideline. In Part III, the circumstances in which Standard Precautions, Transmission-Based Precautions, and a Protective Environment are applied are discussed. See Tables 4 and 5 for summaries of the key elements of these sets of precautions III.A. Standard Precautions Standard Precautions combine the major features of Universal Precautions (UP) 780,896 and Body Substance Isolation (BSI) 640 and are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. Standard Precautions include a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which healthcare is delivered (Table 4). These include: hand hygiene; use of gloves, gown, mask, eye protection, or face shield, depending on the anticipated exposure; and safe injection practices. Also, equipment or items in the patient environment likely to have been contaminated with infectious body fluids must be handled in a manner to prevent transmission of infectious agents (e.g. wear gloves for direct contact, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). The application of Standard Precautions during patient care is determined by the nature of the HCW-patient interaction and the extent of anticipated blood, body fluid, or pathogen exposure. For some interactions (e.g., performing venipuncture), only gloves may be needed; during other interactions (e.g., intubation), use of gloves, gown, and face shield or mask and goggles is necessary. Education and training on the principles and rationale for recommended practices are critical elements of Standard Precautions because they facilitate appropriate decision-making and promote adherence when HCWs are faced with new circumstances 655,[681][682][683][684][685][686] . An example of the importance of the use of Standard Precautions is intubation, especially under emergency circumstances when infectious agents may not be suspected, but later are identified (e.g., SARS-CoV, N. meningitides). The application of Standard Precautions is described below and summarized in Table 4. Guidance on donning and removing gloves, gowns and other PPE is presented in the Figure . Standard Precautions are also intended to protect patients by ensuring that healthcare personnel do not carry infectious agents to patients on their hands or via equipment used during patient care.\n# III.A.1. New Elements of Standard Precautions\nInfection control problems that are identified in the course of outbreak investigations often indicate the need for new recommendations or reinforcement of existing infection control recommendations to protect patients. Because such recommendations are considered a standard of care and may not be included in other guidelines, they are added here to Standard Precautions. Three such areas of practice that have been added are: Respiratory Hygiene/Cough Etiquette, safe injection practices, and use of masks for insertion of catheters or injection of material into spinal or epidural spaces via lumbar puncture procedures (e.g., myelogram, spinal or epidural anesthesia). While most elements of Standard Precautions evolved from Universal Precautions that were developed for protection of healthcare personnel, these new elements of Standard Precautions focus on protection of patients.\n# III.A.1.a. Respiratory Hygiene/Cough Etiquette The transmission of SARS-\nCoV in emergency departments by patients and their family members during the widespread SARS outbreaks in 2003 highlighted the need for vigilance and prompt implementation of infection control measures at the first point of encounter within a healthcare setting (e.g., reception and triage areas in emergency departments, outpatient clinics, and physician offices) 21,254,897 . The strategy proposed has been termed Respiratory Hygiene/Cough Etiquette 9,828 and is intended to be incorporated into infection control practices as a new component of Standard Precautions. The strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections, and applies to any person with signs of illness including cough, congestion, rhinorrhea, or increased production of respiratory secretions when entering a healthcare facility 40,41,43 . The term cough etiquette is derived from recommended source control measures for M. tuberculosis 12,126 . The elements of Respiratory Hygiene/Cough Etiquette include 1) education of healthcare facility staff, patients, and visitors; 2) posted signs, in language(s) appropriate to the population served, with instructions to patients and accompanying family members or friends; 3) source control measures (e.g., covering the mouth/nose with a tissue when coughing and prompt disposal of used tissues, using surgical masks on the coughing person when tolerated and appropriate); 4) hand hygiene after contact with respiratory secretions; and 5) spatial separation, ideally >3 feet, of persons with respiratory infections in common waiting areas when possible. Covering sneezes and coughs and placing masks on coughing patients are proven means of source containment that prevent infected persons from dispersing respiratory secretions into the air 107, 145, 898, 899 . Masking may be difficult in some settings, (e.g., pediatrics, in which case, the emphasis by necessity may be on cough etiquette 900 . Physical proximity of <3 feet has been associated with an increased risk for transmission of infections via the droplet route (e.g., N. meningitidis 103 and group A streptococcus 114 and therefore supports the practice of distancing infected persons from others who are not infected. The effectiveness of good hygiene practices, especially hand hygiene, in preventing transmission of viruses and reducing the incidence of respiratory infections both within and outside [901][902][903] healthcare settings is summarized in several reviews 559,717,904 . These measures should be effective in decreasing the risk of transmission of pathogens contained in large respiratory droplets (e.g., influenza virus 23 , adenovirus 111 , B. pertussis 827 and Mycoplasma pneumoniae 112 . Although fever will be present in many respiratory infections, patients with pertussis and mild upper respiratory tract infections are often afebrile. Therefore, the absence of fever does not always exclude a respiratory infection. Patients who have asthma, allergic rhinitis, or chronic obstructive lung disease also may be coughing and sneezing. While these patients often are not infectious, cough etiquette measures are prudent. Healthcare personnel are advised to observe Droplet Precautions (i.e., wear a mask) and hand hygiene when examining and caring for patients with signs and symptoms of a respiratory infection. Healthcare personnel who have a respiratory infection are advised to avoid direct patient contact, especially with high risk patients. If this is not possible, then a mask should be worn while providing patient care.\n# III.A.1.b. Safe Injection Practices\nThe investigation of four large outbreaks of HBV and HCV among patients in ambulatory care facilities in the United States identified a need to define and reinforce safe injection practices 453 . The four outbreaks occurred in a private medical practice, a pain clinic, an endoscopy clinic, and a hematology/oncology clinic. The primary breaches in infection control practice that contributed to these outbreaks were 1) reinsertion of used needles into a multiple-dose vial or solution container (e.g., saline bag) and 2) use of a single needle/syringe to administer intravenous medication to multiple patients. In one of these outbreaks, preparation of medications in the same workspace where used needle/syringes were dismantled also may have been a contributing factor. These and other outbreaks of viral hepatitis could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications 453,454 . These include the use of a sterile, single-use, disposable needle and syringe for each injection given and prevention of contamination of injection equipment and medication.\nWhenever possible, use of single-dose vials is preferred over multiple-dose vials, especially when medications will be administered to multiple patients. Outbreaks related to unsafe injection practices indicate that some healthcare personnel are unaware of, do not understand, or do not adhere to basic principles of infection control and aseptic technique. A survey of US healthcare workers who provide medication through injection found that 1% to 3% reused the same needle and/or syringe on multiple patients 905 . Among the deficiencies identified in recent outbreaks were a lack of oversight of personnel and failure to follow-up on reported breaches in infection control practices in ambulatory settings. Therefore, to ensure that all healthcare workers understand and adhere to recommended practices, principles of infection control and aseptic technique need to be reinforced in training programs and incorporated into institutional polices that are monitored for adherence 454 .\n# III.A.1.c. Infection Control Practices for Special Lumbar Puncture Procedues\nIn 2004, CDC investigated eight cases of post-myelography meningitis that either were reported to CDC or identified through a survey of the Emerging Infections Network of the Infectious Disease Society of America. Blood and/or cerebrospinal fluid of all eight cases yielded streptococcal species consistent with oropharyngeal flora and there were changes in the CSF indices and clinical status indicative of bacterial meningitis. Equipment and products used during these procedures (e.g., contrast media) were excluded as probable sources of contamination. Procedural details available for seven cases determined that antiseptic skin preparations and sterile gloves had been used. However, none of the clinicians wore a face mask, giving rise to the speculation that droplet transmission of oralpharyngeal flora was the most likely explanation for these infections. Bacterial meningitis following myelogram and other spinal procedures (e.g., lumbar puncture, spinal and epidural anesthesia, intrathecal chemotherapy) has been reported previously [906][907][908][909][910][911][912][913][914][915] . As a result, the question of whether face masks should be worn to prevent droplet spread of oral flora during spinal procedures (e.g., myelogram, lumbar puncture, spinal anesthesia) has been debated 916,917 . Face masks are effective in limiting the dispersal of oropharyngeal droplets 918 and are recommended for the placement of central venous catheters 919 . In October 2005, the Healthcare Infection Control Practices Advisory Committee (HICPAC) reviewed the evidence and concluded that there is sufficient experience to warrant the additional protection of a face mask for the individual placing a catheter or injecting material into the spinal or epidural space.\n# III.B. Transmission-Based Precautions\nThere are three categories of Transmission-Based Precautions: Contact Precautions, Droplet Precautions, and Airborne Precautions. Transmission-Based Precautions are used when the route(s) of transmission is (are) not completely interrupted using Standard Precautions alone. For some diseases that have multiple routes of transmission (e.g., SARS), more than one Transmission-Based Precautions category may be used. When used either singly or in combination, they are always used in addition to Standard Precautions. See Appendix A for recommended precautions for specific infections. When Transmission-Based Precautions are indicated, efforts must be made to counteract possible adverse effects on patients (i.e., anxiety, depression and other mood disturbances [920][921][922] , perceptions of stigma 923 , reduced contact with clinical staff [924][925][926] , and increases in preventable adverse events 565 in order to improve acceptance by the patients and adherence by HCWs.\n# III.B.1. Contact Precautions\nContact Precautions are intended to prevent transmission of infectious agents, including epidemiologically important microorganisms, which are spread by direct or indirect contact with the patient or the patient's environment as described in I.B.3.a. The specific agents and circumstance for which Contact Precautions are indicated are found in Appendix A. The application of Contact Precautions for patients infected or colonized with MDROs is described in the 2006 HICPAC/CDC MDRO guideline 927 . Contact Precautions also apply where the presence of excessive wound drainage, fecal incontinence, or other discharges from the body suggest an increased potential for extensive environmental contamination and risk of transmission. A singlepatient room is preferred for patients who require Contact Precautions. When a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (e.g., cohorting, keeping the patient with an existing roommate). In multi-patient rooms, >3 feet spatial separation between beds is advised to reduce the opportunities for inadvertent sharing of items between the infected/colonized patient and other patients. Healthcare personnel caring for patients on Contact Precautions wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. Donning PPE upon room entry and discarding before exiting the patient room is done to contain pathogens, especially those that have been implicated in transmission through environmental contamination (e.g., VRE, C. difficile, noroviruses and other intestinal tract pathogens; RSV) 54,72,73,78,274,275,740 .\n# III.B.2. Droplet Precautions\nDroplet Precautions are intended to prevent transmission of pathogens spread through close respiratory or mucous membrane contact with respiratory secretions as described in I.B.3.b. Because these pathogens do not remain infectious over long distances in a healthcare facility, special air handling and ventilation are not required to prevent droplet transmission. Infectious agents for which Droplet Precautions are indicated are found in Appendix A and include B. pertussis, influenza virus, adenovirus, rhinovirus, N. meningitides, and group A streptococcus (for the first 24 hours of antimicrobial therapy). A single patient room is preferred for patients who require Droplet Precautions. When a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (e.g., cohorting, keeping the patient with an existing roommate). Spatial separation of > 3 feet and drawing the curtain between patient beds is especially important for patients in multi-bed rooms with infections transmitted by the droplet route. Healthcare personnel wear a mask (a respirator is not necessary) for close contact with infectious patient; the mask is generally donned upon room entry. Patients on Droplet Precautions who must be transported outside of the room should wear a mask if tolerated and follow Respiratory Hygiene/Cough Etiquette.\n# III.B.3. Airborne Precautions\nAirborne Precautions prevent transmission of infectious agents that remain infectious over long distances when suspended in the air (e.g., rubeola virus [measles], varicella virus [chickenpox], M. tuberculosis, and possibly SARS-CoV) as described in I.B.3.c and Appendix A. The preferred placement for patients who require Airborne Precautions is in an airborne infection isolation room (AIIR). An AIIR is a single-patient room that is equipped with special air handling and ventilation capacity that meet the American Institute of Architects/Facility Guidelines Institute (AIA/FGI) standards for AIIRs (i.e., monitored negative pressure relative to the surrounding area, 12 air exchanges per hour for new construction and renovation and 6 air exchanges per hour for existing facilities, air exhausted directly to the outside or recirculated through HEPA filtration before return) 12,13 . Some states require the availability of such rooms in hospitals, emergency departments, and nursing homes that care for patients with M. tuberculosis. A respiratory protection program that includes education about use of respirators, fit-testing, and user seal checks is required in any facility with AIIRs. In settings where Airborne Precautions cannot be implemented due to limited engineering resources (e.g., physician offices), masking the patient, placing the patient in a private room (e.g., office examination room) with the door closed, and providing N95 or higher level respirators or masks if respirators are not available for healthcare personnel will reduce the likelihood of airborne transmission until the patient is either transferred to a facility with an AIIR or returned to the home environment, as deemed medically appropriate. Healthcare personnel caring for patients on Airborne Precautions wear a mask or respirator, depending on the disease-specific recommendations (Respiratory Protection II.E.4, Table 2, and Appendix A), that is donned prior to room entry. Whenever possible, non-immune HCWs should not care for patients with vaccine-preventable airborne diseases (e.g., measles, chickenpox, and smallpox).\n# III.C. Syndromic and empiric applications of Transmission-Based Precautions Diagnosis of many infections requires laboratory confirmation.\nSince laboratory tests, especially those that depend on culture techniques, often require two or more days for completion, Transmission-Based Precautions must be implemented while test results are pending based on the clinical presentation and likely pathogens. Use of appropriate Transmission-Based Precautions at the time a patient develops symptoms or signs of transmissible infection, or arrives at a healthcare facility for care, reduces transmission opportunities. While it is not possible to identify prospectively all patients needing Transmission-Based Precautions, certain clinical syndromes and conditions carry a sufficiently high risk to warrant their use empirically while confirmatory tests are pending (Table 2). Infection control professionals are encouraged to modify or adapt this table according to local conditions.\n# III.D. Discontinuation of Transmission-Based Precautions Transmission-\nBased Precautions remain in effect for limited periods of time (i.e., while the risk for transmission of the infectious agent persists or for the duration of the illness (Appendix A). For most infectious diseases, this duration reflects known patterns of persistence and shedding of infectious agents associated with the natural history of the infectious process and its treatment. For some diseases (e.g., pharyngeal or cutaneous diphtheria, RSV), Transmission-Based Precautions remain in effect until culture or antigen-detection test results document eradication of the pathogen and, for RSV, symptomatic disease is resolved. For other diseases, (e.g., M. tuberculosis) state laws and regulations, and healthcare facility policies, may dictate the duration of precautions 12 ). In immunocompromised patients, viral shedding can persist for prolonged periods of time (many weeks to months) and transmission to others may occur during that time; therefore, the duration of contact and/or droplet precautions may be prolonged for many weeks 500,[928][929][930][931][932][933] . The duration of Contact Precautions for patients who are colonized or infected with MDROs remains undefined. MRSA is the only MDRO for which effective decolonization regimens are available 867 . However, carriers of MRSA who have negative nasal cultures after a course of systemic or topical therapy may resume shedding MRSA in the weeks that follow therapy 934,935 . Although early guidelines for VRE suggested discontinuation of Contact Precautions after three stool cultures obtained at weekly intervals proved negative 740 , subsequent experiences have indicated that such screening may fail to detect colonization that can persist for >1 year 27,[936][937][938] . Likewise, available data indicate that colonization with VRE, MRSA 939 , and possibly MDR-GNB, can persist for many months, especially in the presence of severe underlying disease, invasive devices, and recurrent courses of antimicrobial agents. It may be prudent to assume that MDRO carriers are colonized permanently and manage them accordingly. Alternatively, an interval free of hospitalizations, antimicrobial therapy, and invasive devices (e.g., 6 or 12 months) before reculturing patients to document clearance of carriage may be used. Determination of the best strategy awaits the results of additional studies. See the 2006 HICPAC/CDC MDRO guideline 927 for discussion of possible criteria to discontinue Contact Precautions for patients colonized or infected with MDROs.\n# III.E. Application of Transmission-Based Precautions in ambulatory and home care settings Although Transmission-Based Precautions generally\napply in all healthcare settings, exceptions exist. For example, in home care, AIIRs are not available. Furthermore, family members already exposed to diseases such as varicella and tuberculosis would not use masks or respiratory protection, but visiting HCWs would need to use such protection. Similarly, management of patients colonized or infected with MDROs may necessitate Contact Precautions in acute care hospitals and in some LTCFs when there is continued transmission, but the risk of transmission in ambulatory care and home care, has not been defined. Consistent use of Standard Precautions may suffice in these settings, but more information is needed.\n# III.F. Protective Environment\nA Protective Environment is designed for allogeneic HSCT patients to minimize fungal spore counts in the air and reduce the risk of invasive environmental fungal infections (see Table 5 for specifications) 11, [13][14][15] . The need for such controls has been demonstrated in studies of aspergillus outbreaks associated with construction 11,14,15,157,158 . As defined by the American Insitute of Architecture 13 and presented in detail in the Guideline for Environmental Infection Control 2003 11,861 , air quality for HSCT patients is improved through a combination of environmental controls that include 1) HEPA filtration of incoming air; 2) directed room air flow; 3) positive room air pressure relative to the corridor; 4) well-sealed rooms (including sealed walls, floors, ceilings, windows, electrical outlets) to prevent flow of air from the outside; 5) ventilation to provide >12 air changes per hour; 6) strategies to minimize dust (e.g., scrubbable surfaces rather than upholstery 940 and carpet 941 , and routinely cleaning crevices and sprinkler heads); and 7) prohibiting dried and fresh flowers and potted plants in the rooms of HSCT patients. The latter is based on molecular typing studies that have found indistinguishable strains of Aspergillus terreus in patients with hematologic malignancies and in potted plants in the vicinity of the patients [942][943][944] . The desired quality of air may be achieved without incurring the inconvenience or expense of laminar airflow 15,157 . To prevent inhalation of fungal spores during periods when construction, renovation, or other dust-generating activities that may be ongoing in and around the health-care facility, it has been advised that severely immunocompromised patients wear a high-efficiency respiratory-protection device (e.g., an N95 respirator) when they leave the Protective Environment 11, 14,945 ). The use of masks or respirators by HSCT patients when they are outside of the Protective Environment for prevention of environmental fungal infections in the absence of construction has not been evaluated. A Protective Environment does not include the use of barrier precautions beyond those indicated for Standard and Transmission-Based Precautions. No published reports support the benefit of placing solid organ transplants or other immunocompromised patients in a Protective Environment.\n# Part IV:\n\n# Recommendations\nThese recommendations are designed to prevent transmission of infectious agents among patients and healthcare personnel in all settings where healthcare is delivered. As in other CDC/HICPAC guidelines, each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and when possible, economic impact. The CDC/HICPAC system for categorizing recommendations is as follows: Category IA Strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies. Category IB Strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. Category IC Required for implementation, as mandated by federal and/or state regulation or standard. Category II Suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. No recommendation; unresolved issue. Practices for which insufficient evidence or no consensus regarding efficacy exists.\n# I. Administrative Responsibilities\nHealthcare organization administrators should ensure the implementation of recommendations in this section. underlying conditions that predispose to serious adverse outcomes) y Analyze data to identify trends that may indicated increased rates of transmission y Feedback information on trends in the incidence and prevalence of HAIs, probable risk factors, and prevention strategies and their impact to the appropriate healthcare providers, organization administrators, and as required by local and state health authorities III.C. Develop and implement strategies to reduce risks for transmission and evaluate effectiveness 566, 673, 684, 970 963 971 . Category IB III.D. When transmission of epidemiologically-important organisms continues despite implementation and documented adherence to infection prevention and control strategies, obtain consultation from persons knowledgeable in infection control and healthcare epidemiology to review the situation and recommend additional measures for control 566 247 687 . Category IB III.E. Review periodically information on community or regional trends in the incidence and prevalence of epidemiologically-important organisms (e.g., influenza, RSV, pertussis, invasive group A streptococcal disease, MRSA, VRE) (including in other healthcare facilities) that may impact transmission of organisms within the facility 398, 687, 972, 973 974 . Category II\n# IV.\nStandard Precautions Assume that every person is potentially infected or colonized with an organism that could be transmitted in the healthcare setting and apply the following infection control practices during the delivery of health care. IV.A. Hand Hygiene IV.A.1. During the delivery of healthcare, avoid unnecessary touching of surfaces in close proximity to the patient to prevent both contamination of clean hands from environmental surfaces and transmission of pathogens from contaminated hands to surfaces 72, 73 739, 800, 975{CDC, 2001 #970 . Category IB/IC IV.A.2. When hands are visibly dirty, contaminated with proteinaceous material, or visibly soiled with blood or body fluids, wash hands with either a nonantimicrobial soap and water or an antimicrobial soap and water 559 . Category IA IV.A.3. If hands are not visibly soiled, or after removing visible material with nonantimicrobial soap and water, decontaminate hands in the clinical situations described in IV.A.2.a-f. The preferred method of hand decontamination is with an alcohol-based hand rub 562,978 .\nAlternatively, hands may be washed with an antimicrobial soap and water. Frequent use of alcohol-based hand rub immediately following handwashing with nonantimicrobial soap may increase the frequency of dermatitis 559 . Category IB Perform hand hygiene: IV.A.3.a. Before having direct contact with patients 664,979 . Category IB IV.A.3.b. After contact with blood, body fluids or excretions, mucous membranes, nonintact skin, or wound dressings 664 . Category IA IV.A.3.c. After contact with a patient's intact skin (e.g., when taking a pulse or blood pressure or lifting a patient) 167,976,979,980 . Category IB IV.A.3.d. If hands will be moving from a contaminated-body site to a clean-body site during patient care. Category II IV.A.3.e. After contact with inanimate objects (including medical equipment) in the immediate vicinity of the patient 72, 73, 88, 800, 981 982 . Category II IV.A.3.f. After removing gloves 728,741,742 . Category IB IV.A.4. Wash hands with non-antimicrobial soap and water or with antimicrobial soap and water if contact with spores (e.g., C. difficile or Bacillus anthracis) is likely to have occurred. The physical action of washing and rinsing hands under such circumstances is recommended because alcohols, chlorhexidine, iodophors, and other antiseptic agents have poor activity against spores 559,956,983 .\nCategory II IV.A.5.\nDo not wear artificial fingernails or extenders if duties include direct contact with patients at high risk for infection and associated adverse outcomes (e.g., those in ICUs or operating rooms) 30,31,559,[722][723][724] . Category IA IV.A.5.a. Develop an organizational policy on the wearing of non-natural nails by healthcare personnel who have direct contact with patients outside of the groups specified above 984 IV.E.1. Establish policies and procedures for containing, transporting, and handling patient-care equipment and instruments/devices that may be contaminated with blood or body fluids 18,739,975 . Category IB/IC IV.E.2. Remove organic material from critical and semi-critical instrument/devices, using recommended cleaning agents before high level disinfection and sterilization to enable effective disinfection and sterilization processes 836 991, 992 . Category IA IV.E.3. Wear PPE (e.g., gloves, gown), according to the level of anticipated contamination, when handling patient-care equipment and instruments/devices that is visibly soiled or may have been in contact with blood or body fluids 18,739,975 . Category IB/IC IV.F. Care of the environment 11 IV.F.1. Establish policies and procedures for routine and targeted cleaning of environmental surfaces as indicated by the level of patient contact and degree of soiling 11 . Category II IV.F.2.\nClean and disinfect surfaces that are likely to be contaminated with pathogens, including those that are in close proximity to the patient (e.g., bed rails, over bed tables) and frequently-touched surfaces in the patient care environment (e.g., door knobs, surfaces in and surrounding toilets in patients' rooms) on a more frequent schedule compared to that for other surfaces (e.g., horizontal surfaces in waiting rooms) 11 73, 740, 746, 993, 994 72, 800, 835 995 . Category IB IV.F.3.\nUse EPA-registered disinfectants that have microbiocidal (i.e., killing) activity against the pathogens most likely to contaminate the patient-care environment. Use in accordance with manufacturer's instructions 842-844, 956, 996 . Category IB/IC IV.F.3.a. Review the efficacy of in-use disinfectants when evidence of continuing transmission of an infectious agent (e.g., rotavirus, C. difficile, norovirus) may indicate resistance to the in-use product and change to a more effective disinfectant as indicated 275,842,847 . Category II IV.F. 4.\nIn facilities that provide health care to pediatric patients or have waiting areas with child play toys (e.g., obstetric/gynecology offices and clinics), establish policies and procedures for cleaning and disinfecting toys at regular intervals 379 80 . Category IB • Use the following principles in developing this policy and procedures: Category II y Select play toys that can be easily cleaned and disinfected y Do not permit use of stuffed furry toys if they will be shared y Clean and disinfect large stationary toys (e.g., climbing equipment) at least weekly and whenever visibly soiled y If toys are likely to be mouthed, rinse with water after disinfection; alternatively wash in a dishwasher y When a toy requires cleaning and disinfection, do so immediately or store in a designated labeled container separate from toys that are clean and ready for use IV.F.5.\nInclude multi-use electronic equipment in policies and procedures for preventing contamination and for cleaning and disinfection, especially those items that are used by patients, those used during delivery of patient care, and mobile devices that are moved in and out of patient rooms frequently (e.g., daily) 850 851, 852, 997 . Category IB IV.F.5.a. No recommendation for use of removable protective covers or washable keyboards. Unresolved issue IV.G. Textiles and laundry IV.G.1. Handle used textiles and fabrics with minimum agitation to avoid contamination of air, surfaces and persons 739,998,999 . Category IB/IC IV.G.2. If laundry chutes are used, ensure that they are properly designed, maintained, and used in a manner to minimize dispersion of aerosols from contaminated laundry 11, 13, 1000, 1001 . Category IB/IC IV.H. Safe injection practices\nThe following recommendations apply to the use of needles, cannulas that replace needles, and, where applicable intravenous delivery systems 454 IV.H.1. Use aseptic technique to avoid contamination of sterile injection equipment 1002,1003 . Category IA IV.H.2. Do not administer medications from a syringe to multiple patients, even if the needle or cannula on the syringe is changed. Needles, cannulae and syringes are sterile, single-use items; they should not be reused for another patient nor to access a medication or solution that might be used for a subsequent patient 453,919,1004,1005 . Category IA IV.H.3. Use fluid infusion and administration sets (i.e., intravenous bags, tubing and connectors) for one patient only and dispose appropriately after use. Consider a syringe or needle/cannula contaminated once it has been used to enter or connect to a patient's intravenous infusion bag or administration set 453 . Category IB IV.H.4. Use single-dose vials for parenteral medications whenever possible 453 . Category IA IV.H.5. Do not administer medications from single-dose vials or ampules to multiple patients or combine leftover contents for later use 369 453, 1005 . Category IA IV.H.6. If multidose vials must be used, both the needle or cannula and syringe used to access the multidose vial must be sterile 453,1002 . Category IA IV.H.7. Do not keep multidose vials in the immediate patient treatment area and store in accordance with the manufacturer's recommendations; discard if sterility is compromised or questionable 453,1003 . Category IA IV.H.8. Do not use bags or bottles of intravenous solution as a common source of supply for multiple patients 453,1006 . Category IB IV.I. Infection control practices for special lumbar puncture procedures Wear a surgical mask when placing a catheter or injecting material into the spinal canal or subdural space (i.e., during myelograms, lumbar puncture and spinal or epidural anesthesia 906 907-909 910, 911 912-914, 918 1007 . Category IB IV.J. Worker safety Adhere to federal and state requirements for protection of healthcare personnel from exposure to bloodborne pathogens 739 . Category IC\n# V. Transmission-Based Precautions\nV.A. General principles V.A.1.\nIn addition to Standard Precautions, use Transmission-Based Precautions for patients with documented or suspected infection or colonization with highly transmissible or epidemiologically-important pathogens for which additional precautions are needed to prevent transmission (see Appendix A) 24,93,126,141,306,806,1008 regarding patient placement on a case-by-case basis, balancing infection risks to other patients in the room, the presence of risk factors that increase the likelihood of transmission, and the potential adverse psychological impact on the infected or colonized patient 920,921 . Category II V.B.2.c. In ambulatory settings, place patients who require Contact Precautions in an examination room or cubicle as soon as possible 20 . Category II V.B.3.\nUse of personal protective equipment V.B.3.a. Gloves Wear gloves whenever touching the patient's intact skin 24,89,134,559,746,837 or surfaces and articles in close proximity to the patient (e.g., medical equipment, bed rails) 72,73,88,837 . Don gloves upon entry into the room or cubicle.\nCategory IB V.B.3.b. Gowns V.B.3.b.i.\nWear a gown whenever anticipating that clothing will have direct contact with the patient or potentially contaminated environmental surfaces or equipment in close proximity to the patient. Don gown upon entry into the room or cubicle. Remove gown and observe hand hygiene before leaving the patient-care environment 24,88,134,745,837 .\nCategory IB V.B.3.b.ii.\nAfter gown removal, ensure that clothing and skin do not contact potentially contaminated environmental surfaces that could result in possible transfer of microorganism to other patients or environmental surfaces 72,73 . Patient-care equipment and instruments/devices V.B.5.a. Handle patient-care equipment and instruments/devices according to Standard Precautions 739,836 . Category IB/IC V.B.5.b. In acute care hospitals and long-term care and other residential settings, use disposable noncritical patient-care equipment (e.g., blood pressure cuffs) or implement patient-dedicated use of such equipment. If common use of equipment for multiple patients is unavoidable, clean and disinfect such equipment before use on another patient 24,88,796,836,837,854,1016 . Category IB V.B.5.c. In home care settings V.B.5.c.i.\nCategory II V.B.\nLimit the amount of non-disposable patient-care equipment brought into the home of patients on Contact Precautions. Whenever possible, leave patient-care equipment in the home until discharge from home care services. Category II V.B.5.c.ii.\nIf noncritical patient-care equipment (e.g., stethoscope) cannot remain in the home, clean and disinfect items before taking them from the home using a low-to intermediate-level disinfectant. Alternatively, place contaminated reusable items in a plastic bag for transport and subsequent cleaning and disinfection. Category II V.B.5.d. In ambulatory settings, place contaminated reusable noncritical patient-care equipment in a plastic bag for transport to a soiled utility area for reprocessing. Category II V.B.6.\nEnvironmental measures Ensure that rooms of patients on Contact Precautions are prioritized for frequent cleaning and disinfection (e.g., at least daily) with a focus on frequently-touched surfaces (e.g., bed rails, overbed table, bedside commode, lavatory surfaces in patient bathrooms, doorknobs) and equipment in the immediate vicinity of the patient 11,24,88,746,837 . Category IB V.B.7.\nDiscontinue Contact Precautions after signs and symptoms of the infection have resolved or according to pathogen-specific recommendations in Appendix A. Category IB V.C. Droplet Precautions V.C.1. Use Droplet Precautions as recommended in Appendix A for patients known or suspected to be infected with pathogens transmitted by respiratory droplets (i.e., large-particle droplets >5µ in size) that are generated by a patient who is coughing, sneezing or talking 14, 23, Steinberg, 196914, 23, Steinberg, #170814, 23, Steinberg, , 41, 95, 103, 111, 112, 755, 756, 989, 1017 .\nCategory IB V.C.2.\nPatient placement V.C.2.a. In acute care hospitals, place patients who require Droplet Precautions in a single-patient room when available Category II When single-patient rooms are in short supply, apply the following principles for making decisions on patient placement: y Prioritize patients who have excessive cough and sputum production for single-patient room placement Category II y Place together in the same room (cohort) patients who are infected the same pathogen and are suitable roommates 814 816 . Category IB y If it becomes necessary to place patients who require Droplet Precautions in a room with a patient who does not have the same infection: y Avoid placing patients on Droplet Precautions in the same room with patients who have conditions that may increase the risk of adverse outcome from infection or that may facilitate transmission (e.g., those who are immunocompromised, have or have anticipated prolonged lengths of stay). Category II y Ensure that patients are physically separated (i.e., >3 feet apart) from each other. Draw the privacy curtain between beds to minimize opportunities for close contact 103, 104 410 .\nCategory IB y Change protective attire and perform hand hygiene between contact with patients in the same room, regardless of whether one patient or both patients are on Droplet Precautions 741-743, 988, 1014, 1015 . Category IB V.C.2.b. In long-term care and other residential settings, make decisions regarding patient placement on a case-by-case basis after considering infection risks to other patients in the room and available alternatives 410 . Category II V.C.2.c. In ambulatory settings, place patients who require Droplet\nPrecautions in an examination room or cubicle as soon as possible. Instruct patients to follow recommendations for Respiratory Hygiene/Cough Etiquette 447, 448 9, 828 . Category II V.C.3.\nUse of personal protective equipment V.C.3.a. Don a mask upon entry into the patient room or cubicle 14,23,41,103,111,113,115,827 . Category IB V.C. Use Airborne Precautions as recommended in Appendix A for patients known or suspected to be infected with infectious agents transmitted person-to-person by the airborne route (e.g., M tuberculosis 12 , measles 34,122,1020 , chickenpox 123,773,1021 , disseminated herpes zoster 1022 . Category IA/IC V.D.2.\nPatient placement V.D.2.a. In acute care hospitals and long-term care settings, place patients who require Airborne Precautions in an AIIR that has been constructed in accordance with current guidelines [11][12][13] . Category IA/IC V.D.2.a.i.\nProvide at least six (existing facility) or 12 (new construction/renovation) air changes per hour. V.D.2.a.ii.\nDirect exhaust of air to the outside. If it is not possible to exhaust air from an AIIR directly to the outside, the air may be returned to the air-handling system or adjacent spaces if all air is directed through HEPA filters. V.D.2.a.iii. Whenever an AIIR is in use for a patient on Airborne Precautions, monitor air pressure daily with visual indicators (e.g., smoke tubes, flutter strips), regardless of the presence of differential pressure sensing devices (e.g., manometers) 11, 12, 1023, 1024 . V.D.2.a.iv. Keep the AIIR door closed when not required for entry and exit. V.D.2.b. When an AIIR is not available, transfer the patient to a facility that has an available AIIR 12 . Category II V.D.2.c. In the event of an outbreak or exposure involving large numbers of patients who require Airborne Precautions: y Consult infection control professionals before patient placement to determine the safety of alternative room that do not meet engineering requirements for an AIIR. y Place together (cohort) patients who are presumed to have the same infection( based on clinical presentation and diagnosis when known) in areas of the facility that are away from other patients, especially patients who are at increased risk for infection (e.g., immunocompromised patients). y Use temporary portable solutions (e.g., exhaust fan) to create a negative pressure environment in the converted area of the facility. Discharge air directly to the outside,away from people and air intakes, or direct all the air through HEPA filters before it is introduced to other air spaces 12 Category II V.D. Place the patient in an AIIR as soon as possible. If an AIIR is not available, place a surgical mask on the patient and place him/her in an examination room. Once the patient leaves, the room should remain vacant for the appropriate time, generally one hour, to allow for a full exchange of air 11,12,122 . Category IB/IC V.D.2.d.iii. Instruct patients with a known or suspected airborne infection to wear a surgical mask and observe Respiratory Hygiene/Cough Etiquette. Once in an AIIR, the mask may be removed; the mask should remain on if the patient is not in an AIIR 12,107,145,899 . Category IB/IC V.D.3.\nPersonnel restrictions Restrict susceptible healthcare personnel from entering the rooms of patients known or suspected to have measles (rubeola), varicella (chickenpox), disseminated zoster, or smallpox if other immune healthcare personnel are available 17,775 . Category IB V.D.4.\nUse of PPE V.D.4.a. Wear a fit-tested NIOSH-approved N95 or higher level respirator for respiratory protection when entering the room or home of a patient when the following diseases are suspected or confirmed: y Infectious pulmonary or laryngeal tuberculosis or when infectious tuberculosis skin lesions are present and procedures that would aerosolize viable organisms (e.g., irrigation, incision and drainage, whirlpool treatments) are performed 12,1025,1026 . Category IB y Smallpox (vaccinated and unvaccinated). Respiratory protection is recommended for all healthcare personnel, including those with a documented \"take\" after smallpox vaccination due to the risk of a genetically engineered virus against which the vaccine may not provide protection, or of exposure to a very large viral load (e.g., from high-risk aerosol-generating procedures, immunocompromised patients, hemorrhagic or flat smallpox 108,129 . Category II V.D.4.b. No recommendation is made regarding the use of PPE by healthcare personnel who are presumed to be immune to measles (rubeola) or varicella-zoster based on history of disease, vaccine, or serologic testing when caring for an individual with known or suspected measles, chickenpox or disseminated zoster, due to difficulties in establishing definite immunity 1027,1028 . Unresolved issue V.D.4.c. No recommendation is made regarding the type of personal protective equipment (i.e., surgical mask or respiratory protection with a N95 or higher respirator) to be worn by susceptible healthcare personnel who must have contact with patients with known or suspected measles, chickenpox or disseminated herpes zoster. Unresolved issue V.D.5.\nPatient transport V.D.5.a. In acute care hospitals and long-term care and other residential settings, limit transport and movement of patients outside of the room to medically-necessary purposes. Category II V.D.5.b. If transport or movement outside an AIIR is necessary, instruct patients to wear a surgical mask, if possible, and observe Respiratory Hygiene/Cough Etiquette 12 . Category II V.D.5.c. For patients with skin lesions associated with varicella or smallpox or draining skin lesions caused by M. tuberculosis, cover the affected areas to prevent aerosolization or contact with the infectious agent in skin lesions 108,1025,1026,[1029][1030][1031] . Category IB V.D.5.d. Healthcare personnel transporting patients who are on Airborne Precautions do not need to wear a mask or respirator during transport if the patient is wearing a mask and infectious skin lesions are covered. Category II V.D.6.\nExposure management Immunize or provide the appropriate immune globulin to susceptible persons as soon as possible following unprotected contact (i.e., exposed) to a patient with measles, varicella or smallpox: Category IA y Administer measles vaccine to exposed susceptible persons within 72 hours after the exposure or administer immune globulin within six days of the exposure event for high-risk persons in whom vaccine is contraindicated 17,[1032][1033][1034][1035] . y Administer varicella vaccine to exposed susceptible persons within 120 hours after the exposure or administer varicella immune globulin (VZIG or alternative product), when available, within 96 hours for high-risk persons in whom vaccine is contraindicated (e.g., immunocompromised patients, pregnant women, newborns whose mother's varicella onset was <5 days before or within 48 hours after delivery 888,[1035][1036][1037] 13 . Category IB VI.C.1.b. Directed room airflow with the air supply on one side of the room that moves air across the patient bed and out through an exhaust on the opposite side of the room 13 . Category IB VI.C.1.c. Positive air pressure in room relative to the corridor (pressure differential of >12.5 Pa [0.01-in water gauge]) 13 . Category IB VI.C.1.c.i.\nMonitor air pressure daily with visual indicators (e.g., smoke tubes, flutter strips) 11, 1024 . Category IA VI.C.1.d. Well-sealed rooms that prevent infiltration of outside air 13 .\nCategory IB VI.C.1.e. At least 12 air changes per hour 13 . Category IB VI.C.2. Lower dust levels by using smooth, nonporous surfaces and finishes that can be scrubbed, rather than textured material (e.g., upholstery). Wet dust horizontal surfaces whenever dust detected and routinely clean crevices and sprinkler heads where dust may accumulate 940,941 . Category II VI.C.3. Avoid carpeting in hallways and patient rooms in areas 941 .\nCategory IB VI.C.4. Prohibit dried and fresh flowers and potted plants [942][943][944] . Category II VI.D. Minimize the length of time that patients who require a Protective Environment are outside their rooms for diagnostic procedures and other activities 11,158,945 . Category IB VI.E. During periods of construction, to prevent inhalation of respirable particles that could contain infectious spores, provide respiratory protection (e.g., N95 respirator) to patients who are medically fit to tolerate a respirator when they are required to leave the Protective Environment 945 158 . Barrier precautions, (e.g., masks, gowns, gloves) are not required for healthcare personnel in the absence of suspected or confirmed infection in the patient or if they are not indicated according to Standard Precautions 15 . Category II VI.F.4.\nCategory\nImplement Airborne Precautions for patients who require a Protective Environment room and who also have an airborne infectious disease (e.g., pulmonary or laryngeal tuberculosis, acute varicella-zoster). Category IA VI.F.4.a. Ensure that the Protective Environment is designed to maintain positive pressure 13 . Category IB VI.F.4.b. Use an anteroom to further support the appropriate air-balance relative to the corridor and the Protective Environment; provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct if the return air must be recirculated 13,1041 . Category IB VI.F.4.c. If an anteroom is not available, place the patient in an AIIR and use portable, industrial-grade HEPA filters in the room to enhance filtration of spores 1042 . Category II Preamble The mode(s) and risk of transmission for each specific disease agent included in Appendix A were reviewed. Principle sources consulted for the development of disease-specific recommendations for Appendix A included infectious disease manuals and textbooks 833,1043,1044 . The published literature was searched for evidence of person-to-person transmission in healthcare and non-healthcare settings with a focus on reported outbreaks that would assist in developing recommendations for all settings where healthcare is delivered. Criteria used to assign Transmission-Based Precautions categories follow:\n• A Transmission-Based Precautions category was assigned if there was strong evidence for person-to-person transmission via droplet, contact, or airborne routes in healthcare or non-healthcare settings and/or if patient factors (e.g., diapered infants, diarrhea, draining wounds) increased the risk of transmission • Transmission-Based Precautions category assignments reflect the predominant mode(s) of transmission\n• If there was no evidence for person-to-person transmission by droplet, contact or airborne routes, Standard Precautions were assigned • If there was a low risk for person-to-person transmission and no evidence of healthcare-associated transmission, Standard Precautions were assigned • Standard Precautions were assigned for bloodborne pathogens (e.g., hepatitis B and C viruses, human immunodeficiency virus) as per CDC recommendations for Universal Precautions issued in 1988 780 . Subsequent experience has confirmed the efficacy of Standard Precautions to prevent exposure to infected blood and body fluid 778,779,866 .\nAdditional information relevant to use of precautions was added in the comments column to assist the caregiver in decision-making. Citations were added as needed to support a change in or provide additional evidence for recommendations for a specific disease and for new infectious agents (e.g., SARS-CoV, avian influenza) that have been added to Appendix A. The reader may refer to more detailed discussion concerning modes of transmission and emerging pathogens in the background text and for MDRO control in Appendix B. Use Contact Precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. Persons who clean areas heavily contaminated with feces or vomitus may benefit from wearing masks since virus can be aerosolized from these body substances 142, 147 148 ; ensure consistent environmental cleaning and disinfection with focus on restrooms even when apparently unsoiled 273,1064 ). Hypochlorite solutions may be required when there is continued transmission [290][291][292] . Alcohol is less active, but there is no evidence that alcohol antiseptic handrubs are not effective for hand decontamination 294 . Cohorting of affected patients to separate airspaces and toilet facilities may help interrupt transmission during outbreaks. [1076][1077][1078][1079] . Install screens in windows and doors in endemic areas. Use DEET-containing mosquito repellants and clothing to cover extremities Marburg virus disease (see viral hemorrhagic fevers) Measles (rubeola) A 4 days after onset of rash; DI in immune compromised Susceptible HCWs should not enter room if immune care providers are available; no recommendation for face protection for immune HCW; no recommendation for type of face protection for susceptible HCWs, i.e., mask or respirator 1027,1028 . For exposed susceptibles, post-exposure vaccine within 72 hrs. or immune globulin within 6 days when available 17,1032,1034 precautions are implemented always, hospitals must have systems in place to evaluate patients routinely according to these criteria as part of their preadmission and admission care. † Patients with the syndromes or conditions listed below may present with atypical signs or symptoms (e.g.neonates and adults with pertussis may not have paroxysmal or severe cough). The clinician's index of suspicion should be guided by the prevalence of specific conditions in the community, as well as clinical judgment. ‡ The organisms listed under the column \"Potential Pathogens\" are not intended to represent the complete, or even most likely, diagnoses, but rather possible etiologic agents that require additional precautions beyond Standard Precautions until they can be ruled out. § These pathogens include enterohemorrhagic Escherichia coli O157:H7, Shigella spp, hepatitis A virus, noroviruses, rotavirus, C. difficile. Cutaneous (contact with spores);RT (inhalation of spores);GIT (ingestion of spores -rare) Comment: Spores can be inhaled into the lower respiratory tract. The infectious dose of B. anthracis in humans by any route is not precisely known. In primates, the LD50 (i.e., the dose required to kill 50% of animals) for an aerosol challenge with B. anthracis is estimated to be 8,000-50,000 spores; the infectious dose may be as low as 1-3 spores\n# APPENDIX A 1\n\n# TYPE AND DURATION OF PRECAUTIONS RECOMMENDED FOR SELECTED INFECTIONS AND CONDITIONS\n\n# Rotavirus\n\n# Incubation Period\nCutaneous: 1 to12 days; RT: Usually 1 to 7 days but up to 43 days reported; GIT: 15-72 hours\n# Clinical Features\nCutaneous: Painless, reddish papule, which develops a central vesicle or bulla in 1-2 days; over next 3-7 days lesion becomes pustular, and then necrotic, with black eschar; extensive surrounding edema. RT: initial flu-like illness for 1-3 days with headache, fever, malaise, cough; by day 4 severe dyspnea and shock, and is usually fatal (85%-90% if untreated; meningitis in 50% of RT cases. GIT: ; if intestinal form, necrotic, ulcerated edematous lesions develop in intestines with fever, nausea and vomiting, progression to hematemesis and bloody diarrhea; 25 GIT: Ingestion of toxin-containing food, RT: Inhalation of toxin containing aerosol cause disease. Comment: Toxin ingested or potentially delivered by aerosol in bioterrorist incidents. LD 50 for type A is 0.001 μg/ml/kg.\n# Incubation Period\n1-5 days.\n# Clinical Features\nPtosis, generalized weakness, dizziness, dry mouth and throat, blurred vision, diplopia, dysarthria, dysphonia, and dysphagia followed by symmetrical descending paralysis and respiratory failure.\n# Diagnosis\nClinical diagnosis; identification of toxin in stool, serology unless toxin-containing material available for toxin neutralization bioassays.\n# Infectivity\nNot transmitted from person to person. Exposure to toxin necessary for disease.\n# Recommended Precautions\nStandard Precautions.\n# Disease Ebola Hemorrhagic Fever Site(s) of Infection; Transmission Mode\nAs a rule infection develops after exposure of mucous membranes or RT, or through broken skin or percutaneous injury.\n# Incubation Period\n2-19 days, usually 5-10 days\n# Clinical Features\nFebrile illnesses with malaise, myalgias, headache, vomiting and diarrhea that are rapidly complicated by hypotension, shock, and hemorrhagic features. Massive hemorrhage in < 50% pts.\n# Diagnosis\nEtiologic diagnosis can be made using RT-PCR, serologic detection of antibody and antigen, pathologic assessment with immunohistochemistry and viral culture with EM confirmation of morphology,\n# Infectivity\nPerson-to-person transmission primarily occurs through unprotected contact with blood and body fluids; percutaneous injuries (e.g., needlestick) associated with a high rate of transmission; transmission in healthcare settings has been reported but is prevented by use of barrier precautions.\n# Recommended Precautions\nHemorrhagic fever specific barrier precautions: If disease is believed to be related to intentional release of a bioweapon, epidemiology of transmission is unpredictable pending observation of disease transmission. Until the nature of the pathogen is understood and its transmission pattern confirmed, Standard, Contact and Airborne Precautions should be used. Once the pathogen is characterized, if the epidemiology of transmission is consistent with natural disease, Droplet Precautions can be substituted for Airborne Precautions. Emphasize: 1) use of sharps safety devices and safe work practices, 2) hand hygiene; 3) barrier protection against blood and body fluids upon entry into room (single gloves and fluidresistant or impermeable gown, face/eye protection with masks, goggles or face shields); and 4) appropriate waste handling. Use N95 or higher respirators when performing aerosol-generating procedures. In settings where AIIRs are unavailable or the large numbers of patients cannot be accommodated by existing AIIRs, observe Droplet Precautions (plus Standard Precautions and Contact Precautions) and segregate patients from those not suspected of VHF infection. Limit blooddraws to those essential to care. See text for discussion and Appendix A for recommendations for naturally occurring VHFs.\n# Disease\nPlague 2 Site(s) of Infection; Transmission Mode RT: Inhalation of respiratory droplets. Comment: Pneumonic plague most likely to occur if used as a biological weapon, but some cases of bubonic and primary septicemia may also occur. Infective dose 100 to 500 bacteria Incubation Period 1 to 6, usually 2 to 3 days.\n# Clinical Features\nPneumonic: fever, chills, headache, cough, dyspnea, rapid progression of weakness, and in a later stage hemoptysis, circulatory collapse, and bleeding diathesis Diagnosis Presumptive diagnosis from Gram stain or Wayson stain of sputum, blood, or lymph node aspirate; definitive diagnosis from cultures of same material, or paired acute/convalescent serology.\n# Infectivity\nPerson-to-person transmission occurs via respiratory droplets risk of transmission is low during first 20-24 hours of illness and requires close contact. Respiratory secretions probably are not infectious within a few hours after initiation of appropriate therapy.\n# Recommended Precautions\nStandard Precautions, Droplet Precautions until patients have received 48 hours of appropriate therapy. Chemoprophylaxis: Consider antibiotic prophylaxis for HCWs with close contact exposure.\ntransmit the infection when the disease is in the end stage. These persons cough copious amounts of bloody sputum that contains many plague bacteria. Patients in the early stage of primary pneumonic plague (approximately the first 20-24 h) apparently pose little risk [1,2]. Antibiotic medication rapidly clears the sputum of plague bacilli, so that a patient generally is not infective within hours after initiation of effective antibiotic treatment [3]. This means that in modern times many patients will never reach a stage where they pose a significant risk to others. Even in the end stage of disease, transmission only occurs after close contact. Simple protective measures, such as wearing masks, good hygiene, and avoiding close contact, have been effective to interrupt transmission during many pneumonic plague outbreaks [2]. In the United States, the last known cases of person to person transmission of pneumonic plague occurred in 1925 [2]. Only immune HCWs to care for pts; post-exposure vaccine within 4 days. Vaccinia: HCWs cover vaccination site with gauze and semi-permeable dressing until scab separates (>21 days). Observe hand hygiene. Adverse events with virus-containing lesions: Standard plus Contact Precautions until all lesions crusted b Transmission by the airborne route is a rare event; Airborne Precautions is recommended when possible, but in the event of mass exposures, barrier precautions and containment within a designated area are most important 204,212 . c Vaccinia adverse events with lesions containing infectious virus include inadvertent autoinoculation, ocular lesions (blepharitis, conjunctivitis), generalized vaccinia, progressive vaccinia, eczema vaccinatum; bacterial superinfection also requires addition of contact precautions if exudates cannot be contained 216,217 . Pneumonic: malaise, cough, sputum production, dyspnea; Typhoidal: fever, prostration, weight loss and frequently an associated pneumonia.\n# Disease\n\n# Diagnosis\nDiagnosis usually made with serology on acute and convalescent serum specimens; bacterium can be detected by PCR (LRN) or isolated from blood and other body fluids on cysteine-enriched media or mouse inoculation.\n# Infectivity\nPerson-to-person spread is rare. Laboratory workers who encounter/handle cultures of this organism are at high risk for disease if exposed.\n# Recommended Precautions\nStandard Precautions \n# 130\n* * During aerosol-generating procedures on patients with suspected or proven infections transmitted by respiratory aerosols (e.g., SARS), wear a fit-tested N95 or higher respirator in addition to gloves, gown,and face/eye protection. (e.g., flutter strips, smoke tubes) or a hand held pressure gauge • Self-closing door on all room exits • Maintain back-up ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for PE areas and take immediate steps to restore the fixed ventilation system • For patients who require both a PE and Airborne Infection Isolation, use an anteroom to ensure proper air balance relationships and provide independent exhaust of contaminated air to the outside or place a HEPA filter in the exhaust duct. If an anteroom is not available, place patient in an AIIR and use portable ventilation units, industrial-grade HEPA filters to enhance filtration of spores. Bioaerosols. An airborne dispersion of particles containing whole or parts of biological entities, such as bacteria, viruses, dust mites, fungal hyphae, or fungal spores. Such aerosols usually consist of a mixture of mono-dispersed and aggregate cells, spores or viruses, carried by other materials, such as respiratory secretions and/or inert particles. Infectious bioaerosols (i.e., those that contain biological agents capable of causing an infectious disease) can be generated from human sources (e.g., expulsion from the respiratory tract during coughing, sneezing, talking or singing; during suctioning or wound irrigation), wet environmental sources (e.g. HVAC and cooling tower water with Legionella) or dry sources (e.g.,constuction dust with spores produced by Aspergillus spp.). Bioaerosols include large respiratory droplets and small droplet nuclei (Cole EC. AJIC 1998;26: 453-64).\n# IV. Surfaces\nCaregivers.. All persons who are not employees of an organization, are not paid, and provide or assist in providing healthcare to a patient (e.g., family member, friend) and acquire technical training as needed based on the tasks that must be performed.\nCohorting. In the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients). During outbreaks, healthcare personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff).\nColonization. Proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression. The presence of a microorganism within a host may occur with varying duration, but may become a source of potential transmission. In many instances, colonization and carriage are synonymous.\nDroplet nuclei. Microscopic particles < 5 µm in size that are the residue of evaporated droplets and are produced when a person coughs, sneezes, shouts, or sings. These particles can remain suspended in the air for prolonged periods of time and can be carried on normal air currents in a room or beyond, to adjacent spaces or areas receiving exhaust air. \n# Hand hygiene.\nA general term that applies to any one of the following: 1) handwashing with plain (nonantimicrobial) soap and water); 2) antiseptic handwash (soap containing antiseptic agents and water); 3) antiseptic handrub (waterless antiseptic product, most often alcohol-based, rubbed on all surfaces of hands); or 4) surgical hand antisepsis (antiseptic handwash or antiseptic handrub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora) 559 .\n# Healthcare-associated infection (HAI).\nAn infection that develops in a patient who is cared for in any setting where healthcare is delivered (e.g., acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (i.e., was not incubating or present at the time healthcare was provided). In ambulatory and home settings, HAI would apply to any infection that is associated with a medical or surgical intervention. Since the geographic location of infection acquisition is often uncertain, the preferred term is considered to be healthcare-associated rather than healthcare-acquired. \n# Hematopoietic stem cell transplantation (HSCT).\nAny transplantation of bloodor bone marrow-derived hematopoietic stem cells, regardless of donor type (e.g., allogeneic or autologous) or cell source (e.g., bone marrow, peripheral blood, or placental/umbilical cord blood); associated with periods of severe immunosuppression that vary with the source of the cells, the intensity of chemotherapy required, and the presence of graft versus host disease (MMWR 2000; 49: RR-10).\nHigh-efficiency particulate air (HEPA) filter. An air filter that removes >99.97% of particles > 0.3µm (the most penetrating particle size) at a specified flow rate of air. HEPA filters may be integrated into the central air handling systems, installed at the point of use above the ceiling of a room, or used as portable units (MMWR 2003; 52: RR-10).\nHome care. A wide-range of medical, nursing, rehabilitation, hospice and social services delivered to patients in their place of residence (e.g., private residence, senior living center, assisted living facility). Home health-care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy.\n# Immunocompromised patients.\nThose patients whose immune mechanisms are deficient because of congenital or acquired immunologic disorders (e.g., human immunodeficiency virus [HIV] infection, congenital immune deficiency syndromes), chronic diseases such as diabetes mellitus, cancer, emphysema, or cardiac failure, ICU care, malnutrition, and immunosuppressive therapy of another disease process [e.g., radiation, cytotoxic chemotherapy, anti-graftrejection medication, corticosteroids, monoclonal antibodies directed against a specific component of the immune system]). The type of infections for which an immunocompromised patient has increased susceptibility is determined by the severity of immunosuppression and the specific component(s) of the immune system that is affected. Patients undergoing allogeneic HSCT and those with chronic graft versus host disease are considered the most vulnerable to HAIs.\nImmunocompromised states also make it more difficult to diagnose certain infections (e.g., tuberculosis) and are associated with more severe clinical disease states than persons with the same infection and a normal immune system.\nInfection. The transmission of microorganisms into a host after evading or overcoming defense mechanisms, resulting in the organism's proliferation and invasion within host tissue(s). Host responses to infection may include clinical symptoms or may be subclinical, with manifestations of disease mediated by direct organisms pathogenesis and/or a function of cell-mediated or antibody responses that result in the destruction of host tissues.\n# Infection control and prevention professional (ICP).\nA person whose primary training is in either nursing, medical technology, microbiology, or epidemiology and who has acquired special training in infection control. Responsibilities may include collection, analysis, and feedback of infection data and trends to healthcare providers; consultation on infection risk assessment, prevention and control strategies; performance of education and training activities; implementation of evidence-based infection control practices or those mandated by regulatory and licensing agencies; application of epidemiologic principles to improve patient outcomes; participation in planning renovation and construction projects (e.g., to ensure appropriate containment of construction dust); evaluation of new products or procedures on patient outcomes; oversight of employee health services related to infection prevention; implementation of preparedness plans; communication within the healthcare setting, with local and state health departments, and with the community at large concerning infection control issues; and participation in research. Certification in infection control (CIC) is available through the Certification Board of Infection Control and Epidemiology.\n# Infection control and prevention program.\nA multidisciplinary program that includes a group of activities to ensure that recommended practices for the prevention of healthcare-associated infections are implemented and followed by HCWs, making the healthcare setting safe from infection for patients and healthcare personnel. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires the following five components of an infection control program for accreditation: 1) surveillance: monitoring patients and healthcare personnel for acquisition of infection and/or colonization; 2) investigation: identification and analysis of infection problems or undesirable trends; 3) prevention: implementation of measures to prevent transmission of infectious agents and to reduce risks for device-and procedure-related infections; 4) control: evaluation and management of outbreaks; and 5) reporting: provision of information to external agencies as required by state and federal law and regulation (www.jcaho.org). The infection control program staff has the ultimate authority to determine infection control policies for a healthcare organization with the approval of the organization's governing body.\n# Long-term care facilities (LTCFs\n). An array of residential and outpatient facilities designed to meet the bio-psychosocial needs of persons with sustained self-care deficits. These include skilled nursing facilities, chronic disease hospitals, nursing homes, foster and group homes, institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and longterm psychiatric hospitals.\n# Mask.\nA term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks (www.fda.gov/cdrh/ode/guidance/094.html#4).\n# Multidrug-resistant organisms (MDROs).\nIn general, bacteria that are resistant to one or more classes of antimicrobial agents and usually are resistant to all but one or two commercially available antimicrobial agents (e.g., MRSA, VRE, extended spectrum beta-lactamase [ESBL]-producing or intrinsically resistant gram-negative bacilli) 176 .\n# Nosocomial infection.\nA term that is derived from two Greek words \"nosos\" (disease) and \"komeion\" (to take care of) and refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission.\n# Personal protective equipment (PPE).\nA variety of barriers used alone or in combination to protect mucous membranes, skin, and clothing from contact with infectious agents. PPE includes gloves, masks, respirators, goggles, face shields, and gowns.\n# Procedure Mask.\nA covering for the nose and mouth that is intended for use in general patient care situations. These masks generally attach to the face with ear loops rather than ties or elastic. Unlike surgical masks, procedure masks are not regulated by the Food and Drug Administration.\nProtective Environment. A specialized patient-care area, usually in a hospital, that has a positive air flow relative to the corridor (i.e., air flows from the room to the outside adjacent space). The combination of high-efficiency particulate air (HEPA) filtration, high numbers (>12) of air changes per hour (ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients with a severely compromised immune system (e.g., those who have received allogeneic hemopoietic stem-cell transplant [HSCT]) and decrease the risk of exposure to spores produced by environmental fungi. Other components include use of scrubbable surfaces instead of materials such as upholstery or carpeting, cleaning to prevent dust accumulation, and prohibition of fresh flowers or potted plants.\nQuasi-experimental studies. Studies to evaluate interventions but do not use randomization as part of the study design. These studies are also referred to as nonrandomized, pre-post-intervention study designs. These studies aim to demonstrate causality between an intervention and an outcome but cannot achieve the level of confidence concerning attributable benefit obtained through a randomized, controlled trial. In hospitals and public health settings, randomized control trials often cannot be implemented due to ethical, practical and urgency reasons; therefore, quasi-experimental design studies are used commonly. However, even if an intervention appears to be effective statistically, the question can be raised as to the possibility of alternative explanations for the result.. Such study design is used when it is not logistically feasible or ethically possible to conduct a randomized, controlled trial, (e.g., during outbreaks). Within the classification of quasi-experimental study designs, there is a hierarchy of design features that may contribute to validity of results (Harris et al. CID 2004:38: 1586).\n# Residential care setting.\nA facility in which people live, minimal medical care is delivered, and the psychosocial needs of the residents are provided for.\n# Respirator.\nA personal protective device worn by healthcare personnel to protect them from inhalation exposure to airborne infectious agents that are < 5 μm in size. These include infectious droplet nuclei from patients with M. tuberculosis, variola virus [smallpox], SARS-CoV), and dust particles that contain infectious particles, such as spores of environmental fungi (e.g., Aspergillus sp. \n# Respiratory Hygiene/ Cough Etiquette.\nA combination of measures designed to minimize the transmission of respiratory pathogens via droplet or airborne routes in healthcare settings. The components of Respiratory Hygiene/Cough Etiquette are 1) covering the mouth and nose during coughing and sneezing, 2) using tissues to contain respiratory secretions with prompt disposal into a notouch receptacle, 3) offering a surgical mask to persons who are coughing to decrease contamination of the surrounding environment, and 4) turning the head away from others and maintaining spatial separation, ideally >3 feet, when coughing. These measures are targeted to all patients with symptoms of respiratory infection and their accompanying family members or friends beginning at the point of initial encounter with a healthcare setting (e.g., reception/triage in emergency departments, ambulatory clinics, healthcare provider offices) 126 (Srinivasin A ICHE 2004; 25: 1020; www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm).\nSafety culture/climate. The shared perceptions of workers and management regarding the expectations of safety in the work environment. A hospital safety climate includes the following six organizational components: 1) senior management support for safety programs; 2) absence of workplace barriers to safe work practices; 3) cleanliness and orderliness of the worksite; 4) minimal conflict and good communication among staff members; 5) frequent safetyrelated feedback/training by supervisors; and 6) availability of PPE and engineering controls 620 .\nSource Control. The process of containing an infectious agent either at the portal of exit from the body or within a confined space. The term is applied most frequently to containment of infectious agents transmitted by the respiratory route but could apply to other routes of transmission, (e.g., a draining wound, vesicular or bullous skin lesions). Respiratory Hygiene/Cough Etiquette that encourages individuals to \"cover your cough\" and/or wear a mask is a source control measure. The use of enclosing devices for local exhaust ventilation (e.g., booths for sputum induction or administration of aerosolized medication) is another example of source control.\n# Standard Precautions.\nA group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status. Standard Precautions is a combination and expansion of Universal Precautions 780 and Body Substance Isolation 1102 . Standard Precautions is based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. Standard Precautions includes hand hygiene, and depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield. Also, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents, (e.g. wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient).\n# Surgical mask.\nA device worn over the mouth and nose by operating room personnel during surgical procedures to protect both surgical patients and operating room personnel from transfer of microorganisms and body fluids. Surgical masks also are used to protect healthcare personnel from contact with large infectious droplets (>5 μm in size). According to draft guidance issued by the Food and Drug Administration on May 15, 2003, surgical masks are evaluated using standardized testing procedures for fluid resistance, bacterial filtration efficiency, differential pressure (air exchange), and flammability in order to mitigate the risks to health associated with the use of surgical masks. These specifications apply to any masks that are labeled surgical, laser, isolation, or dental or medical procedure (www.fda.gov/cdrh/ode/guidance/094.html#4). Surgical masks do not protect against inhalation of small particles or droplet nuclei and should not be confused with particulate respirators that are recommended for protection against selected airborne infectious agents, (e.g., Mycobacterium tuberculosis).\n# Appendix A:\n\n# APPENDIX A 1\n\n# TYPE AND DURATION OF PRECAUTIONS RECOMMENDED FOR SELECTED INFECTIONS AND CONDITIONS\n\n# APPENDIX A 1\n\n# TYPE AND DURATION OF PRECAUTIONS RECOMMENDED FOR SELECTED INFECTIONS AND CONDITIONS\n\n# HAND HYGIENE\nPerform hand hygiene immediately after removing all PPE!"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":283,"cells":{"id":{"kind":"string","value":"f0cea40b8c66e7440fafad90fe85defd3516d7e8"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Centers for Disease Control and Prevention. Prevention and control of meningococcal disease and Meningococcal disease and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(No. RR-7):.# INTRODUCTION\nEach year, 2,400-3,000 cases of meningococcal disease occur in the United States, resulting in a rate of 0.8-1.3 per 100,000 population (1)(2)(3). The case-fatality ratio for meningococcal disease is 10% (2 ), despite the continued sensitivity of meningococcus to many antibiotics, including penicillin (4 ). Meningococcal disease also causes substantial morbidity: 11%-19% of survivors have sequelae (e.g., neurologic disability, limb loss, and hearing loss ). During 1991-1998, the highest rate of meningococcal disease occurred among infants aged <1 year; however, the rate for persons aged 18-23 years was also higher than that for the general population (1.4 per 100,000) (CDC, National Electronic Telecommunications System for Surveillance, unpublished data).\n\n# BACKGOUND\nIn the United States, 95%-97% of cases of meningococcal disease are sporadic; however, since 1991, the frequency of localized outbreaks has increased (7)(8). Most of these outbreaks have been caused by serogroup C. However, in the past 3 years, localized outbreaks caused by serogroup Y and B organisms have also been reported (8 ). The proportion of sporadic meningococcal cases caused by serogroup Y also increased from 2% during 1989-1991 to 30% during 1992-1996 (2,9 ). The proportion of cases caused by each serogroup varies by age group; more than half of cases among infants aged <1 year are caused by serogroup B, for which no vaccine is licensed or available in the United States (2,10 ).\nPersons who have certain medical conditions are at increased risk for developing meningococcal disease, particularly persons who have deficiencies in the terminal common complement pathway (C3, C5-9) (11 ). Antecedent viral infection, household crowding, chronic underlying illness, and both active and passive smoking also are associated with increased risk for meningococcal disease (12)(13)(14)(15)(16)(17)(18)(19). During outbreaks, bar or nightclub patronage and alcohol use have also been associated with higher risk for disease (20)(21)(22). In the United States, blacks and persons of low socioeconomic status have been consistently at higher risk for meningococcal disease (2,3,12,18 ). However, race and low socioeconomic status are likely risk markers, rather than risk factors, for this disease.\nA recent multi-state, case-control study, in which controls were matched to casepatients by age group, revealed that in a multivariable analysis (controlling for sex and education), active and passive smoking, recent respiratory illness, corticosteroid use, new residence, new school, Medicaid insurance, and household crowding were all associated with increased risk for meningococcal disease (13 ). Income and race were not associated with increased risk. Additional research is needed to identify groups at risk that could benefit from prevention efforts.\n\n# MENINGOCOCCAL POLYSACCHARIDE VACCINES\nThe quadrivalent A, C, Y, W-135 vaccine (Menomune ® -A,C,Y,W-135, manufactured by Aventis Pasteur) is the formulation currently available in the United States (23 ). Each dose consists of 50 µg of the four purified bacterial capsular polysaccharides. Menomune ® is available in single-dose and 10-dose vials. (Fifty-dose vials are no longer available.)\n\n# Primary Vaccination\nFor both adults and children, vaccine is administered subcutaneously as a single, 0.5-ml dose. The vaccine can be administered at the same time as other vaccines but should be given at a different anatomic site. Protective levels of antibody are usually achieved within 7-10 days of vaccination.\n\n# Vaccine Immunogenicity and Efficacy\nThe immunogenicity and clinical efficacy of the serogroups A and C meningococcal vaccines have been well established. The serogroup A polysaccharide induces antibody in some children as young as 3 months of age, although a response comparable with that occurring in adults is not achieved until age 4-5 years. The serogroup C component is poorly immunogenic in recipients aged 2 years (30)(31)(32); although clinical protection has not been documented, vaccination with these polysaccharides induces bactericidal antibody. The antibody responses to each of the four polysaccharides in the quadrivalent vaccine are serogroupspecific and independent. Reduced clinical efficacy has not been demonstrated among persons who have received multiple doses of vaccine. However, recent serologic studies have suggested that multiple doses of serogroup C polysaccharide may cause immunologic tolerance to the group C polysaccharide (33,34 ).\n\n# Duration of Protection\nIn infants and children aged 90% to <10% 3 years after vaccination among children who were aged <4 years when vaccinated; efficacy was 67% among children who were ≥4 years of age at vaccination (39 ).\n\n# RECOMMENDATIONS FOR USE OF MENINGOCOCCAL VACCINE\nCurrent Advisory Committee on Immunization Practices (ACIP) guidelines (1 ) suggest that routine vaccination of civilians with the quadrivalent meningococcal polysaccharide vaccine is not recommended because of its relative ineffectiveness in children aged <2 years (the age group with the highest risk for sporadic disease) and because of its relatively short duration of protection. However, the vaccine is recommended for use in control of serogroup C meningococcal outbreaks. An outbreak is defined by the occurrence of three or more confirmed or probable cases of serogroup C meningococcal disease during a period of ≤3 months, with a resulting primary attack rate of at least 10 cases per 100,000 population. For calculation of this threshold, population-based rates are used and not age-specific attack rates, as have been calculated for college students. These recommendations are based on experience with serogroup C meningococcal outbreaks, but these principles may be applicable to outbreaks caused by the other vaccine-preventable meningococcal serogroups, including Y, W-135, and A.\nCollege freshmen, particularly those living in dormitories or residence halls, are at modestly increased risk for meningococcal disease compared with persons the same age who are not attending college. Therefore, ACIP has developed recommendations that address educating students and their parents about the risk for disease and about the vaccine so they can make individualized, informed decisions regarding vaccination. (See MMWR Vol. 49, RR-7, which can be referenced in the pages following this report.)\nRoutine vaccination with the quadrivalent vaccine is also recommended for certain high-risk groups, including persons who have terminal complement component deficiencies and those who have anatomic or functional asplenia. Research, industrial, and clinical laboratory personnel who are exposed routinely to Neisseria meningitidis in solutions that may be aerosolized also should be considered for vaccination (1 ).\nVaccination with the quadrivalent vaccine may benefit travelers to and U.S. citizens residing in countries in which N. meningitidis is hyperendemic or epidemic, particularly if contact with the local population will be prolonged. Epidemics of meningococcal disease are recurrent in that part of sub-Saharan Africa known as the \"meningitis belt,\" which extends from Senegal in the West to Ethiopia in the East (40 ). Epidemics in the meningitis belt usually occur during the dry season (i.e., from December to June); thus, vaccination is recommended for travelers visiting this region during that time. Information concerning geographic areas for which vaccination is recommended can be obtained from international health clinics for travelers, state health departments, and CDC (telephone 332-4559; internet /).\n\n# Revaccination\nRevaccination may be indicated for persons at high risk for infection (e.g., persons residing in areas in which disease is epidemic), particularly for children who were first vaccinated when they were <4 years of age; such children should be considered for revaccination after 2-3 years if they remain at high risk. Although the need for revaccination of older children and adults has not been determined, antibody levels rapidly decline over 2-3 years, and if indications still exist for vaccination, revaccination may be considered 3-5 years after receipt of the initial dose (1 ).\n\n# Precautions and Contraindications\nPolysaccharide meningococcal vaccines (both A/C and A/C/Y/W-135) have been extensively used in mass vaccination programs as well as in the military and among international travelers. Adverse reactions to polysaccharide meningococcal vaccines are generally mild; the most frequent reaction is pain and redness at the injection site, lasting for 1-2 days. Estimates of the incidence of such local reactions have varied, ranging from 4% to 56% (41,42 ). Transient fever occurred in up to 5% of vaccinees in some studies and occurs more commonly in infants (24,43 ).\nSevere reactions to polysaccharide meningococcal vaccine are uncommon (24,32,41-48 ) (R. Ball, U.S. Food and Drug Administration, personal communication). Most studies report the rate of systemic allergic reactions (e.g., urticaria, wheezing, and rash) as 0.0-0.1 per 100,000 vaccine doses (24,48 ). Anaphylaxis has been documented in <0.1 per 100,000 vaccine doses (23,47 ). Neurological reactions (e.g., seizures, anesthesias, and paresthesias) are also infrequently observed (42,47 ).\nThe Vaccine Adverse Events Reporting System (VAERS) is a passive surveillance system that detects adverse events that are temporally (but not necessarily causally) associated with vaccination, including adverse events that occur in military personnel. During 1991-1998, a total of 4,568,572 doses of polysaccharide meningococcal vaccine were distributed; 222 adverse events were reported for a rate of 49 adverse events per million doses. In 1999, 42 reports of adverse events were received, but the total number of vaccine doses distributed in 1999 is not yet available (R. Ball, U.S. Food and Drug Administration, personal communication). In the United States from July 1990 through October 1999, a total of 264 adverse events (and no deaths) were reported. Of these adverse events, 226 were categorized as \"less serious,\" with fever, headache, dizziness, and injection-site reactions most commonly reported. Thirty-eight serious adverse events (i.e., those that require hospitalization, are life-threatening, or result in permanent disability) that were temporally associated with vaccination were reported. Serious injection site reactions were reported in eight patients and allergic reactions in three patients. Four cases of Guillain-Barré Syndrome were reported in adults 7-16 days after receiving multiple vaccinations simultaneously, and one case of Guillain-Barré Syndrome was reported in a 9-year-old boy 32 days after receiving meningococcal vaccine alone. An additional seven patients reported serious nervous system abnormalities (e.g., convulsions, paresthesias, diploplia, and optic neuritis); all of these patients received multiple vaccinations simultaneously, making assessment of the role of meningococcal vaccine difficult. Of the 15 miscelleneous adverse events, only three occurred after meningococcal vaccine was administered alone. The minimal number of serious adverse events coupled with the substantial amount of vaccine distributed (>4 million doses) indicate that the vaccine can be considered safe (R. Ball, U.S. Food and Drug Administration, personal communication).\nStudies of vaccination during pregnancy have not documented adverse effects among either pregnant women or newborns (49-51 ). Based on data from studies involving the use of meningococcal vaccines and other polysaccharide vaccines during pregnancy, altering meningococcal vaccination recommendations during pregnancy is unnecessary.\n\n# ANTIMICROBIAL CHEMOPROPHYLAXIS\nIn the United States, the primary means for prevention of sporadic meningococcal disease is antimicrobial chemoprophylaxis of close contacts of infected persons (Table 1). Close contacts include a) household members, b) day care center contacts, and c) anyone directly exposed to the patient's oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management). The attack rate for household contacts exposed to patients who have sporadic meningococcal disease is an estimated four cases per 1,000 persons exposed, which is 500-800 times greater than for the total population (52 ). Because the rate of secondary disease for close contacts is highest during the first few days after onset of disease in the index patient, antimicrobial chemoprophylaxis should be administered as soon as possible (ideally within 24 hours after identification of the index patient). Conversely, chemoprophylaxis administered >14 days after onset of illness in the index patient is probably of limited or no value. Oropharyngeal or nasopharyngeal cultures are not helpful in determining the need for chemoprophylaxis and may unnecessarily delay institution of this preventive measure.\nRifampin, ciprofloxacin, and ceftriaxone are all 90%-95% effective in reducing nasopharyngeal carriage of N. meningitidis and are all acceptable alternatives for chemoprophylaxis (53)(54)(55)(56). Systemic antimicrobial therapy of meningococcal disease with agents other than ceftriaxone or other third-generation cephalosporins may not reliably eradicate nasopharyngeal carriage of N. meningitidis. If other agents have been used for treatment, the index patient should receive chemoprophylactic antibiotics for eradication of nasopharyngeal carriage before being discharged from the hospital (57 ).\n\n# PROSPECTS FOR IMPROVED MENINGOCOCCAL VACCINES\nSerogroup A, C, Y, and W-135 meningococcal polysaccharides have been chemically conjugated to protein carriers. These meningococcal conjugate vaccines provoke a T-cell-dependent response that induces a stronger immune response in infants, primes immunologic memory, and leads to booster response to subsequent doses. These vaccines are expected to provide a longer duration of immunity than polysaccharides, even when administered in an infant series, and may provide herd immunity through protection from nasopharyngeal carriage. Clinical trials evaluating these vaccines are ongoing (58)(59)(60). When compared with polysaccharide vaccine, conjugated A and C meningococcal vaccines in infants and toddlers have resulted in similar side effects but improved immune response. Prior vaccination with group C polysaccharide likely does not prevent induction of memory by a subsequent dose of conjugate vaccine (61 ).\nIn late 1999, conjugate C meningococcal vaccines were introduced in the United Kingdom, where rates of meningococcal disease are approximately 2 per 100,000 population, and 30%-40% of cases are caused by serogroup C (62 ). In phase I of this program, infants are being vaccinated at 2, 3, and 4 months concurrently with DTP, Hib, and polio vaccines. Children aged 4-13 months are receiving \"catch-up\" vaccinations. Children aged 15-17 years are receiving one dose of conjugate C vaccine, and entering college students are receiving one dose of bivalent A/C polysaccharide vaccine. In phase II, scheduled to start in June 2000, a dose of conjugate vaccine will be administered to children aged 14 months-14 years and to persons aged 18-20 years who are not enrolled in college (62 ).\nConjugate meningococcal vaccines should be available in the United States within the next 2-4 years. In the interim, the polysaccharide vaccine should not be incorporated into the routine childhood immunization schedule, because the currently available meningococcal polysaccharide vaccines provide limited efficacy of short duration in young children (39 ), in whom the risk for disease is highest (2,3 ).\nBecause the group B polysaccharide is not immunogenic in humans, immunization strategies have focused primarily on noncapsular antigens (10,63 ). Several of these vaccines, developed from specific strains of serogroup B meningococci, have been safe, immunogenic, and efficacious among children and adults and have been used to control outbreaks in South America and Scandinavia (64)(65)(66)(67)(68). Strain-specific differences in outer-membrane proteins suggest that these vaccines may not provide protection against all serogroup B meningococci (69 ). No serogroup B vaccine is currently licensed or available in the United States.\n\n# CONCLUSIONS\nN. meningitidis is a leading cause of bacterial meningitis and sepsis in older children and young adults in the United States. Antimicrobial chemoprophylaxis of close contacts of persons who have sporadic meningococcal disease is the primary means for prevention of meningococcal disease in the United States.\nThe quadrivalent polysaccharide meningococcal vaccine (which protects against serogroups A, C, Y, and W-135) is recommended for control of serogroup C meningococcal disease outbreaks and for use among persons in certain high-risk groups. Travelers to countries in which disease is hyperendemic or epidemic may benefit from vaccination. In addition, college freshmen, especially those who live in dormitories, should be educated about meningococcal disease and the vaccine so that they can make an educated decision about vaccination.\nConjugate C meningococcal vaccines were recently introduced into routine childhood immunization schedules in the United Kingdom. These vaccines should be available in the United States within 2-4 years, offering a better tool for control and prevention of meningococcal disease.\n\n# Meningococcal Disease and College Students\n\n# Recommendations of the Advisory Committee on Immunization Practices (ACIP) INTRODUCTION\nNeisseria meningitidis causes both sporadic disease and outbreaks. As a result of the control of Haemophilus influenzae type b infections, N. meningitidis has become the leading cause of bacterial meningitis in children and young adults in the United States (1 ). Outbreaks of meningococcal disease were rare in the United States in the 1980s; however, since 1991, the frequency of localized outbreaks has increased (2 ). From July 1994 through July 1997, 42 meningococcal outbreaks were reported, four of which occurred at colleges (3 ). However, outbreaks continue to represent <3% of total U.S. cases (3 ).\nRates of meningococcal disease remain highest for infants, but in the past decade, rates have increased among adolescents and young adults (4 ). During 1994-1998, approximately two thirds of cases among persons aged 18-23 years were caused by serogroups C, Y, or W135 and therefore were potentially preventable with available vaccines (5 ) (CDC, unpublished data) (Figure 1). Although the quadrivalent meningococcal polysaccharide vaccine is safe and efficacious (5,6 ), decisions about who to target for vaccination require understanding of the groups at risk, the burden of disease, and the potential benefits of vaccination.\nNew data are available regarding the risk for meningococcal disease in college students. This report reviews these data and provides medical professionals with guidelines concerning meningococcal disease and college students.\n\n# BACKGROUND Meningococcal Disease in the Military\nMilitary recruits and college freshmen have several common characteristics (e.g., age, diverse geographic backgrounds, and crowded living conditions). Therefore, data obtained from recruits have been used to evaluate meningococcal disease and vaccine among college freshmen.\nBefore 1971, rates of meningococcal disease were elevated among U.S. military recruits. Outbreaks frequently followed large-scale mobilizations, and recruits in their (11 ), and by Fall 1982, all recruits were receiving the quadrivalent polysaccharide vaccine (7 ). However, rates of meningococcal disease in U.S. Army personnel declined before the 1971 vaccination campaigns (7 ), suggesting that smaller recruit populations at training installations and the natural periodicity of outbreaks may have contributed to the decline in disease. Rates of meningococcal disease remain low in the military, and large outbreaks no longer occur. Since 1990, records of all hospitalizations of active duty service members in military hospitals worldwide have been integrated with military personnel records in the Defense Medical Surveillance System (DMSS). During 1990-1998, the overall rate of hospitalizations from meningococcal disease among enlisted, active-duty service members was 0.51 per 100,000 person-years (J. Brundage, DMSS Army Medical Surveillance Activity, personal communication). Approximately 180,000 military recruits receive a single dose of quadrivalent polysaccharide meningococcal vaccine annually. Revaccination is only indicated when military personnel are traveling to countries in which N. meningitidis is hyperendemic or epidemic (D. Trump, personal communication).\nBefore 1999, students reporting to two of the U.S. military academies routinely received meningococcal vaccine. Last year, the other academies initiated meningococcal vaccine programs.\n\n# MENINGOCOCCAL DISEASE AND COLLEGE STUDENTS\nFour recent studies provide data concerning the risk for sporadic meningococcal disease among college students (Table 1) (12)(13)(14)(15). The earliest of these studies was conducted during the 1990-1991 and 1991-1992 school years. A questionnaire designed to evaluate risk factors for meningococcal disease among college students was sent to 1,900 universities, resulting in a 38% response rate (12 ). Forty-three cases of meningococcal disease were reported during the 2 years from colleges with a total enrollment of 4,393,744 students, for a low overall incidence of 1.0 per 100,000 population per year. However, cases of meningococcal disease occurred 9-23 times more frequently in students residing in dormitories than in those residing in other types of accommodations. The low response rate and the inability of the study to control for other risk factors (e.g., freshman status) make these results difficult to interpret. N/A= not applicable.\n\n# MMWR June 30, 2000\nIn a retrospective, cohort study conducted in Maryland for the period 1992-1997, 67 cases of meningococcal disease among persons aged 16-30 years were identified by active, laboratory-based surveillance (13 ). Of those cases, 14 were among students attending Maryland colleges, and 11 were among those in 4-year colleges. The overall incidence of meningococcal disease in Maryland college students was similar to the incidence in the U.S. population of persons the same age (1.74/100,000 vs. 1.44/100,000, respectively); however, rates of disease were elevated among students living in dormitories compared with students living off-campus (3.2/100,000 vs. 0.96/100,000, p=0.05).\nU.S. surveillance for meningococcal disease in college students was initiated in 1998; from September 1998 through August 1999, 90 cases of meningococcal disease were reported to CDC (14 ). These cases represent approximately 3% of the total cases of meningococcal disease that occur each year in the United States. Eighty-seven (97%) cases occurred in undergraduate students, and 40 (44%) occurred among the 2.27 million freshman students entering college each year (16 ). Among undergraduates, of the 71 (82%) isolates for which serogroup information was available, 35 (49%) were serogroup C, 17 (24%) were serogroup B, 15 (21%) were serogroup Y, and one (1%) was serogroup W-135. Eight (9%) students died. Of the five students who died for whom serogroup information was available, four had serogroup C isolates and one had serogroup Y.\nU.S. surveillance data from the 1998-1999 school year suggest that the overall rate of meningococcal disease among undergraduate college students is lower than the rate among persons aged 18-23 years who are not enrolled in college (Table 2) (0.7 vs. 1.5/100,000, respectively) (14,16 ). However, rates were higher among specific subgroups of college students. Among the approximately 590,000 freshmen who live in dormitories (17 ), the rate of meningococcal disease was 4.6/100,000, higher than any age group in the population other than children aged <2 years, but lower than the threshold of 10/100,000 recommended for initiating meningococcal vaccination campaigns (6 ).\nOf 90 students who had meningococcal disease attending college during the 1998- 1999 school year, 50 were enrolled in a case-control study and matched to 148 controls by school, sex, and undergraduate vs. graduate status (14 ). In a multivariable analysis, freshmen living in dormitories were at higher risk for meningococcal disease. In addition, white race, radiator heat, and recent upper respiratory infection were associated with disease.\nIn contrast to the United States, overall rates of meningococcal disease in the United Kingdom are higher among university students compared with non-students of similar age (15 ). From September 1994 through March 1997, university students had an increased annual rate of meningococcal disease (13.2/100,000) compared with nonstudents of similar age in the same health districts (5.5/100,000) and in those health districts without universities (3.7/100,000). As in the United States, regression analysis revealed that \"catered hall accommodations,\" the U.K. equivalent of dormitories, were the main risk factor. Higher rates of disease were observed at universities providing catered hall accommodations for >10% of their student population compared with those providing such housing for <10% of students (15.3/100,000 vs. 5.9/100,000). The increased rate of disease among university students has prompted the United Kingdom to initiate routine vaccination of incoming university students with a bivalent A/C polysaccharide vaccine as part of a new vaccination program (see MMWR 2000; Vol.49, No. RR-6 which can be referenced in the pages preceding this report) (18 ).\n\n# MENINGOCOCCAL VACCINE AND COLLEGE STUDENTS\nOn September 30, 1997, the American College Health Association (ACHA), which represents about half of colleges that have student health services, released a statement recommending that \"college health services a more proactive role in alerting students and their parents about the dangers of meningococcal disease,\" that \"college students consider vaccination against potentially fatal meningococcal disease,\" and that \"colleges and universities ensure all students have access to a vaccination program for those who want to be vaccinated\" (Dr. MarJeanne Collins, Chairman, ACHA Vaccine Preventable Diseases Task Force, personal communication). Parent and college student advocates have also encouraged more widespread use of meningococcal vaccine in college students. In a joint study by ACHA and CDC, surveys were sent to 1,200 ACHA-member schools; of 691 responding schools, 57 (8%) reported that preexposure meningococcal vaccination campaigns had been conducted on their campus since September 1997. A median of 32 students were vaccinated at each school (range: 1-2,300) (J. Capparella, unpublished data). During the 1998-1999 school year, 3%-5% of 148 students enrolled in a case-control study reported receiving prophylactic meningococcal vaccination (14 ). Before the 1999 fall semester, many schools mailed information packets to incoming freshmen; data are not yet available regarding the proportion of students who have been vaccinated. worst case scenarios were evaluated by varying cost of vaccine and administration (range: $54-$88), costs per hospitalization ($10,924-$24,030), value of premature death based on lifetime productivity ($1.3-$4.8 million), cost of side effects of vaccine per case ($3,500-$12,270 per one million doses), and average cost of treating a case of sequelae ($0-$1,476). Vaccination coverage (60% and 100%) and vaccine efficacy (80% and 90%) were also varied for evaluation purposes. Vaccination of freshmen who live in dormitories would result in the administration of approximately 300,000-500,000 doses of vaccine each year, preventing 15-30 cases of meningococcal disease and one to three deaths each year. The cost per case prevented would be $600,000-$1.8 million, at a cost per death prevented of $7 million to $20 million.\n\n# Cost-effectiveness of meningococcal vaccine in college students\nVaccination of all freshman would result in the administration of approximately 1.4-2.3 million doses of vaccine each year, preventing 37-69 cases of meningococcal disease and two to four deaths caused by meningococcal disease each year. The cost per case prevented would be $1.4-2.9 million, at a cost per death prevented of $22 million to $48 million.\nThese data are similar to data derived from previous studies (19 ). They suggest that for society as a whole, vaccination of college students is unlikely to be cost-effective (Scott et al, unpublished data).\n\n# RECOMMENDATIONS FOR USE OF MENINGOCOCCAL POLYSACCHARIDE VACCINE IN COLLEGE STUDENTS\nCollege freshmen, particularly those who live in dormitories, are at modestly increased risk for meningococcal disease relative to other persons their age. Vaccination with the currently available quadrivalent meningococcal polysaccharide vaccine will decrease the risk for meningococcal disease among such persons. Vaccination does not eliminate risk because a) the vaccine confers no protection against serogroup B disease and b) although the vaccine is highly effective against serogroups C, Y, W-135, and A, efficacy is <100%.\nThe risk for meningococcal disease among college students is low; therefore, vaccination of all college students, all freshmen, or only freshmen who live in dormitories or residence halls is not likely to be cost-effective for society as a whole. Thus, ACIP is issuing the following recommendations regarding the use of meningococcal polysaccharide vaccines for college students.\n- Providers of medical care to incoming and current college freshmen, particularly those who plan to or already live in dormitories and residence halls, should, during routine medical care, inform these students and their parents about meningococcal disease and the benefits of vaccination. ACIP does not recommend that the level of increased risk among freshmen warrants any specific changes in living situations for freshmen.\n- College freshmen who want to reduce their risk for meningococcal disease should either be administered vaccine (by a doctor's office or student health service) or directed to a site where vaccine is available.\n- The risk for meningococcal disease among non-freshmen college students is similar to that for the general population. However, the vaccine is safe and efficacious and therefore can be provided to non-freshmen undergraduates who want to reduce their risk for meningococcal disease.\n- Colleges should inform incoming and/or current freshmen, particularly those who plan to live or already live in dormitories or residence halls, about meningococcal disease and the availability of a safe and effective vaccine.\n- Public health agencies should provide colleges and health-care providers with information about meningococcal disease and the vaccine as well as information regarding how to obtain vaccine.\n\n# Additional Considerations about Vaccination of College Students\nAlthough the need for revaccination of older children has not been determined, antibody levels decline rapidly over 2-3 years (6 ). Revaccination may be considered for freshmen who were vaccinated more than 3-5 years earlier (5 ). Routine revaccination of college students who were vaccinated as freshmen is not indicated.\nCollege students who are at higher risk for meningococcal disease because of a) underlying immune deficiencies or b) travel to countries in which N. meningitidis is hyperendemic or epidemic (i.e., the meningitis belt of sub-Saharan Africa) should be vaccinated (6 ). College students who are employed as research, industrial, and clinical laboratory personnel who are routinely exposed to N. meningitidis in solutions that may be aerosolized should be considered for vaccination (6 ).\nNo data are available regarding whether other closed civilian populations with characteristics similar to college freshman living in dormitories (e.g., preparatory school students) are at the same increased risk for disease. Prevention efforts should focus on groups in whom higher risk has been documented.\n\n# CONCLUSIONS\nCollege freshmen, especially those who live in dormitories, are at a modestly increased risk for meningococcal disease compared with other persons of the same age, and vaccination with the currently available quadrivalent meningococcal polysaccharide vaccine will decrease their risk for meningococcal disease. Continued surveillance is necessary to evaluate the impact of these recommendations, which have already prompted many universities and clinicians to offer vaccine to college freshmen.\nConsultation on the use of these recommendations or other issues regarding meningococcal disease is available from the Meningitis and Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC (telephone: 639-3158).\n\n# The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on"},"raw_text":{"kind":"string","value":"Centers for Disease Control and Prevention. Prevention and control of meningococcal disease and Meningococcal disease and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(No. RR-7):[inclusive page numbers].# INTRODUCTION\nEach year, 2,400-3,000 cases of meningococcal disease occur in the United States, resulting in a rate of 0.8-1.3 per 100,000 population (1)(2)(3). The case-fatality ratio for meningococcal disease is 10% (2 ), despite the continued sensitivity of meningococcus to many antibiotics, including penicillin (4 ). Meningococcal disease also causes substantial morbidity: 11%-19% of survivors have sequelae (e.g., neurologic disability, limb loss, and hearing loss [5,6 ]). During 1991-1998, the highest rate of meningococcal disease occurred among infants aged <1 year; however, the rate for persons aged 18-23 years was also higher than that for the general population (1.4 per 100,000) (CDC, National Electronic Telecommunications System for Surveillance, unpublished data).\n# BACKGOUND\nIn the United States, 95%-97% of cases of meningococcal disease are sporadic; however, since 1991, the frequency of localized outbreaks has increased (7)(8). Most of these outbreaks have been caused by serogroup C. However, in the past 3 years, localized outbreaks caused by serogroup Y and B organisms have also been reported (8 ). The proportion of sporadic meningococcal cases caused by serogroup Y also increased from 2% during 1989-1991 to 30% during 1992-1996 (2,9 ). The proportion of cases caused by each serogroup varies by age group; more than half of cases among infants aged <1 year are caused by serogroup B, for which no vaccine is licensed or available in the United States (2,10 ).\nPersons who have certain medical conditions are at increased risk for developing meningococcal disease, particularly persons who have deficiencies in the terminal common complement pathway (C3, C5-9) (11 ). Antecedent viral infection, household crowding, chronic underlying illness, and both active and passive smoking also are associated with increased risk for meningococcal disease (12)(13)(14)(15)(16)(17)(18)(19). During outbreaks, bar or nightclub patronage and alcohol use have also been associated with higher risk for disease (20)(21)(22). In the United States, blacks and persons of low socioeconomic status have been consistently at higher risk for meningococcal disease (2,3,12,18 ). However, race and low socioeconomic status are likely risk markers, rather than risk factors, for this disease.\nA recent multi-state, case-control study, in which controls were matched to casepatients by age group, revealed that in a multivariable analysis (controlling for sex and education), active and passive smoking, recent respiratory illness, corticosteroid use, new residence, new school, Medicaid insurance, and household crowding were all associated with increased risk for meningococcal disease (13 ). Income and race were not associated with increased risk. Additional research is needed to identify groups at risk that could benefit from prevention efforts.\n# MENINGOCOCCAL POLYSACCHARIDE VACCINES\nThe quadrivalent A, C, Y, W-135 vaccine (Menomune ® -A,C,Y,W-135, manufactured by Aventis Pasteur) is the formulation currently available in the United States (23 ). Each dose consists of 50 µg of the four purified bacterial capsular polysaccharides. Menomune ® is available in single-dose and 10-dose vials. (Fifty-dose vials are no longer available.)\n# Primary Vaccination\nFor both adults and children, vaccine is administered subcutaneously as a single, 0.5-ml dose. The vaccine can be administered at the same time as other vaccines but should be given at a different anatomic site. Protective levels of antibody are usually achieved within 7-10 days of vaccination.\n# Vaccine Immunogenicity and Efficacy\nThe immunogenicity and clinical efficacy of the serogroups A and C meningococcal vaccines have been well established. The serogroup A polysaccharide induces antibody in some children as young as 3 months of age, although a response comparable with that occurring in adults is not achieved until age 4-5 years. The serogroup C component is poorly immunogenic in recipients aged <18-24 months (24,25 ). The serogroups A and C vaccines have demonstrated estimated clinical efficacies of ≥85% in school-aged children and adults and are useful in controlling outbreaks (26)(27)(28)(29). Serogroups Y and W-135 polysaccharides are safe and immunogenic in adults and in children aged >2 years (30)(31)(32); although clinical protection has not been documented, vaccination with these polysaccharides induces bactericidal antibody. The antibody responses to each of the four polysaccharides in the quadrivalent vaccine are serogroupspecific and independent. Reduced clinical efficacy has not been demonstrated among persons who have received multiple doses of vaccine. However, recent serologic studies have suggested that multiple doses of serogroup C polysaccharide may cause immunologic tolerance to the group C polysaccharide (33,34 ).\n# Duration of Protection\nIn infants and children aged <5 years, measurable levels of antibodies against the group A and C polysaccharides decrease substantially during the first 3 years following a single dose of vaccine; in healthy adults, antibody levels also decrease, but antibodies are still detectable up to 10 years after vaccine administration (25,(35)(36)(37)(38). Similarly, although vaccine-induced clinical protection likely persists in school-aged children and adults for at least 3 years, the efficacy of the group A vaccine in children aged <5 years may decrease markedly within this period. In one study, efficacy declined from >90% to <10% 3 years after vaccination among children who were aged <4 years when vaccinated; efficacy was 67% among children who were ≥4 years of age at vaccination (39 ).\n# RECOMMENDATIONS FOR USE OF MENINGOCOCCAL VACCINE\nCurrent Advisory Committee on Immunization Practices (ACIP) guidelines (1 ) suggest that routine vaccination of civilians with the quadrivalent meningococcal polysaccharide vaccine is not recommended because of its relative ineffectiveness in children aged <2 years (the age group with the highest risk for sporadic disease) and because of its relatively short duration of protection. However, the vaccine is recommended for use in control of serogroup C meningococcal outbreaks. An outbreak is defined by the occurrence of three or more confirmed or probable cases of serogroup C meningococcal disease during a period of ≤3 months, with a resulting primary attack rate of at least 10 cases per 100,000 population. For calculation of this threshold, population-based rates are used and not age-specific attack rates, as have been calculated for college students. These recommendations are based on experience with serogroup C meningococcal outbreaks, but these principles may be applicable to outbreaks caused by the other vaccine-preventable meningococcal serogroups, including Y, W-135, and A.\nCollege freshmen, particularly those living in dormitories or residence halls, are at modestly increased risk for meningococcal disease compared with persons the same age who are not attending college. Therefore, ACIP has developed recommendations that address educating students and their parents about the risk for disease and about the vaccine so they can make individualized, informed decisions regarding vaccination. (See MMWR Vol. 49, RR-7, which can be referenced in the pages following this report.)\nRoutine vaccination with the quadrivalent vaccine is also recommended for certain high-risk groups, including persons who have terminal complement component deficiencies and those who have anatomic or functional asplenia. Research, industrial, and clinical laboratory personnel who are exposed routinely to Neisseria meningitidis in solutions that may be aerosolized also should be considered for vaccination (1 ).\nVaccination with the quadrivalent vaccine may benefit travelers to and U.S. citizens residing in countries in which N. meningitidis is hyperendemic or epidemic, particularly if contact with the local population will be prolonged. Epidemics of meningococcal disease are recurrent in that part of sub-Saharan Africa known as the \"meningitis belt,\" which extends from Senegal in the West to Ethiopia in the East (40 ). Epidemics in the meningitis belt usually occur during the dry season (i.e., from December to June); thus, vaccination is recommended for travelers visiting this region during that time. Information concerning geographic areas for which vaccination is recommended can be obtained from international health clinics for travelers, state health departments, and CDC (telephone [404] 332-4559; internet http://www.cdc.gov/travel/).\n# Revaccination\nRevaccination may be indicated for persons at high risk for infection (e.g., persons residing in areas in which disease is epidemic), particularly for children who were first vaccinated when they were <4 years of age; such children should be considered for revaccination after 2-3 years if they remain at high risk. Although the need for revaccination of older children and adults has not been determined, antibody levels rapidly decline over 2-3 years, and if indications still exist for vaccination, revaccination may be considered 3-5 years after receipt of the initial dose (1 ).\n# Precautions and Contraindications\nPolysaccharide meningococcal vaccines (both A/C and A/C/Y/W-135) have been extensively used in mass vaccination programs as well as in the military and among international travelers. Adverse reactions to polysaccharide meningococcal vaccines are generally mild; the most frequent reaction is pain and redness at the injection site, lasting for 1-2 days. Estimates of the incidence of such local reactions have varied, ranging from 4% to 56% (41,42 ). Transient fever occurred in up to 5% of vaccinees in some studies and occurs more commonly in infants (24,43 ).\nSevere reactions to polysaccharide meningococcal vaccine are uncommon (24,32,41-48 ) (R. Ball, U.S. Food and Drug Administration, personal communication). Most studies report the rate of systemic allergic reactions (e.g., urticaria, wheezing, and rash) as 0.0-0.1 per 100,000 vaccine doses (24,48 ). Anaphylaxis has been documented in <0.1 per 100,000 vaccine doses (23,47 ). Neurological reactions (e.g., seizures, anesthesias, and paresthesias) are also infrequently observed (42,47 ).\nThe Vaccine Adverse Events Reporting System (VAERS) is a passive surveillance system that detects adverse events that are temporally (but not necessarily causally) associated with vaccination, including adverse events that occur in military personnel. During 1991-1998, a total of 4,568,572 doses of polysaccharide meningococcal vaccine were distributed; 222 adverse events were reported for a rate of 49 adverse events per million doses. In 1999, 42 reports of adverse events were received, but the total number of vaccine doses distributed in 1999 is not yet available (R. Ball, U.S. Food and Drug Administration, personal communication). In the United States from July 1990 through October 1999, a total of 264 adverse events (and no deaths) were reported. Of these adverse events, 226 were categorized as \"less serious,\" with fever, headache, dizziness, and injection-site reactions most commonly reported. Thirty-eight serious adverse events (i.e., those that require hospitalization, are life-threatening, or result in permanent disability) that were temporally associated with vaccination were reported. Serious injection site reactions were reported in eight patients and allergic reactions in three patients. Four cases of Guillain-Barré Syndrome were reported in adults 7-16 days after receiving multiple vaccinations simultaneously, and one case of Guillain-Barré Syndrome was reported in a 9-year-old boy 32 days after receiving meningococcal vaccine alone. An additional seven patients reported serious nervous system abnormalities (e.g., convulsions, paresthesias, diploplia, and optic neuritis); all of these patients received multiple vaccinations simultaneously, making assessment of the role of meningococcal vaccine difficult. Of the 15 miscelleneous adverse events, only three occurred after meningococcal vaccine was administered alone. The minimal number of serious adverse events coupled with the substantial amount of vaccine distributed (>4 million doses) indicate that the vaccine can be considered safe (R. Ball, U.S. Food and Drug Administration, personal communication).\nStudies of vaccination during pregnancy have not documented adverse effects among either pregnant women or newborns (49-51 ). Based on data from studies involving the use of meningococcal vaccines and other polysaccharide vaccines during pregnancy, altering meningococcal vaccination recommendations during pregnancy is unnecessary.\n# ANTIMICROBIAL CHEMOPROPHYLAXIS\nIn the United States, the primary means for prevention of sporadic meningococcal disease is antimicrobial chemoprophylaxis of close contacts of infected persons (Table 1). Close contacts include a) household members, b) day care center contacts, and c) anyone directly exposed to the patient's oral secretions (e.g., through kissing, mouth-to-mouth resuscitation, endotracheal intubation, or endotracheal tube management). The attack rate for household contacts exposed to patients who have sporadic meningococcal disease is an estimated four cases per 1,000 persons exposed, which is 500-800 times greater than for the total population (52 ). Because the rate of secondary disease for close contacts is highest during the first few days after onset of disease in the index patient, antimicrobial chemoprophylaxis should be administered as soon as possible (ideally within 24 hours after identification of the index patient). Conversely, chemoprophylaxis administered >14 days after onset of illness in the index patient is probably of limited or no value. Oropharyngeal or nasopharyngeal cultures are not helpful in determining the need for chemoprophylaxis and may unnecessarily delay institution of this preventive measure.\nRifampin, ciprofloxacin, and ceftriaxone are all 90%-95% effective in reducing nasopharyngeal carriage of N. meningitidis and are all acceptable alternatives for chemoprophylaxis (53)(54)(55)(56). Systemic antimicrobial therapy of meningococcal disease with agents other than ceftriaxone or other third-generation cephalosporins may not reliably eradicate nasopharyngeal carriage of N. meningitidis. If other agents have been used for treatment, the index patient should receive chemoprophylactic antibiotics for eradication of nasopharyngeal carriage before being discharged from the hospital (57 ). \n# PROSPECTS FOR IMPROVED MENINGOCOCCAL VACCINES\nSerogroup A, C, Y, and W-135 meningococcal polysaccharides have been chemically conjugated to protein carriers. These meningococcal conjugate vaccines provoke a T-cell-dependent response that induces a stronger immune response in infants, primes immunologic memory, and leads to booster response to subsequent doses. These vaccines are expected to provide a longer duration of immunity than polysaccharides, even when administered in an infant series, and may provide herd immunity through protection from nasopharyngeal carriage. Clinical trials evaluating these vaccines are ongoing (58)(59)(60). When compared with polysaccharide vaccine, conjugated A and C meningococcal vaccines in infants and toddlers have resulted in similar side effects but improved immune response. Prior vaccination with group C polysaccharide likely does not prevent induction of memory by a subsequent dose of conjugate vaccine (61 ).\nIn late 1999, conjugate C meningococcal vaccines were introduced in the United Kingdom, where rates of meningococcal disease are approximately 2 per 100,000 population, and 30%-40% of cases are caused by serogroup C (62 ). In phase I of this program, infants are being vaccinated at 2, 3, and 4 months concurrently with DTP, Hib, and polio vaccines. Children aged 4-13 months are receiving \"catch-up\" vaccinations. Children aged 15-17 years are receiving one dose of conjugate C vaccine, and entering college students are receiving one dose of bivalent A/C polysaccharide vaccine. In phase II, scheduled to start in June 2000, a dose of conjugate vaccine will be administered to children aged 14 months-14 years and to persons aged 18-20 years who are not enrolled in college (62 ).\nConjugate meningococcal vaccines should be available in the United States within the next 2-4 years. In the interim, the polysaccharide vaccine should not be incorporated into the routine childhood immunization schedule, because the currently available meningococcal polysaccharide vaccines provide limited efficacy of short duration in young children (39 ), in whom the risk for disease is highest (2,3 ).\nBecause the group B polysaccharide is not immunogenic in humans, immunization strategies have focused primarily on noncapsular antigens (10,63 ). Several of these vaccines, developed from specific strains of serogroup B meningococci, have been safe, immunogenic, and efficacious among children and adults and have been used to control outbreaks in South America and Scandinavia (64)(65)(66)(67)(68). Strain-specific differences in outer-membrane proteins suggest that these vaccines may not provide protection against all serogroup B meningococci (69 ). No serogroup B vaccine is currently licensed or available in the United States.\n# CONCLUSIONS\nN. meningitidis is a leading cause of bacterial meningitis and sepsis in older children and young adults in the United States. Antimicrobial chemoprophylaxis of close contacts of persons who have sporadic meningococcal disease is the primary means for prevention of meningococcal disease in the United States.\nThe quadrivalent polysaccharide meningococcal vaccine (which protects against serogroups A, C, Y, and W-135) is recommended for control of serogroup C meningococcal disease outbreaks and for use among persons in certain high-risk groups. Travelers to countries in which disease is hyperendemic or epidemic may benefit from vaccination. In addition, college freshmen, especially those who live in dormitories, should be educated about meningococcal disease and the vaccine so that they can make an educated decision about vaccination.\nConjugate C meningococcal vaccines were recently introduced into routine childhood immunization schedules in the United Kingdom. These vaccines should be available in the United States within 2-4 years, offering a better tool for control and prevention of meningococcal disease.\n# Meningococcal Disease and College Students\n\n# Recommendations of the Advisory Committee on Immunization Practices (ACIP) INTRODUCTION\nNeisseria meningitidis causes both sporadic disease and outbreaks. As a result of the control of Haemophilus influenzae type b infections, N. meningitidis has become the leading cause of bacterial meningitis in children and young adults in the United States (1 ). Outbreaks of meningococcal disease were rare in the United States in the 1980s; however, since 1991, the frequency of localized outbreaks has increased (2 ). From July 1994 through July 1997, 42 meningococcal outbreaks were reported, four of which occurred at colleges (3 ). However, outbreaks continue to represent <3% of total U.S. cases (3 ).\nRates of meningococcal disease remain highest for infants, but in the past decade, rates have increased among adolescents and young adults (4 ). During 1994-1998, approximately two thirds of cases among persons aged 18-23 years were caused by serogroups C, Y, or W135 and therefore were potentially preventable with available vaccines (5 ) (CDC, unpublished data) (Figure 1). Although the quadrivalent meningococcal polysaccharide vaccine is safe and efficacious (5,6 ), decisions about who to target for vaccination require understanding of the groups at risk, the burden of disease, and the potential benefits of vaccination.\nNew data are available regarding the risk for meningococcal disease in college students. This report reviews these data and provides medical professionals with guidelines concerning meningococcal disease and college students.\n# BACKGROUND Meningococcal Disease in the Military\nMilitary recruits and college freshmen have several common characteristics (e.g., age, diverse geographic backgrounds, and crowded living conditions). Therefore, data obtained from recruits have been used to evaluate meningococcal disease and vaccine among college freshmen.\nBefore 1971, rates of meningococcal disease were elevated among U.S. military recruits. Outbreaks frequently followed large-scale mobilizations, and recruits in their (11 ), and by Fall 1982, all recruits were receiving the quadrivalent polysaccharide vaccine (7 ). However, rates of meningococcal disease in U.S. Army personnel declined before the 1971 vaccination campaigns (7 ), suggesting that smaller recruit populations at training installations and the natural periodicity of outbreaks may have contributed to the decline in disease. Rates of meningococcal disease remain low in the military, and large outbreaks no longer occur. Since 1990, records of all hospitalizations of active duty service members in military hospitals worldwide have been integrated with military personnel records in the Defense Medical Surveillance System (DMSS). During 1990-1998, the overall rate of hospitalizations from meningococcal disease among enlisted, active-duty service members was 0.51 per 100,000 person-years (J. Brundage, DMSS Army Medical Surveillance Activity, personal communication). Approximately 180,000 military recruits receive a single dose of quadrivalent polysaccharide meningococcal vaccine annually. Revaccination is only indicated when military personnel are traveling to countries in which N. meningitidis is hyperendemic or epidemic (D. Trump, personal communication).\nBefore 1999, students reporting to two of the U.S. military academies routinely received meningococcal vaccine. Last year, the other academies initiated meningococcal vaccine programs.\n# MENINGOCOCCAL DISEASE AND COLLEGE STUDENTS\nFour recent studies provide data concerning the risk for sporadic meningococcal disease among college students (Table 1) (12)(13)(14)(15). The earliest of these studies was conducted during the 1990-1991 and 1991-1992 school years. A questionnaire designed to evaluate risk factors for meningococcal disease among college students was sent to 1,900 universities, resulting in a 38% response rate (12 ). Forty-three cases of meningococcal disease were reported during the 2 years from colleges with a total enrollment of 4,393,744 students, for a low overall incidence of 1.0 per 100,000 population per year. However, cases of meningococcal disease occurred 9-23 times more frequently in students residing in dormitories than in those residing in other types of accommodations. The low response rate and the inability of the study to control for other risk factors (e.g., freshman status) make these results difficult to interpret. N/A= not applicable.\n# MMWR June 30, 2000\nIn a retrospective, cohort study conducted in Maryland for the period 1992-1997, 67 cases of meningococcal disease among persons aged 16-30 years were identified by active, laboratory-based surveillance (13 ). Of those cases, 14 were among students attending Maryland colleges, and 11 were among those in 4-year colleges. The overall incidence of meningococcal disease in Maryland college students was similar to the incidence in the U.S. population of persons the same age (1.74/100,000 vs. 1.44/100,000, respectively); however, rates of disease were elevated among students living in dormitories compared with students living off-campus (3.2/100,000 vs. 0.96/100,000, p=0.05).\nU.S. surveillance for meningococcal disease in college students was initiated in 1998; from September 1998 through August 1999, 90 cases of meningococcal disease were reported to CDC (14 ). These cases represent approximately 3% of the total cases of meningococcal disease that occur each year in the United States. Eighty-seven (97%) cases occurred in undergraduate students, and 40 (44%) occurred among the 2.27 million freshman students entering college each year (16 ). Among undergraduates, of the 71 (82%) isolates for which serogroup information was available, 35 (49%) were serogroup C, 17 (24%) were serogroup B, 15 (21%) were serogroup Y, and one (1%) was serogroup W-135. Eight (9%) students died. Of the five students who died for whom serogroup information was available, four had serogroup C isolates and one had serogroup Y.\nU.S. surveillance data from the 1998-1999 school year suggest that the overall rate of meningococcal disease among undergraduate college students is lower than the rate among persons aged 18-23 years who are not enrolled in college (Table 2) (0.7 vs. 1.5/100,000, respectively) (14,16 ). However, rates were higher among specific subgroups of college students. Among the approximately 590,000 freshmen who live in dormitories (17 ), the rate of meningococcal disease was 4.6/100,000, higher than any age group in the population other than children aged <2 years, but lower than the threshold of 10/100,000 recommended for initiating meningococcal vaccination campaigns (6 ).\nOf 90 students who had meningococcal disease attending college during the 1998- 1999 school year, 50 were enrolled in a case-control study and matched to 148 controls by school, sex, and undergraduate vs. graduate status (14 ). In a multivariable analysis, freshmen living in dormitories were at higher risk for meningococcal disease. In addition, white race, radiator heat, and recent upper respiratory infection were associated with disease.\nIn contrast to the United States, overall rates of meningococcal disease in the United Kingdom are higher among university students compared with non-students of similar age (15 ). From September 1994 through March 1997, university students had an increased annual rate of meningococcal disease (13.2/100,000) compared with nonstudents of similar age in the same health districts (5.5/100,000) and in those health districts without universities (3.7/100,000). As in the United States, regression analysis revealed that \"catered hall accommodations,\" the U.K. equivalent of dormitories, were the main risk factor. Higher rates of disease were observed at universities providing catered hall accommodations for >10% of their student population compared with those providing such housing for <10% of students (15.3/100,000 vs. 5.9/100,000). The increased rate of disease among university students has prompted the United Kingdom to initiate routine vaccination of incoming university students with a bivalent A/C polysaccharide vaccine as part of a new vaccination program (see MMWR 2000; Vol.49, No. RR-6 which can be referenced in the pages preceding this report) (18 ).\n# MENINGOCOCCAL VACCINE AND COLLEGE STUDENTS\nOn September 30, 1997, the American College Health Association (ACHA), which represents about half of colleges that have student health services, released a statement recommending that \"college health services [take] a more proactive role in alerting students and their parents about the dangers of meningococcal disease,\" that \"college students consider vaccination against potentially fatal meningococcal disease,\" and that \"colleges and universities ensure all students have access to a vaccination program for those who want to be vaccinated\" (Dr. MarJeanne Collins, Chairman, ACHA Vaccine Preventable Diseases Task Force, personal communication). Parent and college student advocates have also encouraged more widespread use of meningococcal vaccine in college students. In a joint study by ACHA and CDC, surveys were sent to 1,200 ACHA-member schools; of 691 responding schools, 57 (8%) reported that preexposure meningococcal vaccination campaigns had been conducted on their campus since September 1997. A median of 32 students were vaccinated at each school (range: 1-2,300) (J. Capparella, unpublished data). During the 1998-1999 school year, 3%-5% of 148 students enrolled in a case-control study reported receiving prophylactic meningococcal vaccination (14 ). Before the 1999 fall semester, many schools mailed information packets to incoming freshmen; data are not yet available regarding the proportion of students who have been vaccinated. worst case scenarios were evaluated by varying cost of vaccine and administration (range: $54-$88), costs per hospitalization ($10,924-$24,030), value of premature death based on lifetime productivity ($1.3-$4.8 million), cost of side effects of vaccine per case ($3,500-$12,270 per one million doses), and average cost of treating a case of sequelae ($0-$1,476). Vaccination coverage (60% and 100%) and vaccine efficacy (80% and 90%) were also varied for evaluation purposes. Vaccination of freshmen who live in dormitories would result in the administration of approximately 300,000-500,000 doses of vaccine each year, preventing 15-30 cases of meningococcal disease and one to three deaths each year. The cost per case prevented would be $600,000-$1.8 million, at a cost per death prevented of $7 million to $20 million.\n# Cost-effectiveness of meningococcal vaccine in college students\nVaccination of all freshman would result in the administration of approximately 1.4-2.3 million doses of vaccine each year, preventing 37-69 cases of meningococcal disease and two to four deaths caused by meningococcal disease each year. The cost per case prevented would be $1.4-2.9 million, at a cost per death prevented of $22 million to $48 million.\nThese data are similar to data derived from previous studies (19 ). They suggest that for society as a whole, vaccination of college students is unlikely to be cost-effective (Scott et al, unpublished data).\n# RECOMMENDATIONS FOR USE OF MENINGOCOCCAL POLYSACCHARIDE VACCINE IN COLLEGE STUDENTS\nCollege freshmen, particularly those who live in dormitories, are at modestly increased risk for meningococcal disease relative to other persons their age. Vaccination with the currently available quadrivalent meningococcal polysaccharide vaccine will decrease the risk for meningococcal disease among such persons. Vaccination does not eliminate risk because a) the vaccine confers no protection against serogroup B disease and b) although the vaccine is highly effective against serogroups C, Y, W-135, and A, efficacy is <100%.\nThe risk for meningococcal disease among college students is low; therefore, vaccination of all college students, all freshmen, or only freshmen who live in dormitories or residence halls is not likely to be cost-effective for society as a whole. Thus, ACIP is issuing the following recommendations regarding the use of meningococcal polysaccharide vaccines for college students.\nq Providers of medical care to incoming and current college freshmen, particularly those who plan to or already live in dormitories and residence halls, should, during routine medical care, inform these students and their parents about meningococcal disease and the benefits of vaccination. ACIP does not recommend that the level of increased risk among freshmen warrants any specific changes in living situations for freshmen.\nq College freshmen who want to reduce their risk for meningococcal disease should either be administered vaccine (by a doctor's office or student health service) or directed to a site where vaccine is available.\nq The risk for meningococcal disease among non-freshmen college students is similar to that for the general population. However, the vaccine is safe and efficacious and therefore can be provided to non-freshmen undergraduates who want to reduce their risk for meningococcal disease.\nq Colleges should inform incoming and/or current freshmen, particularly those who plan to live or already live in dormitories or residence halls, about meningococcal disease and the availability of a safe and effective vaccine.\nq Public health agencies should provide colleges and health-care providers with information about meningococcal disease and the vaccine as well as information regarding how to obtain vaccine.\n# Additional Considerations about Vaccination of College Students\nAlthough the need for revaccination of older children has not been determined, antibody levels decline rapidly over 2-3 years (6 ). Revaccination may be considered for freshmen who were vaccinated more than 3-5 years earlier (5 ). Routine revaccination of college students who were vaccinated as freshmen is not indicated.\nCollege students who are at higher risk for meningococcal disease because of a) underlying immune deficiencies or b) travel to countries in which N. meningitidis is hyperendemic or epidemic (i.e., the meningitis belt of sub-Saharan Africa) should be vaccinated (6 ). College students who are employed as research, industrial, and clinical laboratory personnel who are routinely exposed to N. meningitidis in solutions that may be aerosolized should be considered for vaccination (6 ).\nNo data are available regarding whether other closed civilian populations with characteristics similar to college freshman living in dormitories (e.g., preparatory school students) are at the same increased risk for disease. Prevention efforts should focus on groups in whom higher risk has been documented.\n# CONCLUSIONS\nCollege freshmen, especially those who live in dormitories, are at a modestly increased risk for meningococcal disease compared with other persons of the same age, and vaccination with the currently available quadrivalent meningococcal polysaccharide vaccine will decrease their risk for meningococcal disease. Continued surveillance is necessary to evaluate the impact of these recommendations, which have already prompted many universities and clinicians to offer vaccine to college freshmen.\nConsultation on the use of these recommendations or other issues regarding meningococcal disease is available from the Meningitis and Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC (telephone: [404] 639-3158).\n# The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":284,"cells":{"id":{"kind":"string","value":"27ff075c6327e0c1913e2e54e034b81d55f23f55"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Compared with older children and adults, infants aged <12 months have substantially higher rates of pertussis and the largest burden of pertussis-related deaths. Since 2004, a mean of 3,055 infant pertussis cases with more than 19 deaths has been reported each year through the National Notifiable Diseases Surveillance System (CDC, unpublished data, 2011). The majority of pertussis cases, hospitalizations, and deaths occur in infants aged ≤2 months, who are too young to be vaccinated; therefore, other strategies are required for prevention of pertussis in this age group. Since 2005, the Advisory Committee on Immunization Practices (ACIP) has recommended tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) booster vaccines to unvaccinated postpartum mothers and other family members of newborn infants to protect infants from pertussis, a strategy referred to as cocooning (1). Over the past 5 years, cocooning programs have proven difficult to implement widely (2,3). Cocooning programs might achieve moderate vaccination coverage among postpartum mothers but have had limited success in vaccinating fathers or other family members. On June 22, 2011, ACIP made recommendations for use of Tdap in unvaccinated pregnant women and updated recommendations on cocooning and special situations. This report summarizes data considered and conclusions made by ACIP and provides guidance for implementing its recommendations.#\nACIP recommends a single Tdap dose for persons aged 11 through 18 years who have completed the recommended childhood diphtheria and tetanus toxoids and pertussis/diphtheria and tetanus toxoids and acellular pertussis (DTP/DTaP) vaccination series and for adults aged 19 through 64 years who have not previously received Tdap (1,4). ACIP also recommends that adults aged 65 years and older receive a single dose of Tdap if they have or anticipate having close contact with an infant aged <12 months and previously have not received Tdap (5). Two Tdap vaccines are available in the United States. Adacel (Sanofi Pasteur) is licensed for use in persons aged 11 through 64 years. Boostrix (GlaxoSmithKline Biologicals) is licensed for use in persons aged ≥10 years (6).\nThe ACIP Pertussis Vaccines Work Group reviewed unpublished Tdap safety data from pregnancy registries and the Vaccine Adverse Event Reporting System (VAERS) and published studies on use of Tdap in pregnant women. The Work Group also considered the epidemiology of pertussis in infants and provider and program feedback, and then presented policy options for consideration to ACIP. These updated recommendations on use of Tdap in pregnant women are consistent with the goal of reducing the burden of pertussis in infants.\n\n# Safety of Tdap in Pregnant Women\nIn prelicensure evaluations, the safety of administering a booster dose of Tdap to pregnant women was not studied. Because information on use of Tdap in pregnant women was lacking, both manufacturers of Tdap established pregnancy registries to collect information and pregnancy outcomes from pregnant women vaccinated with Tdap. Data on the safety of administering Tdap to pregnant women are now available. ACIP reviewed published and unpublished data from VAERS, Sanofi Pasteur (Adacel) and GlaxoSmithKline (Boostrix) pregnancy registries, and small studies (7,8). ACIP concluded that available data from these studies did not suggest any elevated frequency or unusual patterns of adverse events in pregnant women who received Tdap and that the few serious adverse events reported were unlikely to have been caused by the vaccine. Both tetanus and diphtheria toxoids (Td) and tetanus toxoid vaccines have been used extensively in pregnant women worldwide to prevent neonatal tetanus. Tetanus-and diphtheria-toxoid containing vaccines administered during pregnancy have not been shown to be teratogenic (9,10). From a safety perspective, ACIP concluded that administration of Tdap after 20 weeks' gestation is preferred to minimize the risk for any low-frequency adverse event and the possibility that any spurious association might appear causative.\n\n# Transplacental Maternal Antibodies\nFor infants, transplacentally transferred maternal antibodies might provide protection against pertussis in early life and before beginning the primary DTaP series. Several studies provide evidence supporting the existence of efficient transplacental transfer of pertussis antibodies (7,11,12). Cord blood from newborn infants whose mothers received Tdap during pregnancy or before pregnancy had higher concentrations of pertussis antibodies when compared with cord blood from newborn infants of unvaccinated mothers (7,11). The half-life of transferred maternal pertussis antibodies is approximately 6 weeks (12). The effectiveness of maternal antipertussis antibodies in preventing infant pertussis is not yet known, but pertussis-specific antibodies likely confer protection and modify the severity of pertussis illness (13,14). In addition, a woman vaccinated with Tdap during pregnancy likely will be protected at time of delivery, and therefore less likely to transmit pertussis to her infant. After receipt of Tdap, boosted pertussis-specific antibody levels peak after several weeks, followed by a decline over several months (15,16). To optimize the concentration of maternal antibodies transferred to the fetus, ACIP concluded that unvaccinated pregnant women should receive Tdap, preferably in the third or late second (after 20 weeks gestation) trimester.\n\n# Interference with Infant Immune Response to Primary DTaP Vaccination\nSeveral studies have suggested that maternal pertussis antibodies can inhibit active pertussis-specific antibody production after administration of DTaP vaccine to infants of mothers vaccinated with Tdap during pregnancy, referred to as blunting (12,17). Because correlates of protection are not fully understood, the clinical importance of blunting of an infant's immune response is not clear. Evidence suggests that any blunting would be short-lived because circulating maternal antibodies decline rapidly (12,18). Circulating maternal pertussis antibodies might reduce an infant's risk for pertussis in the first few months of life but slightly increase risk for disease because of a blunted immune response after receipt of primary DTaP doses. The benefit would be to reduce the risk for disease and death in infants aged <3 months, but the trade-off might be to increase the occurrence of pertussis in older infants; however, this group experiences a substantially lower burden of hospitalizations and mortality (National Notifiable Diseases Surveillance System, CDC, unpublished data, 2011).\nCurrently, two clinical trials are being conducted to measure the immune response of infants receiving DTaP immunization at ages 2, 4, and 6 months whose mothers received Tdap during the third trimester of pregnancy (19,20). These trials also are designed to evaluate safety and immunogenicity of Tdap during pregnancy, but are not sufficiently powered to assess disease endpoints. Analysis of interim data from one trial (19, unpublished data) measured infant antibody to pertussis antigens in a blinded fashion for two groups: infants whose mothers received Tdap and infants whose mothers received Td. The first group had elevated antipertussis antibody levels compared with the second at birth and before dose 1, which might be the result of passive antibody transfer, but had lower antipertussis antibody levels after dose 3. In both groups, antipertussis antibody levels were comparable before doses 2 and 3. Although the first group had lower antipertussis antibody levels after dose 3, the evidence of sufficient immune response to DTaP doses compared with the second group was reassuring. ACIP concluded that the interim data are consistent with previously published literature suggesting a short duration of blunting of the infant response, and that the potential benefit of protection from maternal antibodies in newborn infants outweighs the potential risk for shifting disease burden to later in infancy.\n\n# Cocooning\nCocooning is defined as the strategy of vaccinating pregnant women immediately postpartum and all other close contacts of infants aged <12 months with Tdap to reduce the risk for transmission of pertussis to infants. Cocooning has been recommended by ACIP since 2005. Cocooning programs have achieved moderate postpartum coverage among mothers but have had limited success in vaccinating fathers or other family members (3) (CDC, unpublished data, 2011). Programmatic challenges make implementation of cocooning programs complex and also impede program expansion and sustainability (2). The effectiveness of vaccinating postpartum mothers and close contacts to protect infants from pertussis is not yet known, but the delay in antibody response among those vaccinated with Tdap after an infant's birth might result in insufficient protection to infants during the first weeks of life (21). ACIP concluded that cocooning alone is an insufficient strategy to prevent pertussis morbidity and mortality in newborn infants. Regardless, ACIP concluded that cocooning likely provides indirect protection to infants and firmly supports vaccination with Tdap for unvaccinated persons who anticipate close contact with an infant.\n\n# Decision and Cost Effectiveness Analysis\nA decision analysis and cost effectiveness model was developed to assess the impact and cost effectiveness of maternal Tdap vaccination during pregnancy compared with immediately postpartum. The model showed that Tdap vaccination during pregnancy would prevent more infant cases, hospitalizations, and deaths compared with the postpartum dose for two reasons: 1) vaccination during pregnancy benefits the mother and infant by providing earlier protection to the mother, thereby protecting the infant at birth; and 2) vaccination during late pregnancy maximizes transfer of maternal antibodies to the infant, likely providing direct protection to the infant for a period after birth. Model results were most sensitive to efficacy of maternal antibodies and risk for disease as a result of blunting; however, a sensitivity analysis in which infants were assumed to have as little as 20% efficacy of maternal antibodies and a 60% increase in risk for disease as a result of blunting found that maternal vaccination during pregnancy was more cost effective and prevented a greater proportion of infant cases and deaths than postpartum maternal vaccination (22).\n\n# Guidance for Use\nMaternal vaccination. ACIP recommends that women's health-care personnel implement a Tdap vaccination program for pregnant women who previously have not received Tdap. Health-care personnel should administer Tdap during pregnancy, preferably during the third or late second trimester (after 20 weeks' gestation). If not administered during pregnancy, Tdap should be administered immediately postpartum.\nCocooning. ACIP recommends that adolescents and adults (e.g., parents, siblings, grandparents, childcare providers, and health-care personnel) who have or anticipate having close contact with an infant aged <12 months should receive a single dose of Tdap to protect against pertussis if they have not previously received Tdap. Ideally, these adolescents and adults should receive Tdap at least 2 weeks before beginning close contact with the infant.\n\n# Special Situations\nPregnant women due for tetanus booster. If a tetanus and diphtheria booster vaccination is indicated during pregnancy for a woman who has previously not received Tdap (i.e., more than 10 years since previous Td), then Tdap should be administered during pregnancy, preferably during the third or late second trimester (after 20 weeks' gestation).\nWound management for pregnant women. As part of standard wound management care to prevent tetanus, a tetanus toxoid--containing vaccine might be recommended for wound management in a pregnant woman if 5 years or more have elapsed since last receiving Td. If a tetanus booster is indicated for a pregnant woman who previously has not received Tdap, Tdap should be administered.\nPregnant women with unknown or incomplete tetanus vaccination. To ensure protection against maternal and neonatal tetanus, pregnant women who have never been vaccinated against tetanus should receive three vaccinations containing tetanus and reduced diphtheria toxoids. The recommended schedule is 0, 4 weeks, and 6 to 12 months. Tdap should replace 1 dose of Td, preferably during the third or late second trimester (after 20 weeks' gestation) of pregnancy."},"raw_text":{"kind":"string","value":"Compared with older children and adults, infants aged <12 months have substantially higher rates of pertussis and the largest burden of pertussis-related deaths. Since 2004, a mean of 3,055 infant pertussis cases with more than 19 deaths has been reported each year through the National Notifiable Diseases Surveillance System (CDC, unpublished data, 2011). The majority of pertussis cases, hospitalizations, and deaths occur in infants aged ≤2 months, who are too young to be vaccinated; therefore, other strategies are required for prevention of pertussis in this age group. Since 2005, the Advisory Committee on Immunization Practices (ACIP) has recommended tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) booster vaccines to unvaccinated postpartum mothers and other family members of newborn infants to protect infants from pertussis, a strategy referred to as cocooning (1). Over the past 5 years, cocooning programs have proven difficult to implement widely (2,3). Cocooning programs might achieve moderate vaccination coverage among postpartum mothers but have had limited success in vaccinating fathers or other family members. On June 22, 2011, ACIP made recommendations for use of Tdap in unvaccinated pregnant women and updated recommendations on cocooning and special situations. This report summarizes data considered and conclusions made by ACIP and provides guidance for implementing its recommendations.# \nACIP recommends a single Tdap dose for persons aged 11 through 18 years who have completed the recommended childhood diphtheria and tetanus toxoids and pertussis/diphtheria and tetanus toxoids and acellular pertussis (DTP/DTaP) vaccination series and for adults aged 19 through 64 years who have not previously received Tdap (1,4). ACIP also recommends that adults aged 65 years and older receive a single dose of Tdap if they have or anticipate having close contact with an infant aged <12 months and previously have not received Tdap (5). Two Tdap vaccines are available in the United States. Adacel (Sanofi Pasteur) is licensed for use in persons aged 11 through 64 years. Boostrix (GlaxoSmithKline Biologicals) is licensed for use in persons aged ≥10 years (6).\nThe ACIP Pertussis Vaccines Work Group reviewed unpublished Tdap safety data from pregnancy registries and the Vaccine Adverse Event Reporting System (VAERS) and published studies on use of Tdap in pregnant women. The Work Group also considered the epidemiology of pertussis in infants and provider and program feedback, and then presented policy options for consideration to ACIP. These updated recommendations on use of Tdap in pregnant women are consistent with the goal of reducing the burden of pertussis in infants.\n# Safety of Tdap in Pregnant Women\nIn prelicensure evaluations, the safety of administering a booster dose of Tdap to pregnant women was not studied. Because information on use of Tdap in pregnant women was lacking, both manufacturers of Tdap established pregnancy registries to collect information and pregnancy outcomes from pregnant women vaccinated with Tdap. Data on the safety of administering Tdap to pregnant women are now available. ACIP reviewed published and unpublished data from VAERS, Sanofi Pasteur (Adacel) and GlaxoSmithKline (Boostrix) pregnancy registries, and small studies (7,8). ACIP concluded that available data from these studies did not suggest any elevated frequency or unusual patterns of adverse events in pregnant women who received Tdap and that the few serious adverse events reported were unlikely to have been caused by the vaccine. Both tetanus and diphtheria toxoids (Td) and tetanus toxoid vaccines have been used extensively in pregnant women worldwide to prevent neonatal tetanus. Tetanus-and diphtheria-toxoid containing vaccines administered during pregnancy have not been shown to be teratogenic (9,10). From a safety perspective, ACIP concluded that administration of Tdap after 20 weeks' gestation is preferred to minimize the risk for any low-frequency adverse event and the possibility that any spurious association might appear causative.\n# Transplacental Maternal Antibodies\nFor infants, transplacentally transferred maternal antibodies might provide protection against pertussis in early life and before beginning the primary DTaP series. Several studies provide evidence supporting the existence of efficient transplacental transfer of pertussis antibodies (7,11,12). Cord blood from newborn infants whose mothers received Tdap during pregnancy or before pregnancy had higher concentrations of pertussis antibodies when compared with cord blood from newborn infants of unvaccinated mothers (7,11). The half-life of transferred maternal pertussis antibodies is approximately 6 weeks (12). The effectiveness of maternal antipertussis antibodies in preventing infant pertussis is not yet known, but pertussis-specific antibodies likely confer protection and modify the severity of pertussis illness (13,14). In addition, a woman vaccinated with Tdap during pregnancy likely will be protected at time of delivery, and therefore less likely to transmit pertussis to her infant. After receipt of Tdap, boosted pertussis-specific antibody levels peak after several weeks, followed by a decline over several months (15,16). To optimize the concentration of maternal antibodies transferred to the fetus, ACIP concluded that unvaccinated pregnant women should receive Tdap, preferably in the third or late second (after 20 weeks gestation) trimester.\n# Interference with Infant Immune Response to Primary DTaP Vaccination\nSeveral studies have suggested that maternal pertussis antibodies can inhibit active pertussis-specific antibody production after administration of DTaP vaccine to infants of mothers vaccinated with Tdap during pregnancy, referred to as blunting (12,17). Because correlates of protection are not fully understood, the clinical importance of blunting of an infant's immune response is not clear. Evidence suggests that any blunting would be short-lived because circulating maternal antibodies decline rapidly (12,18). Circulating maternal pertussis antibodies might reduce an infant's risk for pertussis in the first few months of life but slightly increase risk for disease because of a blunted immune response after receipt of primary DTaP doses. The benefit would be to reduce the risk for disease and death in infants aged <3 months, but the trade-off might be to increase the occurrence of pertussis in older infants; however, this group experiences a substantially lower burden of hospitalizations and mortality (National Notifiable Diseases Surveillance System, CDC, unpublished data, 2011).\nCurrently, two clinical trials are being conducted to measure the immune response of infants receiving DTaP immunization at ages 2, 4, and 6 months whose mothers received Tdap during the third trimester of pregnancy (19,20). These trials also are designed to evaluate safety and immunogenicity of Tdap during pregnancy, but are not sufficiently powered to assess disease endpoints. Analysis of interim data from one trial (19, unpublished data) measured infant antibody to pertussis antigens in a blinded fashion for two groups: infants whose mothers received Tdap and infants whose mothers received Td. The first group had elevated antipertussis antibody levels compared with the second at birth and before dose 1, which might be the result of passive antibody transfer, but had lower antipertussis antibody levels after dose 3. In both groups, antipertussis antibody levels were comparable before doses 2 and 3. Although the first group had lower antipertussis antibody levels after dose 3, the evidence of sufficient immune response to DTaP doses compared with the second group was reassuring. ACIP concluded that the interim data are consistent with previously published literature suggesting a short duration of blunting of the infant response, and that the potential benefit of protection from maternal antibodies in newborn infants outweighs the potential risk for shifting disease burden to later in infancy.\n# Cocooning\nCocooning is defined as the strategy of vaccinating pregnant women immediately postpartum and all other close contacts of infants aged <12 months with Tdap to reduce the risk for transmission of pertussis to infants. Cocooning has been recommended by ACIP since 2005. Cocooning programs have achieved moderate postpartum coverage among mothers but have had limited success in vaccinating fathers or other family members (3) (CDC, unpublished data, 2011). Programmatic challenges make implementation of cocooning programs complex and also impede program expansion and sustainability (2). The effectiveness of vaccinating postpartum mothers and close contacts to protect infants from pertussis is not yet known, but the delay in antibody response among those vaccinated with Tdap after an infant's birth might result in insufficient protection to infants during the first weeks of life (21). ACIP concluded that cocooning alone is an insufficient strategy to prevent pertussis morbidity and mortality in newborn infants. Regardless, ACIP concluded that cocooning likely provides indirect protection to infants and firmly supports vaccination with Tdap for unvaccinated persons who anticipate close contact with an infant.\n# Decision and Cost Effectiveness Analysis\nA decision analysis and cost effectiveness model was developed to assess the impact and cost effectiveness of maternal Tdap vaccination during pregnancy compared with immediately postpartum. The model showed that Tdap vaccination during pregnancy would prevent more infant cases, hospitalizations, and deaths compared with the postpartum dose for two reasons: 1) vaccination during pregnancy benefits the mother and infant by providing earlier protection to the mother, thereby protecting the infant at birth; and 2) vaccination during late pregnancy maximizes transfer of maternal antibodies to the infant, likely providing direct protection to the infant for a period after birth. Model results were most sensitive to efficacy of maternal antibodies and risk for disease as a result of blunting; however, a sensitivity analysis in which infants were assumed to have as little as 20% efficacy of maternal antibodies and a 60% increase in risk for disease as a result of blunting found that maternal vaccination during pregnancy was more cost effective and prevented a greater proportion of infant cases and deaths than postpartum maternal vaccination (22).\n# Guidance for Use\nMaternal vaccination. ACIP recommends that women's health-care personnel implement a Tdap vaccination program for pregnant women who previously have not received Tdap. Health-care personnel should administer Tdap during pregnancy, preferably during the third or late second trimester (after 20 weeks' gestation). If not administered during pregnancy, Tdap should be administered immediately postpartum.\nCocooning. ACIP recommends that adolescents and adults (e.g., parents, siblings, grandparents, childcare providers, and health-care personnel) who have or anticipate having close contact with an infant aged <12 months should receive a single dose of Tdap to protect against pertussis if they have not previously received Tdap. Ideally, these adolescents and adults should receive Tdap at least 2 weeks before beginning close contact with the infant.\n# Special Situations\nPregnant women due for tetanus booster. If a tetanus and diphtheria booster vaccination is indicated during pregnancy for a woman who has previously not received Tdap (i.e., more than 10 years since previous Td), then Tdap should be administered during pregnancy, preferably during the third or late second trimester (after 20 weeks' gestation).\nWound management for pregnant women. As part of standard wound management care to prevent tetanus, a tetanus toxoid--containing vaccine might be recommended for wound management in a pregnant woman if 5 years or more have elapsed since last receiving Td. If a tetanus booster is indicated for a pregnant woman who previously has not received Tdap, Tdap should be administered.\nPregnant women with unknown or incomplete tetanus vaccination. To ensure protection against maternal and neonatal tetanus, pregnant women who have never been vaccinated against tetanus should receive three vaccinations containing tetanus and reduced diphtheria toxoids. The recommended schedule is 0, 4 weeks, and 6 to 12 months. Tdap should replace 1 dose of Td, preferably during the third or late second trimester (after 20 weeks' gestation) of pregnancy."},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":285,"cells":{"id":{"kind":"string","value":"0f8932a83e23cfcfd3cff542319409ed7ca645d4"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"The purpose of this Compendium is to provide information on rabies to veterinarians, public health officials, and others concerned with rabies control. These recommendations serve as the basis for animal rabies-control programs throughout the United States and facilitate standardization of procedures among jurisdictions, thereby contributing to an effective national rabies-control program. This document is reviewed annually and revised as necessary. Recommendations on immunization procedures are contained in Part I; all animal rabies vaccines licensed by the United States Department of Agriculture (USDA) and marketed in the United States are listed in Part II; Part III details the principles of rabies control.#\nfor wildlife. For this reason and because virus-shedding periods are unknown, wild or exotic carnivores and bats should not be kept as pets. Zoos or research institutions may establish vaccination programs that attempt to protect valuable animals, but these programs should not be in lieu of appropriate public health activities that protect humans. The use of licensed oral vaccines for the mass immunization of wildlife should be considered in selected situations, with the approval of the state agency responsible for animal rabies control.\n\n# E. Accidental Human Exposure to Vaccine\nAccidental inoculation can occur during administration of animal rabies vaccine. Such exposure to inactivated vaccines constitutes no risk for acquiring rabies.\n\n# F. Identification of Vaccinated Animals\nAll agencies and veterinarians should adopt the standard tag system. This practice will aid the administration of local, state, national, and international rabies-control procedures. Animal license tags should be distinguishable in shape and color from rabies tags. Anodized aluminum rabies tags should be no less than 0.064 inches in thickness. rous mammal (or a bat) not available for testing should be regarded as having been exposed to rabies. a. Dogs and Cats. Unvaccinated dogs and cats exposed to a rabid animal should be euthanized immediately. If the owner is unwilling to have this done, the animal should be placed in strict isolation for 6 months and vaccinated 1 month before being released. Animals with expired vaccinations need to be evaluated on a case-by-case basis. Dogs and cats that are currently vaccinated should be revaccinated immediately, kept under the owner's control, and observed for 45 days. b. Livestock. All species of livestock are susceptible to rabies; cattle and horses are among the most frequently infected. Livestock exposed to a rabid animal and currently vaccinated with a vaccine approved by USDA for that species should be revaccinated immediately and observed for 45 days. Unvaccinated livestock should be slaughtered immediately. If the owner is unwilling to have this done, the animal should be kept under close observation for 6 months. The following are recommendations for owners of unvaccinated livestock exposed to rabid animals: 1) If the animal is slaughtered within 7 days of being bitten, its tissues may be eaten without risk of infection, provided liberal portions of the exposed area are discarded. Federal meat inspectors must reject for slaughter any animal known to have been exposed to rabies within 8 months. 2) Neither tissues nor milk from a rabid animal should be used for human or animal consumption. However, because pasteurization temperatures will inactivate rabies virus, drinking pasteurized milk or eating cooked meat does not constitute a rabies exposure.\n\n# Rabies Tags\n3) It is rare to have more than one rabid animal in a herd or to have herbivoreto-herbivore transmission; therefore, it may not be necessary to restrict the rest of the herd if a single animal has been exposed to or infected by rabies. c. Other Animals. Other animals bitten by a rabid animal should be euthanized immediately. Such animals currently vaccinated with a vaccine approved by USDA for that species may be revaccinated immediately and placed in strict isolation for at least 90 days. 6. Management of Animals That Bite Humans. A healthy dog or cat that bites a person should be confined and observed for 10 days; it is recommended that rabies vaccine not be administered during the observation period. Such animals should be evaluated by a veterinarian at the first sign of illness during confinement. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be euthanized, its head removed, and the head shipped under refrigeration for examination by a qualified laboratory designated by the local or state health department. Any stray or unwanted dog or cat that bites a person may be euthanized immediately and the head submitted as described above for rabies examination. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department. Prior vaccination of an animal may not preclude the necessity for euthanasia and testing if the period of virus shedding is unknown for that species. Management of animals other than dogs and cats depends on the species, the circumstances of the bite, and the epidemiology of rabies in the area.\n\n# C. Control Methods in Wildlife\nThe public should be warned not to handle wildlife. Wild mammals (as well as the offspring of wild species crossbred with domestic dogs and cats) that bite or otherwise expose people, pets, or livestock should be considered for euthanasia and rabies examination. A person bitten by any wild mammal should immediately report the incident to a physician who can evaluate the need for antirabies treatment.- 1. Terrestrial Mammals. Continuous and persistent government-funded programs for trapping or poisoning wildlife are not cost effective in reducing wildlife rabies reservoirs on a statewide basis. However, limited control in high-contact areas (e.g., picnic grounds, camps, or suburban areas) might be indicated for the removal of selected high-risk species of wildlife. The state wildlife agency and state health department should be consulted for coordination of any proposed vaccination or population-reduction programs. 2. Bats. Indigenous rabid bats have been reported from every state except Alaska and Hawaii and have caused rabies in at least 22 humans in the United States. However, it is neither feasible nor desirable to control rabies in bats by programs to reduce bat populations. Bats should be excluded from houses and surrounding structures to prevent direct association with humans. Such structures should then be made bat-proof by sealing entrances used by bats.\nThe Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to lists@list.cdc.gov. The body content should read subscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800.\nData in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (404) 332-4555.\nAll material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. 6U.S. Government Printing Office: 1996-733-175/27048 Region IV"},"raw_text":{"kind":"string","value":"The purpose of this Compendium is to provide information on rabies to veterinarians, public health officials, and others concerned with rabies control. These recommendations serve as the basis for animal rabies-control programs throughout the United States and facilitate standardization of procedures among jurisdictions, thereby contributing to an effective national rabies-control program. This document is reviewed annually and revised as necessary. Recommendations on immunization procedures are contained in Part I; all animal rabies vaccines licensed by the United States Department of Agriculture (USDA) and marketed in the United States are listed in Part II; Part III details the principles of rabies control.# \nfor wildlife. For this reason and because virus-shedding periods are unknown, wild or exotic carnivores and bats should not be kept as pets. Zoos or research institutions may establish vaccination programs that attempt to protect valuable animals, but these programs should not be in lieu of appropriate public health activities that protect humans. The use of licensed oral vaccines for the mass immunization of wildlife should be considered in selected situations, with the approval of the state agency responsible for animal rabies control.\n# E. Accidental Human Exposure to Vaccine\nAccidental inoculation can occur during administration of animal rabies vaccine. Such exposure to inactivated vaccines constitutes no risk for acquiring rabies.\n# F. Identification of Vaccinated Animals\nAll agencies and veterinarians should adopt the standard tag system. This practice will aid the administration of local, state, national, and international rabies-control procedures. Animal license tags should be distinguishable in shape and color from rabies tags. Anodized aluminum rabies tags should be no less than 0.064 inches in thickness. rous mammal (or a bat) not available for testing should be regarded as having been exposed to rabies. a. Dogs and Cats. Unvaccinated dogs and cats exposed to a rabid animal should be euthanized immediately. If the owner is unwilling to have this done, the animal should be placed in strict isolation for 6 months and vaccinated 1 month before being released. Animals with expired vaccinations need to be evaluated on a case-by-case basis. Dogs and cats that are currently vaccinated should be revaccinated immediately, kept under the owner's control, and observed for 45 days. b. Livestock. All species of livestock are susceptible to rabies; cattle and horses are among the most frequently infected. Livestock exposed to a rabid animal and currently vaccinated with a vaccine approved by USDA for that species should be revaccinated immediately and observed for 45 days. Unvaccinated livestock should be slaughtered immediately. If the owner is unwilling to have this done, the animal should be kept under close observation for 6 months. The following are recommendations for owners of unvaccinated livestock exposed to rabid animals: 1) If the animal is slaughtered within 7 days of being bitten, its tissues may be eaten without risk of infection, provided liberal portions of the exposed area are discarded. Federal meat inspectors must reject for slaughter any animal known to have been exposed to rabies within 8 months. 2) Neither tissues nor milk from a rabid animal should be used for human or animal consumption. However, because pasteurization temperatures will inactivate rabies virus, drinking pasteurized milk or eating cooked meat does not constitute a rabies exposure.\n# Rabies Tags\n3) It is rare to have more than one rabid animal in a herd or to have herbivoreto-herbivore transmission; therefore, it may not be necessary to restrict the rest of the herd if a single animal has been exposed to or infected by rabies. c. Other Animals. Other animals bitten by a rabid animal should be euthanized immediately. Such animals currently vaccinated with a vaccine approved by USDA for that species may be revaccinated immediately and placed in strict isolation for at least 90 days. 6. Management of Animals That Bite Humans. A healthy dog or cat that bites a person should be confined and observed for 10 days; it is recommended that rabies vaccine not be administered during the observation period. Such animals should be evaluated by a veterinarian at the first sign of illness during confinement. Any illness in the animal should be reported immediately to the local health department. If signs suggestive of rabies develop, the animal should be euthanized, its head removed, and the head shipped under refrigeration for examination by a qualified laboratory designated by the local or state health department. Any stray or unwanted dog or cat that bites a person may be euthanized immediately and the head submitted as described above for rabies examination. Other biting animals that might have exposed a person to rabies should be reported immediately to the local health department. Prior vaccination of an animal may not preclude the necessity for euthanasia and testing if the period of virus shedding is unknown for that species. Management of animals other than dogs and cats depends on the species, the circumstances of the bite, and the epidemiology of rabies in the area.\n# C. Control Methods in Wildlife\nThe public should be warned not to handle wildlife. Wild mammals (as well as the offspring of wild species crossbred with domestic dogs and cats) that bite or otherwise expose people, pets, or livestock should be considered for euthanasia and rabies examination. A person bitten by any wild mammal should immediately report the incident to a physician who can evaluate the need for antirabies treatment.* 1. Terrestrial Mammals. Continuous and persistent government-funded programs for trapping or poisoning wildlife are not cost effective in reducing wildlife rabies reservoirs on a statewide basis. However, limited control in high-contact areas (e.g., picnic grounds, camps, or suburban areas) might be indicated for the removal of selected high-risk species of wildlife. The state wildlife agency and state health department should be consulted for coordination of any proposed vaccination or population-reduction programs. 2. Bats. Indigenous rabid bats have been reported from every state except Alaska and Hawaii and have caused rabies in at least 22 humans in the United States. However, it is neither feasible nor desirable to control rabies in bats by programs to reduce bat populations. Bats should be excluded from houses and surrounding structures to prevent direct association with humans. Such structures should then be made bat-proof by sealing entrances used by bats.\nThe Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to lists@list.cdc.gov. The body content should read subscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at http://www.cdc.gov/ or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800.\nData in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (404) 332-4555.\nAll material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. 6U.S. Government Printing Office: 1996-733-175/27048 Region IV"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":286,"cells":{"id":{"kind":"string","value":"24f7b3ef063e71fcf24f61d85b0392fa597aafb5"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction\nEpidemics of influenza typically occur during the winter months in temperate regions and have been responsible for an average of approximately 36,000 deaths/year in the United States during 1990-1999 (1). Influenza viruses also can cause pandemics, during which rates of illness and death from influenza-related complications can increase worldwide. Influenza viruses cause disease among all age groups (2)(3)(4). Rates of infection are highest among children, but rates of serious illness and death are highest among persons aged >65 years and persons of any age who have medical conditions that place them at increased risk for complications from influenza (2,(5)(6)(7).\nInfluenza vaccination is the primary method for preventing influenza and its severe complications. In this report from the Advisory Committee on Immunization Practices (ACIP), the primary target groups recommended for annual vaccination are 1) persons at increased risk for influenza-related complications (e.g., those aged >65 years, children aged 6-23 months, pregnant women, and persons of any age with certain chronic medical conditions); 2) persons aged 50-64 years because this group has an elevated prevalence of certain chronic medical conditions; and 3) persons who live with or care for persons at high risk (e.g., health-care workers and household contacts who have frequent contact with persons at high risk and who can transmit influenza to those persons at high risk). Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed, chiefly among persons aged 65 years, among children aged 6-23 months, and among health-care workers. ACIP recommends using strategies to improve vaccination levels, including using reminder/recall systems and standing orders programs (19,20). Although influenza vaccination remains the cornerstone for the control and treatment of influenza, information on antiviral medications is also presented because these agents are an adjunct to vaccine.\n\n# Primary Changes and Updates in the Recommendations\nThe 2004 recommendations include four principal changes or updates:\n1. ACIP recommends that healthy children aged 6-23 months, and close contacts of children aged 0-23 months, be vaccinated against influenza (see Target Groups for Vaccination).\n\n# Influenza and Its Burden\n\n# Biology of Influenza\nInfluenza A and B are the two types of influenza viruses that cause epidemic human disease (21). Influenza A viruses are further categorized into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). Influenza B viruses are not categorized into subtypes. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have been in global circulation. In 2001, influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses began circulating widely. Both influenza A and B viruses are further separated into groups on the basis of antigenic characteristics. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses.\nA person's immunity to the surface antigens, including hemagglutinin, reduces the likelihood of infection and severity of disease if infection occurs (22). Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype (23). Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual incorporation of one or more new strains in each year's influenza vaccine.\n\n# Clinical Signs and Symptoms of Influenza\nInfluenza viruses are spread from person to person primarily through the coughing and sneezing of infected persons (21). The incubation period for influenza is 1-4 days, with an average of 2 days (24). Adults typically are infectious from the day before symptoms begin through approximately 5 days after illness onset. Children can be infectious for >10 days, and young children can shed virus for <6 days before their illness onset. Severely immunocompromised persons can shed virus for weeks or months (25)(26)(27)(28).\nUncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis) (29). Among children, otitis media, nausea, and vomiting are also commonly reported with influenza illness (30)(31)(32). Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone (see Role of Laboratory Diagnosis). Reported sensitivities and specificities of clinical definitions for influenza-like illness in studies primarily among adults that include fever and cough have ranged from 63% to 78% and 55% to 71%, respectively, compared with viral culture (33,34). Sensitivity and predictive value of clinical definitions can vary, depending on the degree of co-circulation of other respiratory pathogens and the level of influenza activity (35). A study among older nonhospitalized patients determined that symptoms of fever, cough, and acute onset had a positive predictive value of 30% for influenza (36), whereas a study of hospitalized older patients with chronic cardiopulmonary disease determined that a combination of fever, cough, and illness of <7 days was 78% sensitive and 73% specific for influenza (37). However, a study among vaccinated older persons with chronic lung disease reported that cough was not predictive of influenza infection, although having a fever or feverishness was 68% sensitive and 54% specific for influenza infection (38).\nInfluenza illness typically resolves after a limited number of days for the majority of persons, although cough and malaise can persist for >2 weeks. Among certain persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a coinfection with other viral or bacterial pathogens (39). Young children with influenza infection can have initial symptoms mimicking bacterial sepsis with high fevers (40,41), and <20% of children hospitalized with influenza can have febrile seizures (31,42). Influenza infection has also been associated with encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis, and pericarditis. (31,39,43,44).\n\n# Hospitalizations and Deaths from Influenza\nThe risks for complications, hospitalizations, and deaths from influenza are higher among persons aged >65 years, young children, and persons of any age with certain underlying health conditions (see Persons at Increased Risk for Complications) than among healthy older children and younger adults (1,6,8,(45)(46)(47)(48)(49)(50). Estimated rates of influenza-associated hospitalizations have varied substantially by age group in studies conducted during different influenza epidemics (Table 1).\nAmong children aged 0-4 years, hospitalization rates have ranged from approximately 500/100,000 children for those with high-risk medical conditions to 100/100,000 children for those without high-risk medical conditions (51)(52)(53)(54). Within the 0-4 year age group, hospitalization rates are highest among children aged 0-1 years and are comparable to rates reported among persons >65 years (53,54) (Table 1).\nDuring influenza epidemics from 1969-70 through 1994-95, the estimated overall number of influenza-associated hospitalizations in the United States ranged from approximately 16,000 to 220,000/epidemic. An average of approximately 114,000 influenza-related excess hospitalizations occurred per year, with 57% of all hospitalizations occurring among persons aged <65 years. Since the 1968 influenza A (H3N2) virus pandemic, the greatest numbers of influenza-associated hospitalizations have occurred during epidemics caused by type A (H3N2) viruses, with an estimated average of 142,000 influenza-associated hospitalizations per year (55).\nInfluenza-related deaths can result from pneumonia as well as from exacerbations of cardiopulmonary conditions and other chronic diseases. Older adults account for >90% of deaths attributed to pneumonia and influenza (1,50). In a recent study of influenza epidemics, approximately 19,000 influenza-associated pulmonary and circulatory deaths per influenza season occurred during 1976-1990, compared with approximately 36,000 deaths during 1990-1999 (1). Estimated rates of influenza-associated pulmonary and circulatory deaths/100,000 persons were 0.4-0.6 among persons aged 0-49 years, 7.5 among persons aged 50-64 years, and 98.3 among persons aged >65 years. In the United States, the number of influenza-associated deaths might be increasing in part because the number of older persons is increasing (56). In addition, influenza seasons in which influenza A (H3N2) viruses predominate are associated with higher mortality (57); influenza A (H3N2) viruses predominated in 90% of influenza seasons during 1990-1999, compared with 57% of seasons during 1976-1990 (1).\nDeaths from influenza are uncommon among children with and without high-risk conditions, but do occur (58,59). A study that modeled influenza-related deaths estimated that an average of 92 deaths occurred among children aged 50 years (1). Preliminary reports of laboratory-confirmed pediatric deaths during the 2003-04 influenza season indicated that among these 143 influenzarelated deaths (as of April 10, 2004), 58 (41%) were aged <2 years and, of those aged 2-17 years, 65 (45%) did not have an underlying medical condition traditionally considered to place a person at risk for influenza-related complications (unpublished data, CDC National Center for Infectious Diseases, 2004). Further information is needed regarding the risk of severe influenza-complications and optimal strategies for minimizing severe disease and death among children.\n\n# Options for Controlling Influenza\nIn the United States, the primary option for reducing the effect of influenza is immunoprophylaxis with vaccine. Inactivated (i.e., killed virus) influenza vaccine and live, attenuated influenza vaccine are available for use in the United States (see Recommendations for Using Inactivated and Live, Attenuated Influenza Vaccine). Vaccinating persons at high risk for complications and their contacts each year before seasonal increases in influenza virus circulation is the most effective means of reducing the effect of influenza. Vaccination coverage can be increased by administering vaccine to persons during hospitalizations or routine health-care visits before the influenza season, making special visits to physicians' offices or clinics unnecessary. When vaccine and epidemic strains are well-matched, achieving increased vaccination rates among persons living in closed settings (e.g., nursing homes and other chronic-care facilities) and among staff can reduce the risk for outbreaks by inducing herd immunity (13). Vaccination of health-care workers and other persons in close contact with persons at increased risk for severe influenza illness can also reduce transmission of influenza and subsequent influenzarelated complications. Antiviral drugs used for chemoprophylaxis or treatment of influenza are a key adjunct to vaccine (see Recommendations for Using Antiviral Agents for Influenza). However, antiviral medications are not a substitute for vaccination. viruses are a reassortant of influenza A (H1N1) and (H3N2) viruses, antibody directed against influenza A (H1N1) and influenza (H3N2) vaccine strains will provide protection against circulating influenza A (H1N2) viruses. Influenza viruses for both the inactivated and live attenuated influenza vaccines are initially grown in embryonated hens' eggs. Thus, both vaccines might contain limited amounts of residual egg protein. New Engl J Med 2000;342:232-9. § § Outcomes were for acute pulmonary conditions. Influenza-attributable hospitalization rates for children at high risk were not included in this study. ¶ ¶ Source: Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 1980;112:798-811. * Outcomes were limited to hospitalizations in which either pneumonia or influenza was listed as the first condition on discharge records (Simonsen) or included anywhere in the list of discharge diagnoses (Barker). † † † Source: Simonsen L, Fukuda, K, Schonberger LB, Cox NJ. Impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831-7. § § § Persons at high risk and not at high risk for influenza-related complications are combined. ¶ ¶ ¶ The low estimate is the average during influenza A(H1N1) or influenza B-predominate seasons, and the high estimate is the average during influenza A (H3N2)-predominate seasons.\n\n# Influenza Vaccine Composition\nFor the inactivated vaccine, the vaccine viruses are made noninfectious (i.e., inactivated or killed) (60). Subvirion and purified surface antigen preparations of the inactivated vaccine are available. Manufacturing processes differ by manufacturer. Manufacturers might use different compounds to inactivate influenza viruses and add antibiotics to prevent bacterial contamination. Package inserts should be consulted for additional information.\n\n# Thimerosal\nThimerosal, a mercury-containing compound, has been used as a preservative in vaccines since the 1930s and is used in multidose vials of inactivated influenza vaccine to reduce the likelihood of bacterial contamination. Although no scientific evidence indicates that thimerosal in vaccines leads to serious adverse events in vaccine recipients, in 1999, the U.S. Public Health Service and other organizations recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines to decrease total mercury exposure, chiefly among infants (61)(62)(63). Since mid-2001, vaccines routinely recommended for infants in the United States have been manufactured either without or with only trace amounts of thimerosal to provide a substantial reduction in the total mercury exposure from vaccines for children (64). Vaccines containing trace amounts of thimerosal have <1 mcg mercury/dose. In 1999, 15 of 28 vaccine products for which CDC had contracts did not contain thimerosal as a preservative. In 2004, 27 of 29 products under CDC contract do not contain thimerosal as a preservative.\nInfluenza Vaccines and Thimerosal. LAIV does not contain thimerosal. Thimerosal preservative-containing inactivated influenza vaccines, distributed in multidose containers in the United States, contain 25 mcg of mercury/0.5-mL dose (61,62). Inactivated influenza virus vaccines distributed in the United States as preservative-free vaccines in single-dose syringes contain only trace amounts of thimerosal as a residual from early manufacturing steps. Inactivated influenza vaccine that does not contain thimerosal as a preservative has <1 mcg mercury/0.5-mL dose or <0.5 mcg mercury/0.25-mL dose. This information is included in the package insert provided with each type of inactivated influenza virus vaccine.\nBeginning in 2004, influenza vaccine is part of the routine childhood immunization schedule. For the 2004-05 influenza season, 6-8 million single-dose syringes of inactivated influenza virus vaccine without thimerosal as a preservative probably will be available. This represents a substantial increase in the available amount of inactivated influenza vaccine without thimerosal as a preservative, compared with approximately 3.2 million doses that were available during the 2003-04 influenza season. Inactivated influenza vaccine without thimerosal as a preservative is available from two manufacturers. Chiron produces Fluvirin™, which is approved by the Food and Drug Administration (FDA) for persons aged >4 years. Fluvirin is marketed as a formulation with thimerosal as a preservative in multidose vials and as a formulation without thimerosal as a preservative in 0.5-mL unit dose syringes. Aventis Pasteur produces FluZone ® , which is FDA-approved for persons aged >6 months. FluZone containing thimerosal as a preservative is available in multidose vials. Preservative-free FluZone packaged as 0.25-mL unit dose syringes is available for use among persons aged 6-35 months. The total amount of inactivated influenza vaccine available without thimerosal as a preservative will be increased as manufacturing capabilities are expanded.\nThe risks of severe illness from influenza infection are elevated among both young children and pregnant women, and both groups benefit from vaccination by preventing illness and death from influenza. In contrast, no scientifically conclusive evidence exists of harm from exposure to thimerosal preservative-containing vaccine, whereas evidence is accumulating of lack of any harm resulting from exposure to such vaccines (61,65). Therefore, the benefits of influenza vaccination outweigh the theoretical risk, if any, for thimerosal exposure through vaccination. Nonetheless, certain persons remain concerned regarding exposure to thimerosal. The U.S. vaccine supply for infants and pregnant women is in a period of transition during which thimerosal in vaccines intended for these groups is being reduced by manufacturers as a feasible means of reducing an infant's total exposure to mercury because other environmental sources of exposure are more difficult or impossible to eliminate. Reductions in thimerosal in other vaccines have been achieved already and have resulted in substantially lowered cumulative exposure to thimerosal from vaccination among infants and children. For all of these reasons, persons recommended to receive inactivated influenza vaccine may receive either vaccine preparation, depending on availability. Supplies of inactivated influenza vaccines without thimerosal as a preservative will be increased for the 2004-05 influenza season compared with the 2003-04 season, and they will be included in CDC contracts to meet anticipated public demand in 2004.\n\n# Efficacy and Effectiveness of Inactivated Influenza Vaccine\nThe effectiveness of inactivated influenza vaccine depends primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the viruses in the vaccine and those in circulation. The majority of vaccinated children and young adults develop high postvaccination hemagglutination inhibition antibody titers (66)(67)(68).\n\n# MMWR May 28, 2004\nThese antibody titers are protective against illness caused by strains similar to those in the vaccine (67)(68)(69)(70).\nAdults Aged <65 Years. When the vaccine and circulating viruses are antigenically similar, influenza vaccine prevents influenza illness among approximately 70%-90% of healthy adults aged <65 years (9,12,71,72). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources, including use of antibiotics, when the vaccine and circulating viruses are wellmatched (9)(10)(11)(12)72,73).\nChildren. Children aged as young as 6 months can develop protective levels of antibody after influenza vaccination (66,67,(74)(75)(76)(77), although the antibody response among children at high risk for influenza-related complications might be lower than among healthy children (78,79). In a randomized study among children aged 1-15 years, inactivated influenza vaccine was 77%-91% effective against influenza respiratory illness and was 44%-49%, 74%-76%, and 70%-81% effective against influenza seroconversion among children aged 1-5, 6-10, and 11-15 years, respectively (68). One study (80) reported a vaccine efficacy of 56% against influenza illness among healthy children aged 3-9 years, and another study (81) determined vaccine efficacy of 22%-54% and 60%-78% among children with asthma aged 2-6 years and 7-14 years, respectively. A 2-year randomized study of children aged 6-24 months determined that >89% of children seroconverted to all three vaccine strains during both years (82). During year 1, among 411 children, vaccine efficacy was 66% (95% confidence interval = 34% and 82%) against cultureconfirmed influenza (attack rates: 5.5% and 15.9% among vaccine and placebo groups, respectively). During year 2, among 375 children, vaccine efficacy was -7% (95% CI = -247% and 67%; attack rates: 3.6% and 3.3% among vaccine and placebo groups, respectively; the second year exhibited lower attack rates overall and was considered a mild season). However, no overall reduction in otitis media was reported (82). Other studies report that trivalent inactivated influenza vaccine decreases the incidence of influenza-associated otitis media among young children by approximately 30% (16,17).\nAdults Aged >65 Years. Older persons and persons with certain chronic diseases might develop lower postvaccination antibody titers than healthy young adults and thus can remain susceptible to influenza-related upper respiratory tract infection (83)(84)(85). A randomized trial among noninstitutionalized persons aged >60 years reported a vaccine efficacy of 58% against influenza respiratory illness, but indicated that efficacy might be lower among those aged >70 years (86). The vaccine can also be effective in preventing secondary complications and reducing the risk for influenza-related hospitalization and death among adults >65 years with and without high-risk medical conditions (e.g., heart disease and diabetes) (13)(14)(15)18,87). Among elderly persons not living in nursing homes or similar chronic-care facilities, influenza vaccine is 30%-70% effective in preventing hospitalization for pneumonia and influenza (15,88). Among older persons who do reside in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and deaths. Among this population, the vaccine can be 50%-60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death, although the effectiveness in preventing influenza illness often ranges from 30% to 40% (89)(90)(91).\n\n# Efficacy and Effectiveness of LAIV\nHealthy Children. A randomized, double-blind, placebocontrolled trial among 1,602 healthy children initially aged 15-71 months assessed the efficacy of trivalent LAIV against culture-confirmed influenza during two seasons (92,93). This trial included subsets of 238 healthy children (163 vaccinees and 75 placebo recipients) aged 60-71 months who received 2 doses and 74 children (54 vaccinees and 20 placebo recipients) aged 60-71 months who received a single dose during season one, and a subset of 544 children (375 vaccinees and 169 placebo recipients) aged 60-84 months during season two. Children who continued from season one to season two remained in the same study group. In season one, when vaccine and circulating virus strains were well-matched, efficacy was 93% for all participants, regardless of age, among persons receiving 2 doses of LAIV. Efficacy was 87% in the 60-71-month subset for those who received 2 doses, and was 91% in the subset for those who received 1 or 2 doses. In season two, when the A (H3N2) component was not well-matched between vaccine and circulating virus strains, efficacy was 86% overall and 87% among those aged 60-84 months. The vaccine was 92% efficacious in preventing culture-confirmed influenza during the twoseason study. Other results included a 27% reduction in febrile otitis media and a 28% reduction in otitis media with concomitant antibiotic use. Receipt of LAIV also resulted in decreased fever and otitis media among vaccine recipients who experienced influenza.\nHealthy Adults. A randomized, double-blind, placebocontrolled trial among 4,561 healthy working adults aged 18-64 years assessed multiple endpoints, including reductions in illness, absenteeism, health-care visits, and medication use during peak and total influenza outbreak periods (94). The study was conducted during the 1997-98 influenza season, when the vaccine and circulating A (H3N2) strains were not well-matched. The study did not include testing of viruses by a laboratory. During peak outbreak periods, no difference was identified between LAIV and placebo recipients experiencing any febrile episodes. However, vaccination was associated with reductions in severe febrile illnesses of 19% and febrile upper respiratory tract illnesses of 24%. Vaccination also was associated with fewer days of illness, fewer days of work lost, fewer days with health-care provider visits, and reduced use of prescription antibiotics and over-the-counter medications.\nAmong the subset of 3,637 healthy adults aged 18-49 years, LAIV recipients (n = 2,411) had 26% fewer febrile upperrespiratory illness episodes; 27% fewer lost work days as a result of febrile upper respiratory illness; and 18%-37% fewer days of health-care provider visits caused by febrile illness, compared with placebo recipients (n = 1,226). Days of antibiotic use were reduced by 41%-45% in this age subset.\nAnother randomized, double-blind, placebo-controlled challenge study among 92 healthy adults (LAIV, n = 29; placebo, n = 31; inactivated influenza vaccine, n = 32) aged 18-41 years assessed the efficacy of both LAIV and inactivated vaccine (95). The overall efficacy of LAIV and inactivated influenza vaccine in preventing laboratory-documented influenza from all three influenza strains combined was 85% and 71%, respectively, on the basis of experimental challenge by viruses to which study participants were susceptible before vaccination. The difference between the two vaccines was not statistically significant.\n\n# Cost-Effectiveness of Influenza Vaccine\nInfluenza vaccination can reduce both health-care costs and productivity losses associated with influenza illness. Economic studies of influenza vaccination of persons aged >65 years conducted in the United States have reported overall societal cost savings and substantial reductions in hospitalization and death (15,88,96). Studies of adults aged 65 years, vaccination resulted in a net savings per quality-adjusted life year (QALY) gained and resulted in costs of $23-$256/QALY among younger age groups. Additional studies of the relative costeffectiveness and cost utility of influenza vaccination among children and among adults aged <65 years are needed and should be designed to account for year-to-year variations in influenza attack rates, illness severity, and vaccine efficacy when evaluating the long-term costs and benefits of annual vaccination.\n\n# Vaccination Coverage Levels\nAmong persons aged >65 years, influenza vaccination levels increased from 33% in 1989 (103) to 66% in 1999 (104), surpassing the Healthy People 2000 objective of 60% (105). Vaccine coverage reached the highest levels recorded (68%) during the 1999-00 influenza season, using the percentage of adults reporting influenza vaccination during the past 12 months who participated in the National Health Interview Survey (NHIS) during the first and second quarters of each calendar year as a proxy measure of influenza vaccine coverage for the previous influenza season (104). Possible reasons for the increase in influenza vaccination levels among persons aged >65 years through the 1999-00 influenza season include 1) greater acceptance of preventive medical services by practitioners; 2) increased delivery and administration of vaccine by health-care providers and sources other than physicians; 3) new information regarding influenza vaccine effectiveness, cost-effectiveness, and safety; and 4) initiation of Medicare reimbursement for influenza vaccination in 1993 (8,14,15,89,90,106,107). Vaccine coverage increased more rapidly through the mid-1990s than during subsequent seasons (average annual percentage increase of 4% from 1988-89 to 1996-97 versus 1% from 1996-97 to 1999-00).\nEstimated national adult vaccine coverage for the 2001-02 season (Table 2), the most recent for which complete data are available, was 66% for adults aged >65 years and 34% for adults aged 50-64 years (104; unpublished data, CDC National Immunization Program, 2004). The estimated vaccination coverage among adults with high-risk conditions aged 18-49 years and 50-64 years was 23% and 44%, respectively, substantially lower than the Healthy People 2000 and 2010 objective of 60% (104,105,108). Continued annual monitoring is needed to determine the effects of vaccine supply delays, changes in influenza vaccination recommendations and target groups for vaccination, and other factors related to vaccination coverage among adults and children. The Healthy People 2010 objective is to achieve vaccination coverage for 90% of persons aged >65 years (108).\nReducing racial and ethnic health disparities, including disparities in vaccination coverage, is an overarching national goal (108). Although estimated influenza vaccination coverage for the 1999-00 season reached the highest levels recorded among older black, Hispanic, and white populations, vaccination levels among blacks and Hispanics continue to lag behind those among whites (104,109). Estimated influenza vaccination levels for 2001 among persons aged >65 years were 66% among non-Hispanic whites, 48% among non-Hispanic blacks, and 54% among Hispanics (109,110). Additional strategies are needed to achieve the Healthy People 2010 objectives among all racial and ethnic groups.\nIn 1997 and 1998, vaccination coverage estimates among nursing home residents were 64%-82% and 83%, respectively (111,112). The Healthy People 2010 goal is to achieve influenza vaccination of 90% among nursing home residents, an increase from the Healthy People 2000 goal of 80% (105,108).\nReported vaccination levels are low among children at increased risk for influenza complications. One study conducted among patients in health maintenance organizations reported influenza vaccination percentages ranging from 9% to 10% among children with asthma (113). A 25% vaccination level was reported among children with severe to moderate asthma who attended an allergy and immunology clinic (114). However, a study conducted in a pediatric clinic demonstrated an increase in the vaccination percentage of chil-dren with asthma or reactive airways disease from 5% to 32% after implementing a reminder/recall system (115). One study reported 79% vaccination coverage among children attending a cystic fibrosis treatment center (116). Increasing vaccination coverage among persons who have high-risk conditions and are aged <65 years, including children at high risk, is the highest priority for expanding influenza vaccine use.\nAnnual vaccination is recommended for health-care workers. Nonetheless, NHIS reported vaccination coverage of only 34% and 38% among health-care workers in the 1997 and 2002 surveys, respectively (117,118; unpublished data, CDC National Immunization Program, 2004) (Table 2). Vaccination of health-care workers has been associated with reduced work absenteeism (9) and fewer deaths among nursing home patients (119,120).\nLimited information is available regarding use of influenza vaccine among pregnant women. Among women aged 18-44 years without diabetes responding to the 2001 Behavioral Risk Factor Surveillance System, those reporting they were pregnant were less likely to report influenza vaccination during the past 12 months (13.7%) than those not pregnant (16.8%) (121). Only 12% of pregnant women reported vaccination according to 2002 NHIS data, excluding pregnant women who reported diabetes, heart disease, lung disease, and other selected high-risk conditions (unpublished data, CDC National Immunization Program, 2004) (Table 2). Although - As recommended by the Advisory Committee on Immunization Practices. † CI = Confidence interval. § Persons categorized as being at high risk for influenza-related complications self-reported one or more of the following: 1) ever being told by a physician they had diabetes, emphysema, coronary heart disease, angina, heart attack, or other heart condition; 2) having a diagnosis of cancer in the past 12 months (excluding nonmelanoma skin cancer) or ever being told by a physician they have lymphoma, leukemia, or blood cancer in the past 12 months; 3) being told by a physician they have chronic bronchitis or weak or failing kidneys; or 4) reporting an asthma episode or attack in the past 12 months. ¶ Aged 18-44 years, pregnant at the time of the survey and without high-risk conditions. Adults were classified as health-care workers if they were currently employed in a health-care occupation or in a health-care industry setting, on the basis of standard occupation and industry categories recoded in groups by CDC's National Center for Health Statistics. † † Interviewed adult in each household containing at least one of the following: a child aged 65 years, or any person aged 2-64 years at high risk (see previous footnote § ).\nnot directly measuring influenza vaccination among women who were past the first trimester of pregnancy during influenza season, these data indicate low compliance with the ACIP recommendations for pregnant women. In a study of influenza vaccine acceptance by pregnant women, 71% who were offered the vaccine chose to be vaccinated (122). However, a 1999 survey of obstetricians and gynecologists determined that only 39% administered influenza vaccine to obstetric patients, although 86% agreed that pregnant women's risk for influenzarelated morbidity and mortality increases during the last two trimesters (123).\nRecent data indicate that self-report of influenza vaccination among adults, compared with extraction from the medical record, is both sensitive and specific. Patient self-reports should be accepted as evidence of influenza vaccination in clinical practice (124). However, information on the validity of parents' reports of pediatric influenza vaccination is not yet available.\n\n# Recommendations for Using Inactivated and Live, Attenuated Influenza Vaccines\nBoth the inactivated influenza vaccine and LAIV can be used to reduce the risk of influenza. LAIV is only approved for use among healthy persons aged 5-49 years. Inactivated influenza vaccine is approved for persons aged >6 months, including those with high-risk conditions (see following sections on inactivated influenza vaccine and live, attenuated influenza vaccine).\n\n# Target Groups for Vaccination\n\n# Persons at Increased Risk for Complications\nVaccination with inactivated influenza vaccine is recommended for the following persons who are at increased risk for complications from influenza:\n\n# Persons Aged 50-64 Years\nVaccination is recommended for persons aged 50-64 years because this group has an increased prevalence of persons with high-risk conditions. In 2000, approximately 42 million persons in the United States were aged 50-64 years, of whom 12 million (29%) had one or more high-risk medical conditions (125). Influenza vaccine has been recommended for this entire age group to increase the low vaccination rates among persons in this age group with high-risk conditions (see preceding section). Age-based strategies are more successful in increasing vaccine coverage than patient-selection strategies based on medical conditions. Persons aged 50-64 years without high-risk conditions also receive benefit from vaccination in the form of decreased rates of influenza illness, decreased work absenteeism, and decreased need for medical visits and medication, including antibiotics (9)(10)(11)(12). Further, 50 years is an age when other preventive services begin and when routine assessment of vaccination and other preventive services has been recommended (126,127).\n\n# Persons Who Can Transmit Influenza to Those at High Risk\nPersons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. Decreasing transmission of influenza from caregivers and household contacts to persons at high risk might reduce influenza-related deaths among persons at high risk. Evidence from two studies indicates that vaccination of healthcare personnel is associated with decreased deaths among nursing home patients (119,120). Health-care workers should be vaccinated against influenza annually. Facilities that employ heath-care workers are strongly encouraged to provide vaccine to workers by using approaches that maximize immuni-zation rates. This will protect health-care workers, their patients, and communities, and will improve prevention, patient safety, and reduce disease burden. Health-care workers' influenza immunization rates should be regularly measured and reported. Although rates of health-care worker vaccination are typically <40%, with moderate effort, organized campaigns can attain higher rates of vaccination among this population (118).\nThe following groups should be vaccinated:\n- physicians, nurses, and other personnel in both hospital and outpatient-care settings, including medical emergency response workers (e.g., paramedics and emergency medical technicians); - employees of nursing homes and chronic-care facilities who have contact with patients or residents; - employees of assisted living and other residences for persons in groups at high risk; - persons who provide home care to persons in groups at high risk; and - household contacts (including children) of persons in groups at high risk. In addition, because children aged 0-23 months are at increased risk for influenza-related hospitalization (52-54), vaccination is recommended for their household contacts and out-of-home caregivers, particularly for contacts of children aged 0-5 months, because influenza vaccines have not been approved by FDA for use among children aged <6 months (see Healthy Young Children).\nHealthy persons aged 5-49 years in these groups who are not contacts of severely immunosuppressed persons (see Live, Attenuated Influenza Vaccine Recommendations) can receive either LAIV or inactivated influenza vaccine. All other persons in this group should receive inactivated influenza vaccine.\n\n# Additional Information Regarding Vaccination of Specific Populations Pregnant Women\nInfluenza-associated excess deaths among pregnant women were documented during the pandemics of 1918-19 and 1957-58 (128)(129)(130)(131). Case reports and limited studies also indicate that pregnancy can increase the risk for serious medical complications of influenza (132)(133)(134)(135)(136). An increased risk might result from 1) increases in heart rate, stroke volume, and oxygen consumption; 2) decreases in lung capacity; and 3) changes in immunologic function during pregnancy. A study of the effect of influenza during 17 interpandemic influenza seasons demonstrated that the relative risk for hospitalization for selected cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4 during weeks 14-20 of gestation to 4.7 during weeks 37-42, in comparison with women who were 1-6 months postpartum (137). Women in their third trimester of pregnancy were hospitalized at a rate (i.e., 250/100,000 pregnant women) comparable with that of nonpregnant women who had high-risk medical conditions. Researchers estimate that an average of 1-2 hospitalizations can be prevented for every 1,000 pregnant women vaccinated.\nBecause of the increased risk for influenza-related complications, women who will be pregnant during the influenza season should be vaccinated. Vaccination can occur in any trimester. One study of influenza vaccination of >2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine (138).\n\n# Healthy Young Children\nStudies indicate that rates of hospitalization are higher among young children than older children when influenza viruses are in circulation (51)(52)(53)139,140). The increased rates of hospitalization are comparable with rates for other groups considered at high risk for influenza-related complications. However, the interpretation of these findings has been confounded by co-circulation of respiratory syncytial viruses, which are a cause of serious respiratory viral illness among children and which frequently circulate during the same time as influenza viruses (141)(142)(143). Two recent studies have attempted to separate the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children who do not have high-risk conditions (52,53). Both studies reported that otherwise healthy children aged <2 years, and possibly children aged 2-4 years, are at increased risk for influenza-related hospitalization compared with older healthy children (Table 1). Among the Tennessee Medicaid population during 1973-1993, healthy children aged 6 months-<3 years had rates of influenza-associated hospitalization comparable with or higher than rates among children aged 3-14 years with high-risk conditions (Table 1) (52,54). Another Tennessee study reported a hospitalization rate per year of 3-4/1,000 healthy children aged <2 years for laboratory-confirmed influenza (32).\nBecause children aged 6-23 months are at substantially increased risk for influenza-related hospitalizations, ACIP recommends vaccination of all children in this age group (144). ACIP continues to recommend influenza vaccination of persons aged >6 months who have high-risk medical conditions.\nThe current inactivated influenza vaccine is not approved by FDA for use among children aged <6 months, the pediatric group at greatest risk for influenza-related complications (52). Vaccinating their household contacts and out-of-home caregivers might decrease the probability of influenza infection among these children.\nBeginning in March 2003, the group of children eligible for influenza vaccine coverage under the Vaccines for Children (VFC) program was expanded to include all VFCeligible children aged 6-23 months and VFC-eligible children aged 2-18 years who are household contacts of children aged 0-23 months (145).\n\n# Persons Infected with HIV\nLimited information is available regarding the frequency and severity of influenza illness or the benefits of influenza vaccination among persons with HIV infection (146,147). However, a retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program determined that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than during the peri-influenza periods. The risk for hospitalization was higher for HIV-infected women than for women with other well-recognized high-risk conditions, including chronic heart and lung diseases (148). Another study estimated that the risk for influenza-related death was 9.4-14.6/10,000 persons with acquired immunodeficiency syndrome (AIDS) compared with 0.09-0.10/10,000 among all persons aged 25-54 years and 6.4-7.0/10,000 among persons aged >65 years (149). Other reports indicate that influenza symptoms might be prolonged and the risk for complications from influenza increased for certain HIVinfected persons (150)(151)(152).\nInfluenza vaccination has been demonstrated to produce substantial antibody titers against influenza among vaccinated HIV-infected persons who have minimal AIDS-related symptoms and high CD4 + T-lymphocyte cell counts (153)(154)(155)(156). A limited, randomized, placebo-controlled trial determined that influenza vaccine was highly effective in preventing symptomatic, laboratory-confirmed influenza infection among HIV-infected persons with a mean of 400 CD4 + T-lymphocyte cells/mm 3 ; a limited number of persons with CD4 + T-lymphocyte cell counts of 100 CD4 + cells and among those with <30,000 viral copies of HIV type-1/mL (152). Among persons who have advanced HIV disease and low CD4 + T-lymphocyte cell counts, influenza vaccine might not induce protective antibody titers (155,156); a second dose of vaccine does not improve the immune response in these persons (156,157).\nOne study determined that HIV RNA (ribonucleic acid) levels increased transiently in one HIV-infected person after influenza infection (158). Studies have demonstrated a transient (i.e., 2-4 week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (155,159). Other studies using similar laboratory techniques have not documented a substantial increase in the replication of HIV (160)(161)(162)(163). Deterioration of CD4 + T-lymphocyte cell counts or progression of HIV disease have not been demonstrated among HIVinfected persons after influenza vaccination compared with unvaccinated persons (156,164). Limited information is available concerning the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza infection or influenza vaccination (146,165). Because influenza can result in serious illness, and because influenza vaccination can result in the production of protective antibody titers, vaccination will benefit HIV-infected persons, including HIV-infected pregnant women.\n\n# Breastfeeding Mothers\nInfluenza vaccine does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does not adversely affect the immune response and is not a contraindication for vaccination.\n\n# Travelers\nThe risk for exposure to influenza during travel depends on the time of year and destination. In the tropics, influenza can occur throughout the year. In the temperate regions of the Southern Hemisphere, the majority of influenza activity occurs during April-September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large organized tourist groups (e.g., on cruise ships) that include persons from areas of the world where influenza viruses are circulating (166,167). Persons at high risk for complications of influenza who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to\n- travel to the tropics,\n- travel with organized tourist groups at any time of year, or - travel to the Southern Hemisphere during April-September.\nNo information is available regarding the benefits of revaccinating persons before summer travel who were already vaccinated in the preceding fall. Persons at high risk who receive the previous season's vaccine before travel should be revaccinated with the current vaccine the following fall or winter. Persons aged >50 years and others at high risk should consult with their physicians before embarking on travel during the summer to discuss the symptoms and risks for influenza and May 28, 2004 the advisability of carrying antiviral medications for either prophylaxis or treatment of influenza.\n\n# General Population\nIn addition to the groups for which annual influenza vaccination is recommended, physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza (the vaccine can be administered to children >6 months), depending on vaccine availability (see Influenza Vaccine Supply). Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics.\n\n# Comparison of LAIV with Inactivated Influenza Vaccine\nBoth inactivated influenza vaccine and LAIV are available to reduce the risk of influenza infection and illness. However, the vaccines also differ in key ways (Table 3).\n\n# Major Similarities\nLAIV and inactivated influenza vaccine contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one A (H1N1) virus, and one B virus. Each year, one or more virus strains might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains. Viruses for both vaccines are grown in eggs. Both vaccines are administered annually to provide optimal protection against influenza infection (Table 3).\n\n# Major Differences\nInactivated influenza vaccine contains killed viruses, whereas LAIV contains attenuated viruses still capable of replication. LAIV is administered intranasally by sprayer, whereas inactivated influenza vaccine is administered intramuscularly by injection. LAIV is more expensive than inactivated influenza vaccine. LAIV is approved for use only among healthy persons aged 5-49 years; inactivated influenza vaccine is approved for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions (Table 3).\n\n# Inactivated Influenza Vaccine Recommendations Persons Who Should Not Be Vaccinated with Inactivated Influenza Vaccine\nInactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Prophylactic use of antiviral agents is an option for preventing influenza among such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications from influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information regarding vaccine components is located in package inserts from each manufacturer. Persons with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis.\n\n# Dosage\nDosage recommendations vary according to age group (Table 4). Among previously unvaccinated children aged 1 month apart are recommended for satisfactory antibody responses. If possible, the second dose should be administered before December. If a child aged <9 years receiving vaccine for the first time does not receive a second dose of vaccine within the same season, only 1 dose of vaccine should be administered the following season. Two doses are not required at that time. Among adults, studies have indicated limited or no improvement in antibody response when a second dose is administered during the same season (168)(169)(170). Even when the current influenza vaccine contains one or more antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines during the year after vaccination (171,172). Vaccine prepared for a previous influenza season should not be administered to provide protection for the current season.\n\n# Route\nThe intramuscular route is recommended for influenza vaccine. Adults and older children should be vaccinated in the deltoid muscle. A needle length >1 inch can be considered for these age groups because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults and older children (173).\nInfants and young children should be vaccinated in the anterolateral aspect of the thigh (64). ACIP recommends a needle length of 7/8-1 inch for children aged <12 months for intramuscular vaccination into the anterolateral thigh. When injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8-1.25 inches is recommended (64).\n\n# Side Effects and Adverse Reactions\nWhen educating patients regarding potential side effects, clinicians should emphasize that 1) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and 2) coincidental respiratory disease unrelated to influenza vaccination can occur after vaccination.\n\n# Local Reactions\nIn placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts <2 days (12,(174)(175)(176). These local reactions typically are mild and rarely inter-fere with the person's ability to conduct usual daily activities. One blinded, randomized, cross-over study among 1,952 adults and children with asthma, demonstrated that only body aches were reported more frequently after inactivated influenza vaccine (25.1%) than placebo-injection (20.8%) (177). One study (79) reported 20%-28% of children with asthma aged 9 months-18 years with local pain and swelling and another study (77) reported 23% of children aged 6 months-4 years with chronic heart or lung disease had local reactions. A different study (76) reported no difference in local reactions among 53 children aged 6 months-6 years with high-risk medical conditions or among 305 healthy children aged 3-12 years in a placebo-controlled trial of inactivated influenza vaccine. In a study of 12 children aged 5-32 months, no substantial local or systemic reactions were noted (178).\n\n# Systemic Reactions\nFever, malaise, myalgia, and other systemic symptoms can occur after vaccination with inactivated vaccine and most often affect persons who have had no prior exposure to the - Populations at high risk from complications of influenza infection include persons aged >65 years; residents of nursing homes and other chronic-care facilities that house persons with chronic medical conditions; adults and children with chronic disorders of the pulmonary or cardiovascular systems; adults and children with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression; children and adolescents receiving long-term aspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); pregnant women; and children aged 6-23 months. † No data are available regarding effect on safety or efficacy. § Inactivated influenza vaccine coadministration has been evaluated systematically only among adults with pneumococcal polysaccharide vaccine.\n\n# Yes\nYes influenza virus antigens in the vaccine (e.g., young children) (179,180). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Recent placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (12,(174)(175)(176).\nLess information from published studies is available for children, compared with adults. However, in a randomized crossover study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age group (177). An analysis of 215,600 children aged <18 years and 8,476 children aged 6-23 months enrolled in one of five health maintenance organizations reported no increase in biologically plausible medically attended events during the 2 weeks after inactivated influenza vaccination, compared with control periods 3-4 weeks before and after vaccination (181). In a study of 791 healthy children (68), postvaccination fever was noted among 11.5% of children aged 1-5 years, 4.6% among children aged 6-10 years, and 5.1% among children aged 11-15 years. Among children with high-risk medical conditions, one study of 52 children aged 6 months-4 years reported fever among 27% and irritability and insomnia among 25% (77); and a study among 33 children aged 6-18 months reported that one child had irritability and one had a fever and seizure after vaccination (182). No placebo comparison was made in these studies. However, in pediatric trials of A/New Jersey/76 swine influenza vaccine, no difference was reported between placebo and split-virus vaccine groups in febrile reactions after injection, although the vaccine was associated with mild local tenderness or erythema (76).\nLimited data regarding potential adverse events after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). During January 1, 1991-January 23, 2003, VAERS received 1,072 reports of adverse events among children aged <18 years, including 174 reports of adverse events among children aged 6-23 months. The number of influenza vaccine doses received by children during this time period is unknown. The most frequently reported events among children were fever, injection-site reactions, and rash (unpublished data, CDC, 2003). Because of the limitations of spontaneous reporting systems, determining causality for specific types of adverse events, with the exception of injection-site reactions, is usually not possible by using VAERS data alone.\nHealth-care professionals should promptly report all clinically significant adverse events after influenza vaccination of children to VAERS, even if the health-care professional is not certain that the vaccine caused the event. The Institute of Medicine has specifically recommended reporting of potential neurologic complications (e.g., demyelinating disorders such as Guillain-Barré syndrome), although no evidence exists of a causal relationship between influenza vaccine and neurologic disorders in children.\nImmediate -presumably allergic -reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination (183). These reactions probably result from hypersensitivity to certain vaccine components; the majority of reactions probably are caused by residual egg protein. Although current influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have had hives or swelling of the lips or tongue, or who have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma or other allergic responses to egg protein, might also be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for safely administering influenza vaccine to persons with egg allergies (184)(185)(186). Immunogenicity and side effects of split-and whole-virus vaccines are similar among adults when vaccines are administered at the recommended dosage. § For adults and older children, the recommended site of vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. ¶ Two doses administered at least 1 month apart are recommended for children aged <9 years who are receiving influenza vaccine for the first time.\nHypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (187,188). When reported, hypersensitivity to thimerosal usually has consisted of local, delayed hypersensitivity reactions (187).\n\n# Guillain-Barré Syndrome\nThe 1976 swine influenza vaccine was associated with an increased frequency of GBS (189,190). Among persons who received the swine influenza vaccine in 1976, the rate of GBS was 25 years than persons <25 years (189). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. Obtaining strong epidemiologic evidence for a possible limited increase in risk is difficult for such a rare condition as GBS, which has an annual incidence of 10-20 cases/1 million adults (191). More definitive data probably will require using other methodologies (e.g., laboratory studies of the pathophysiology of GBS).\nDuring three of four influenza seasons studied during 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated but were not statistically significant in any of these studies (192)(193)(194). However, in a study of the 1992-93 and 1993-94 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0-2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately 1 additional case of GBS/1 million persons vaccinated. The combined number of GBS cases peaked 2 weeks after vaccination (195). Thus, investigations to date indicate no substantial increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976), and that, if influenza vaccine does pose a risk, it is probably slightly more than one additional case/1 million persons vaccinated. Cases of GBS after influenza infection have been reported, but no epidemiologic studies have documented such an association (196,197). Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni, as well as upper respiratory tract infections are associated with GBS (191,(198)(199)(200).\nEven if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of approximately 1 additional case/1 million persons vaccinated is substantially less than the risk for severe influenza, which can be prevented by vaccination among all age groups, especially persons aged >65 years and those who have medical indications for influenza vaccination (Table 1) (see Hospitalizations and Deaths from Influenza). The potential benefits of influenza vaccina-tion in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for experiencing vaccine-associated GBS. The average case fatality ratio for GBS is 6% and increases with age (191,201). No evidence indicates that the case fatality ratio for GBS differs among vaccinated persons and those not vaccinated.\nThe incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (192,202). Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown; therefore, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination is prudent. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. Although data are limited, for the majority of persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination.\n\n# Live, Attenuated Influenza Vaccine Recommendations Background\nDescription and Action Mechanisms. LAIVs have been in development since the 1960s in the United States, where they have been evaluated as mono-, bi-, and trivalent formulations (203)(204)(205)(206)(207). The LAIV licensed for use in the United States beginning in 2003 is produced by MedImmune, Inc. (Gaithersburg, Maryland; ) and marketed under the name FluMist™. It is a live, trivalent, intranasally administered vaccine that is - attenuated, producing mild or no signs or symptoms related to influenza virus infection; - temperature-sensitive, a property that limits the replication of the vaccine viruses at 38 º C-39 º C, and thus restricts LAIV viruses from replicating efficiently in human lower airways; and - cold-adapted, replicating efficiently at 25 º C, a temperature that is permissive for replication of LAIV viruses, but restrictive for replication of different wild-type viruses. In animal studies, LAIV viruses replicate in the mucosa of the nasopharynx, inducing protective immunity against viruses included in the vaccine, but replicate inefficiently in the lower airways or lungs.\nThe first step in developing an LAIV was the derivation of two stably attenuated master donor viruses (MDV), one for type A and one for type B influenza viruses. The two MDVs each acquired the cold-adapted, temperature-sensitive, attenuated phenotypes through serial passage in viral culture conducted at progressively lower temperatures. The vaccine viruses in LAIV are reassortant viruses containing genes from these MDVs that confer attenuation, temperature sensitivity, and cold adaptation and genes from the recommended contemporary wild-type influenza viruses, encoding the surface antigens hemagglutinin (HA) and neuraminidase (NA). Thus, MDVs provide the stably attenuated vehicles for presenting influenza HA and NA antigens, to which the protective antibody response is directed, to the immune system. The reassortant vaccine viruses are grown in embryonated hens' eggs. After the vaccine is formulated and inserted into individual sprayers for nasal administration, the vaccine must be stored at -15 º C or colder.\nThe immunogenicity of the approved LAIV has been assessed in multiple studies (96,(208)(209)(210)(211)(212)(213), which included approximately 100 children aged 5-17 years, and approximately 300 adults aged 18-49 years. LAIV virus strains replicate primarily in nasopharyngeal epithelial cells. The protective mechanisms induced by vaccination with LAIV are not completely understood but appear to involve both serum and nasal secretory antibodies. No single laboratory measurement closely correlates with protective immunity induced by LAIV.\nShedding and Transmission of Vaccine Viruses. Available data indicate that both children and adults vaccinated with LAIV can shed vaccine viruses for >2 days after vaccination, although in lower titers than typically occur with shedding of wild-type influenza viruses. Shedding should not be equated with person-to-person transmission of vaccine viruses, although, in rare instances, shed vaccine viruses can be transmitted from vaccinees to nonvaccinated persons.\nOne unpublished study in a child care center setting assessed transmissibility of vaccine viruses from 98 vaccinated to 99 unvaccinated subjects, all aged 8-36 months. Eighty percent of vaccine recipients shed one or more virus strains, with a mean of 7.6 days' duration (214). One vaccine type influenza type B isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient in the same children's play group. The placebo recipient from whom the influenza type B vaccine virus was isolated did not exhibit symptoms that were different from those experienced by vaccine recipients. The estimated probability of acquiring vac-cine virus after close contact with a single LAIV recipient in this child care population was 0.58%-2.4%.\nOne study assessing shedding of vaccine viruses in 20 healthy vaccinated adults aged 18-49 years demonstrated that the majority of shedding occurred within the first 3 days after vaccination, although one subject was noted to shed virus on day 7 after vaccine receipt. No subject shed vaccine viruses >10 days after vaccination. Duration or type of symptoms associated with receipt of LAIV did not correlate with duration of shedding of vaccine viruses. Person-to-person transmission of vaccine viruses was not assessed in this study (215).\nStability of Vaccine Viruses. In clinical trials, viruses shed by vaccine recipients have been phenotypically stable. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt (216). Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes.\n\n# Using Live, Attenuated Influenza Vaccine\nLAIV is an option for vaccination of healthy persons aged 5-49 years, including persons in close contact with groups at high risk and those wanting to avoid influenza. Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response, its ease of administration, and the acceptability of an intranasal rather than intramuscular route of administration.\n\n# Persons Who Should Not Be Vaccinated with LAIV\nThe following populations should not be vaccinated with LAIV:\n\n# Close Contacts of Persons at High Risk for Complications from Influenza\nClose contacts of persons at high risk for complications from influenza should receive influenza vaccine to reduce transmission of wild-type influenza viruses to persons at high risk. Use of inactivated influenza vaccine is preferred for vaccinating household members, health-care workers, and others who have close contact with severely immunosuppressed persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunosuppressed person requires care in a protective environment. The rationale for not using LAIV among health-care workers caring for such patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunosuppressed person and cause disease. No preference exists for inactivated influenza vaccine use by health-care workers or other persons who have close contact with persons with lesser degrees of immunosuppression (e.g., persons with diabetes, persons with asthma taking corticosteroids, or persons infected with human immunodeficiency virus), and no preference exists for inactivated influenza vaccine use by health-care workers or other healthy persons aged 5-49 years in close contact with all other groups at high risk.\nIf a health-care worker receives LAIV, that worker should refrain from contact with severely immunosuppressed patients as described previously for 7 days after vaccine receipt. Hospital visitors who have received LAIV should refrain from contact with severely immunosuppressed persons for 7 days after vaccination; however, such persons need not be excluded from visitation of patients who are not severely immunosuppressed.\n\n# Personnel Who May Administer LAIV\nLow-level introduction of vaccine viruses into the environment is likely unavoidable when administering LAIV. The risk of acquiring vaccine viruses from the environment is unknown but likely to be limited. Severely immunosuppressed persons should not administer LAIV. However, other persons at high risk for influenza complications may administer LAIV. These include persons with underlying medical conditions placing them at high risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged >50 years.\n\n# LAIV Dosage and Administration\nLAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route. LAIV must be stored at -15 º C or colder. LAIV should not be stored in a frost-free freezer (because the temperature might cycle above -15 º C), unless a manufacturer-supplied freezer box is used. LAIV must be thawed before administration. This can be accomplished by holding an individual sprayer in the palm of the hand until thawed, with subsequent immediate administration. Alternatively, the vaccine can be thawed in a refrigerator and stored at 2 º C-8 º C for <24 hours before use. Vaccine should not be refrozen after thawing. LAIV is supplied in a prefilled singleuse sprayer containing 0.5 mL of vaccine. Approximately 0.25 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril. If the vaccine recipient sneezes after administration, the dose should not be repeated.\nLAIV should be administered annually according to the following schedule:\n- Children aged 5-8 years previously unvaccinated at any time with either LAIV or inactivated influenza vaccine should receive 2 doses † of LAIV separated by 6-10 weeks. - Children aged 5-8 years previously vaccinated at any time with either LAIV or inactivated influenza vaccine should receive 1 dose of LAIV. They do not require a second dose. - Persons aged 9-49 years should receive 1 dose of LAIV. LAIV can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infection with or without fever). However, if clinical judgment indicates nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness. Whether concurrent administration of LAIV with other vaccines affects the safety or efficacy of either LAIV or the simultaneously administered vaccine is unknown. In the absence of specific data indicating interference, following the ACIP general recommendations for immunization is prudent (64). Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. An inactivated vaccine can be administered either simultaneously or at any time before or after LAIV. Two live vaccines not administered on the same day should be administered >4 weeks apart when possible.\n\n# LAIV and Use of Influenza Antiviral Medications\nThe effect on safety and efficacy of LAIV coadministration with influenza antiviral medications has not been studied.\n\n# MMWR May 28, 2004\nHowever, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV.\n\n# LAIV Storage\nLAIV must be stored at -15 º C or colder. LAIV should not be stored in a frost-free freezer because the temperature might cycle above -15 º C, unless a manufacturer-supplied freezer box or other strategy is used. LAIV can be thawed in a refrigerator and stored at 2 º C-8 º C for <24 hours before use. It should not be refrozen after thawing. Additional information is available at Wyeth Product Quality (1-800-411-0086) or at http:// www.FluMist.com.\n\n# Side Effects and Adverse Reactions\nTwenty prelicensure clinical trials assessed the safety of the approved LAIV. In these combined studies, approximately 28,000 doses of the vaccine were administered to >20,000 subjects. A subset of these trials were randomized, placebocontrolled studies in which >4,000 healthy children aged 5-17 years and >2,000 healthy adults aged 18-49 years were vaccinated. The incidence of adverse events possibly complicating influenza (e.g., pneumonia, bronchitis, bronchiolitis, or central nervous system events) was not statistically different among LAIV and placebo recipients aged 5-49 years.\nChildren. Signs and symptoms reported more often among vaccine recipients than placebo recipients included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0%-26%), and vomiting (3%-13%), abdominal pain (2%), and myalgias (0%-21%) (208,211,213,(217)(218)(219). These symptoms were associated more often with the first dose and were self-limited. In a subset of healthy children aged 60-71 months from one clinical trial (92,93), certain signs and symptoms were reported more often among LAIV recipients after the first dose (n = 214) than placebo recipients (n = 95) (e.g., runny nose, 48.1% versus 44.2%; headache, 17.8% versus 11.6%; vomiting, 4.7% versus 3.2%; myalgias, 6.1% versus 4.2%), but these differences were not statistically significant. Unpublished data from a study including subjects aged 1-17 years indicated an increase in asthma or reactive airways disease in the subset aged 12-59 months. Because of this, LAIV is not approved for use among children aged <60 months.\nAdults. Among adults, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients (94,220,221). In one clinical trial (94), among a subset of healthy adults aged 18-49 years, signs and symptoms reported more frequently among LAIV recipi-ents (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (13.9% versus 10.8%); runny nose (44.5% versus 27.1%); sore throat (27.8% versus 17.1%); chills (8.6% versus 6.0%); and tiredness/weakness (25.7% versus 21.6%).\nSafety Among Groups at High Risk from Influenza-Related Morbidity. Until additional data are acquired, persons at high risk for experiencing complications from influenza infection (e.g., immunocompromised patients; patients with asthma, cystic fibrosis, or chronic obstructive pulmonary disease; or persons aged >65 years) should not be vaccinated with LAIV. Protection from influenza among these groups should be accomplished by using inactivated influenza vaccine.\nSerious Adverse Events. Serious adverse events among healthy children aged 5-17 years or healthy adults aged 18-49 years occurred at a rate of <1%. Surveillance should continue for adverse events that might not have been detected in previous studies. Health-care professionals should promptly report all clinically significant adverse events after LAIV administration to VAERS, as recommended for inactivated influenza vaccine.\n\n# Recommended Vaccines for Different Age Groups\nWhen vaccinating children aged 6 months-3 years, healthcare providers should use inactivated influenza vaccine that has been approved by FDA for this age group. Inactivated influenza vaccine from Aventis Pasteur, Inc., (FluZone splitvirus) is approved for use among persons aged >6 months. Inactivated influenza vaccine from Chiron (Fluvirin) is labeled in the United States for use only among persons aged >4 years because data to demonstrate efficacy among younger persons have not been provided to FDA. Live, attenuated influenza vaccine from MedImmune (FluMist) is approved for use by healthy persons aged 5-49 years (Table 5).\n\n# Timing of Annual Influenza Vaccination\nThe annual supply of inactivated influenza vaccine and the timing of its distribution cannot be guaranteed in any year. Information regarding the supply of 2004-05 vaccine might not be available until late summer or early fall 2004. To allow vaccine providers to plan for the upcoming vaccination season, taking into account the yearly possibility of vaccine delays or shortages and the need to ensure vaccination of persons at high risk and their contacts, ACIP recommends that vaccine campaigns conducted in October focus their efforts primarily on persons at increased risk for influenza complications and their contacts, including health-care workers. Campaigns conducted in November and later should continue to vaccinate persons at high risk and their contacts, but also vaccinate other persons who wish to decrease their risk for influenza infection. Vaccination efforts for all groups should continue into December and beyond. CDC and other public health agencies will assess the vaccine supply on a continuing basis throughout the manufacturing period and will make recommendations in the summer preceding the 2004-05 influenza season regarding the need for tiered timing of vaccination of different risk groups.\n\n# Vaccination in October and November\nThe optimal time to vaccinate is usually during October-November. ACIP recommends that vaccine providers focus their vaccination efforts in October and earlier primarily on persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6-23 months), household contacts of persons at high risk (including out-of-home caregivers and household contacts of children aged 0-23 months), and health-care workers. Vaccination of children aged <9 years who are receiving vaccine for the first time should also begin in October or earlier because those persons need a booster dose 1 month after the initial dose. Efforts to vaccinate other persons who wish to decrease their risk for influenza infection should begin in November; however, if such persons request vaccination in October, vaccination should not be deferred. Materials to assist providers in prioritizing early vaccine are available at (see also Travelers in this report).\n\n# Timing of Organized Vaccination Campaigns\nPersons planning substantial organized vaccination campaigns should consider scheduling these events after mid-October because the availability of vaccine in any location cannot be ensured consistently in early fall. Scheduling campaigns after mid-October will minimize the need for cancel-lations because vaccine is unavailable. Campaigns conducted before November should focus efforts on vaccination of persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6-23 months), health-care workers, and household contacts of persons at high-risk (including children aged 0-23 months) to the extent feasible.\n\n# Vaccination in December and Later\nAfter November, many persons who should or want to receive influenza vaccine remain unvaccinated. In addition, substantial amounts of vaccine have remained unused during three of the past four influenza seasons. To improve vaccine coverage, influenza vaccine should continue to be offered in December and throughout the influenza season as long as vaccine supplies are available, even after influenza activity has been documented in the community. In the United States, seasonal influenza activity can begin to increase as early as October or November, but influenza activity has not reached peak levels in the majority of recent seasons until late December-early March (Table 6). Therefore, although the timing of influenza activity can vary by region, vaccine administered after November is likely to be beneficial in the majority of influenza seasons. Adults develop peak antibody protection against influenza infection 2 weeks after vaccination (222,223).\n\n# Vaccination Before October\nTo avoid missed opportunities for vaccination of persons at high risk for serious complications, such persons should be offered vaccine beginning in September during routine healthcare visits or during hospitalizations, if vaccine is available. In facilities housing older persons (e.g., nursing homes), vaccination before October typically should be avoided because antibody levels in such persons can begin to decline within a limited time after vaccination (224). In addition, children aged <9 years who have not been previously vaccinated and who need 2 doses before the start of the influenza season can receive their first dose in September or earlier.\n\n# Strategies for Implementing Vaccination Recommendations in Health-Care Settings\nSuccessful vaccination programs combine publicity and education for health-care workers and other potential vaccine recipients, a plan for identifying persons at high risk, use of reminder/recall systems, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs (19,225). Using standing orders programs is recommended for long-term-care facilities (e.g., nursing homes and skilled nursing facilities), hospitals, and home health agencies to ensure the administration of recommended vaccinations for adults (226). Standing orders programs for both influenza and pneumococcal vaccination should be conducted under the supervision of a licensed practitioner according to a physicianapproved facility or agency policy by health-care personnel trained to screen patients for contraindications to vaccination, administer vaccine, and monitor for adverse events. The Centers for Medicare and Medicaid Services (CMS) has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term-care facilities, and home health agencies (226). To the extent allowed by local and state law, these facilities and agencies may implement standing orders for influenza and pneumococcal vaccination of Medicare-and Medicaid-eligible patients. Other settings (e.g., outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces) are encouraged to introduce standing orders programs as well (20). Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following sections.\n\n# Outpatient Facilities Providing Ongoing Care\nStaff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccination. Vaccine should be offered during visits beginning in September and throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the medical record. Patients for whom vaccination is recommended and who do not have regularly scheduled visits dur-ing the fall should be reminded by mail, telephone, or other means of the need for vaccination.\n\n# Outpatient Facilities Providing Episodic or Acute Care\nBeginning each September, acute health-care facilities (e.g., emergency rooms and walk-in clinics) should offer vaccinations to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility.\n\n# Nursing Homes and Other Residential Long-Term-Care Facilities\nDuring October and November each year, vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility or anytime afterwards. All residents should be vaccinated at one time, preceding the influenza season. Residents admitted through March after completion of the facility's vaccination program should be vaccinated at the time of admission.\n\n# Acute-Care Hospitals\nPersons of all ages (including children) with high-risk conditions and persons aged >50 years who are hospitalized at any time during September-March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. In one study, 39%-46% of adult patients hospitalized during the winter with influenza-related diagnoses had been hospitalized during the preceding autumn (227). Thus, the hospital serves as a setting in which persons at increased risk for subsequent hospitalization can be identified and vaccinated. However, vaccination of persons at high risk during or after their hospitalizations is often not done. In a study of hospitalized Medicare patients, only 31.6% were vaccinated before admission, 1.9% during admission, and 10.6% after admission (228). Using standing orders in hospitals increases vaccination rates among hospitalized persons (229).\n\n# Visiting Nurses and Others Providing Home Care to Persons at High Risk\nBeginning in September, nursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home, if necessary. Caregivers and other persons in the household (including children) should be referred for vaccination.\n\n# Other Facilities Providing Services to Persons Aged >50 Years\nBeginning in October, such facilities as assisted living housing, retirement communities, and recreation centers should offer unvaccinated residents and attendees vaccination on-site before the influenza season. Staff education should emphasize the need for influenza vaccine.\n\n# Health-Care Personnel\nBeginning in October each year, health-care facilities should offer influenza vaccinations to all personnel, including night and weekend staff. Particular emphasis should be placed on providing vaccinations to persons who care for members of groups at high risk. Efforts should be made to educate healthcare personnel regarding the benefits of vaccination and the potential health consequences of influenza illness for themselves and their patients. All health-care personnel should be provided convenient access to influenza vaccine at the work site, free of charge, as part of employee health programs (118).\n\n# Influenza Vaccine Supply\nDuring the 2002-03 season, approximately 95 million doses of influenza vaccine were produced, but 12 million doses went unused and had to be destroyed. During the 2003-04 season, approximately 87 million doses of vaccine were produced. During that season, shortages of vaccine were noted in multiple regions of the United States after an unprecedented demand for vaccine lasted longer into the season than usual, caused in part by increased media attention to influenza. On the basis of early projections, manufacturers anticipate production of 90-100 million doses of vaccine for the 2004-05 season.\nInfluenza vaccine delivery delays or vaccine shortages remain possible in part because of the inherent critical time constraints in manufacturing the vaccine given the annual updating of the influenza vaccine strains. Steps being taken to address possible future delays or vaccine shortages include identification and implementation of ways to expand the influenza vaccine supply and improvement of targeted delivery of vaccine to groups at high risk when delays or shortages are expected.\n\n# Future Directions\nACIP plans to review new vaccination strategies for improving prevention and control of influenza, including the possibility of expanding recommendations for use of influenza vaccines. In addition, strategies for regularly monitoring vaccine effectiveness will be reviewed.\n\n# Recommendations for Using Antiviral Agents for Influenza\nAntiviral drugs for influenza are an adjunct to influenza vaccine for controlling and preventing influenza. However, these agents are not a substitute for vaccination. Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir.\nAmantadine and rimantadine are chemically related antiviral drugs known as adamantanes with activity against influenza A viruses but not influenza B viruses. Amantadine was approved in 1966 for chemoprophylaxis of influenza A (H2N2) infection and was later approved in 1976 for treatment and chemoprophylaxis of influenza type A virus infections among adults and children aged >1 year. Rimantadine was approved in 1993 for treatment and chemoprophylaxis of influenza A infection among adults and prophylaxis among children. Although rimantadine is approved only for chemoprophylaxis of influenza A infection among children, certain specialists in the management of influenza consider it appropriate for treatment of influenza A among children (230).\nZanamivir and oseltamivir are chemically related antiviral drugs known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for treating uncomplicated influenza infections. Zanamivir is approved for treating persons aged >7 years, and oseltamivir is approved for treatment for persons aged >1 year. In 2000, oseltamivir was approved for chemoprophylaxis of influenza among persons aged >13 years.\nThe four drugs differ in pharmacokinetics, side effects, routes of administration, approved age groups, dosages, and costs. An overview of the indications, use, administration, and known primary side effects of these medications is presented in the following sections. Information contained in this report might not represent FDA approval or approved labeling for the antiviral agents described. Package inserts should be consulted for additional information.\n\n# Role of Laboratory Diagnosis\nAppropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. Early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because certain bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated, if suspected. In addition, bacterial infections can occur as a complication of influenza.\nInfluenza surveillance information and diagnostic testing can aid clinical judgment and help guide treatment decisions. The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with influenza (29,33,34). Influenza surveillance by state and local health departments and CDC can provide information regarding the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, subtypes, and strains of influenza.\nDiagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR) and immunofluorescence (24). Sensitivity and specificity of any test for influenza might vary by the laboratory that performs the test, the type of test used, and the type of specimen tested. Among respiratory specimens for viral isolation or rapid detection, nasopharyngeal specimens are typically more effective than throat swab specimens (231). As with any diagnostic test, results should be evaluated in the context of other clinical information available to health-care providers.\nCommercial rapid diagnostic tests are available that can be used by laboratories in outpatient settings to detect influenza viruses within 30 minutes (24,232). These rapid tests differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types. Different tests can detect 1) only influenza A viruses; 2) both influenza A and B viruses, but not distinguish between the two types; or 3) both influenza A and B and distinguish between the two. The types of specimens acceptable for use (i.e., throat swab, nasal wash, or nasal swab) also vary by test. The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test (233,234). Because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means. Further, when interpreting results of a rapid influenza test, physicians should consider the positive and negative predictive values of the test in the context of the level of influenza activity in their community. Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests. Additional information concerning diagnostic testing is located at . gov/flu/professionals/labdiagnosis.htm.\nDespite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical, because only culture isolates can provide specific information regarding circulating influenza subtypes and strains. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment and chemoprophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence of antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat.\n\n# Indications for Use Treatment\nWhen administered within 2 days of illness onset to otherwise healthy adults, amantadine and rimantadine can reduce the duration of uncomplicated influenza A illness, and zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day, compared with placebo (72,(235)(236)(237)(238)(239)(240)(241)(242)(243)(244)(245)(246)(247)(248)(249). More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection (250)(251)(252)(253)(254)(255)(256)(257)(258)(259)(260)(261)(262)(263)(264)(265)(266). However, in vitro data and studies of treatment among mice and ferrets (267)(268)(269)(270)(271)(272)(273)(274), in addition to clinical studies, have documented that zanamivir and oseltamivir have activity against influenza B viruses (241,(245)(246)(247)275,276).\nData are limited regarding the effectiveness of the four antiviral agents in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these four antiviral drugs is principally based on studies of patients with uncomplicated influenza (277). Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, zanamivir, and oseltamivir for treatment of influenza among persons at high risk for serious complications of influenza (27,235,237,238,240,241,248,(250)(251)(252)(253)(254). One study assessing oseltamivir treatment primarily among adults reported a reduction in complications necessitating antibiotic therapy compared with placebo (255). Fewer studies of the efficacy of influenza antivirals have been conducted among pediatric populations (235,238,244,245,251,256,257). One study of oseltamivir treatment documented a decreased incidence of otitis media among children (245). Inadequate data exist regarding the safety and efficacy of any of the influenza antiviral drugs for use among children aged <1 year (234).\nTo reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza A illness should be discontinued as soon as clinically warranted, typically after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days.\n\n# Chemoprophylaxis\nChemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in preventing and controlling influenza. Both amantadine and rimantadine are indicated for chemoprophylaxis of influenza A infection, but not influenza B. Both drugs are approximately 70%-90% effective in preventing illness from influenza A infection (72,235,251). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and development of protective antibody against circulating influenza viruses. Therefore, certain persons who take these drugs will develop protective immune responses to circulating influenza viruses. Amantadine and rimantadine do not interfere with the antibody response to the vaccine (235). Both drugs have been studied extensively among nursing home populations as a component of influenza outbreak-control programs, which can limit the spread of influenza within chronic care institutions (235,250,(258)(259)(260).\nAmong the neuraminidase inhibitor antivirals, zanamivir and oseltamivir, only oseltamivir has been approved for prophylaxis, but community studies of healthy adults indicate that both drugs are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (261,262,278). Both antiviral agents have also been reported to prevent influenza illness among persons administered chemoprophylaxis after a household member was diagnosed with influenza (263,275,278). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited in comparison with the adamantanes (247,253,254,(264)(265)(266). One 6-week study of oseltamivir prophylaxis among nursing home residents reported a 92% reduction in influenza illness (247,279). Use of zanamivir has not been reported to impair the immunologic response to influenza vaccine (246,280). Data are not available regarding the efficacy of any of the four antiviral agents in preventing influenza among severely immunocompromised persons.\nWhen determining the timing and duration for administering influenza antiviral medications for prophylaxis, factors related to cost, compliance, and potential side effects should be considered. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost-effective, one study of amantadine or rimantadine prophylaxis reported that the drugs should be taken only during the period of peak influenza activity in a community (281).\nPersons at High Risk Who Are Vaccinated After Influenza Activity Has Begun. Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, development of antibodies in adults after vaccination takes approximately 2 weeks (222,223). When influenza vaccine is administered while influenza viruses are circulating, chemoprophylaxis should be considered for persons at high risk during the time from vaccination until immunity has developed. Children aged <9 years who receive influenza vaccine for the first time can require 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose).\nPersons Who Provide Care to Those at High Risk. To reduce the spread of virus to persons at high risk during community or institutional outbreaks, chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of influenza that might not be controlled by the vaccine, chemoprophylaxis should be considered for all such persons, regardless of their vaccination status.\nPersons Who Have Immune Deficiencies. Chemoprophylaxis can be considered for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with HIV, chiefly those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if chemoprophylaxis is administered.\nOther Persons. Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Chemoprophylaxis can also be offered to persons who wish to avoid influenza illness. Health-care providers and patients should make this decision on an individual basis.\n\n# Control of Influenza Outbreaks in Institutions\nUsing antiviral drugs for treatment and prophylaxis of influenza is a key component of influenza outbreak control in institutions. In addition to antiviral medications, other outbreak-control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, re-offering influenza vaccinations to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (282)(283)(284) (for additional information regarding outbreak control in specific settings, see Additional Information Regarding Influenza Infection Control Among Specific Populations).\nThe majority of published reports concerning use of antiviral agents to control influenza outbreaks in institutions are based on studies of influenza A outbreaks among nursing home populations where amantadine or rimantadine were used (235,250,(258)(259)(260)281). Less information is available concerning use of neuraminidase inhibitors in influenza A or B institutional outbreaks (253,254,266,279,285). When confirmed or suspected outbreaks of influenza occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice can substantially expedite administration of antiviral medications.\nWhen outbreaks occur in institutions, chemoprophylaxis should be administered to all residents, regardless of whether they received influenza vaccinations during the previous fall, and should continue for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza that is not well-matched by the vaccine.\nIn addition to nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings where persons live in close proximity). For example, chemoprophylaxis with rimantadine has been used successfully to control an influenza A outbreak aboard a large cruise ship (167).\nTo limit the potential transmission of drug-resistant virus during outbreaks in institutions, whether in chronic or acutecare settings or other closed settings, measures should be taken to reduce contact as much as possible between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis (see Antiviral Drug-Resistant Strains of Influenza).\n\n# Dosage\nDosage recommendations vary by age group and medical conditions (Table 7).\n\n# Children\nAmantadine. Use of amantadine among children aged 10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is advisable (252).\nRimantadine. Rimantadine is approved for prophylaxis among children aged >1 year and for treatment and prophylaxis among adults. Although rimantadine is approved only for prophylaxis of infection among children, certain specialists in the management of influenza consider it appropriate for treatment among children (230). Use of rimantadine among children aged 10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is recommended (286).\nZanamivir. Zanamivir is approved for treatment among children aged >7 years. The recommended dosage of zanamivir for treatment of influenza is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) (246).\nOseltamivir. Oseltamivir is approved for treatment among persons aged >1 year and for chemoprophylaxis among persons aged >13 years. Recommended treatment dosages for children vary by the weight of the child: the dosage recommendation for children who weigh 15-23 kg, the dosage is 45 mg twice a day; for those weighing >23-40 kg, the dosage is 60 mg twice a day; and for children weighing >40 kg, the dosage is 75 mg twice a day. The treatment dosage for persons aged >13 years is 75 mg twice daily. For children aged >13 years, the recommended dose for prophylaxis is 75 mg once a day (247).\n\n# Persons Aged >65 Years\nAmantadine. The daily dosage of amantadine for persons aged >65 years should not exceed 100 mg for prophylaxis or treatment, because renal function declines with increasing age. For certain older persons, the dose should be further reduced.\nRimantadine. Among older persons, the incidence and severity of central nervous system (CNS) side effects are substantially lower among those taking rimantadine at a dosage of 100 mg/day than among those taking amantadine at dosages adjusted for estimated renal clearance (287). However, chronically ill older persons have had a higher incidence of CNS and gastrointestinal symptoms and serum concentra- (235). For prophylaxis among persons aged >65 years, the recommended dosage is 100 mg/day. For treatment of older persons in the community, a reduction in dosage to 100 mg/day should be considered if they experience side effects when taking a dosage of 200 mg/day. For treatment of older nursing home residents, the dosage of rimantadine should be reduced to 100 mg/day (286).\nZanamivir and Oseltamivir. No reduction in dosage is recommended on the basis of age alone.\n\n# Persons with Impaired Renal Function\nAmantadine. A reduction in dosage is recommended for patients with creatinine clearance <50 mL/min/1.73m 2 . Guidelines for amantadine dosage on the basis of creatinine clearance are located in the package insert. Because recommended dosages on the basis of creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully for adverse reactions. If necessary, further reduction in the dose or discontinuation of the drug might be indicated because of side effects. Hemodialysis contributes minimally to amantadine clearance (288,289).\nRimantadine. A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance <10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including older persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance (290).\nZanamivir. Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in half-life, and increased systemic exposure to zanamivir were observed (246,291). However, a limited number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were substantially higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (292,293). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild to moderate or severe impairment in renal function (246).\nOseltamivir. Serum concentrations of oseltamivir carboxylate (GS4071), the active metabolite of oseltamivir, increase with declining renal function (247,294). For patients with creatinine clearance of 10-30 mL/min (247), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the prophylaxis dosage to 75 mg every other day is recommended. No treatment or prophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment.\n\n# Persons with Liver Disease\nAmantadine. No increase in adverse reactions to amantadine has been observed among persons with liver disease. Rare instances of reversible elevation of liver enzymes among patients receiving amantadine have been reported, although a specific relation between the drug and such changes has not been established (295).\nRimantadine. A reduction in dosage to 100 mg/day is recommended for persons with severe hepatic dysfunction.\nZanamivir and Oseltamivir. Neither of these medications has been studied among persons with hepatic dysfunction.\n\n# Persons with Seizure Disorders\nAmantadine. An increased incidence of seizures has been reported among patients with a history of seizure disorders who have received amantadine (296). Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.\nRimantadine. Seizures (or seizure-like activity) have been reported among persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine (297). The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated.\nZanamivir and Oseltamivir. Seizure events have been reported during postmarketing use of zanamivir and oseltamivir, although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.\n\n# Route\nAmantadine, rimantadine, and oseltamivir are administered orally. Amantadine and rimantadine are available in tablet or syrup form, and oseltamivir is available in capsule or oral suspension form (298,299). Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of correct use of this device (246).\n\n# Pharmacokinetics Amantadine\nApproximately 90% of amantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion (258,(300)(301)(302)(303). Thus, renal clearance of amantadine is reduced substantially among persons with renal insufficiency, and dosages might need to be decreased (see Dosage) (Table 7).\n\n# Rimantadine\nApproximately 75% of rimantadine is metabolized by the liver (251). The safety and pharmacokinetics of rimantadine among persons with liver disease have been evaluated only after single-dose administration (251,304). In a study of persons with chronic liver disease (the majority with stabilized cirrhosis), no alterations in liver function were observed after a single dose. However, for persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease (286).\nRimantadine and its metabolites are excreted by the kidneys. The safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration (251,290). Further studies are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages for patients with renal insufficiency. In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that among healthy persons of the same age (290). Hemodialysis did not contribute to drug clearance. In studies of persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher than those among control patients without renal disease who were the same weight, age, and sex (286,305).\n\n# Zanamivir\nIn studies of healthy volunteers, approximately 7%-21% of the orally inhaled zanamivir dose reached the lungs, and 70%-87% was deposited in the oropharynx (246,306). Approximately 4%-17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5-5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (246,293).\n\n# Oseltamivir\nApproximately 80% of orally administered oseltamivir is absorbed systemically (294). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxy-late has a half-life of 6-10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (247,307). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (308).\n\n# Side Effects and Adverse Reactions\nWhen considering use of influenza antiviral medications (i.e., choice of antiviral drug, dosage, and duration of therapy), clinicians must consider the patient's age, weight, and renal function (Table 7); presence of other medical conditions; indications for use (i.e., prophylaxis or therapy); and the potential for interaction with other medications.\n\n# Amantadine and Rimantadine\nBoth amantadine and rimantadine can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day. However, incidence of CNS side effects (e.g., nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine (308). In a 6-week study of prophylaxis among healthy adults, approximately 6% of participants taking rimantadine at a dosage of 200 mg/day experienced one or more CNS symptoms, compared with approximately 13% of those taking the same dosage of amantadine and 4% of those taking placebo (308). A study of older persons also demonstrated fewer CNS side effects associated with rimantadine compared with amantadine (287). Gastrointestinal side effects (e.g., nausea and anorexia) occur among approximately 1%-3% of persons taking either drug, compared with 1% of persons receiving the placebo (308).\nSide effects associated with amantadine and rimantadine are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week, despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures) (288,296). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among older persons who have been taking amantadine as prophylaxis at a dosage of 200 mg/day (258). Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects (Table 7). In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported (288). Because rimantadine has been marketed for a shorter period than amantadine, its safety among certain patient populations (e.g., chronically ill and older persons) has been evaluated less frequently. Because amantadine has anticholinergic effects and might cause mydriasis, it should not be used among patients with untreated angle closure glaucoma (288).\n\n# Zanamivir\nIn a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease where study medication was administered after use of a B2-agonist, 13% of patients receiving zanamivir and 14% of patients who received placebo (inhaled powdered lactose vehicle) experienced a >20% decline in forced expiratory volume in 1 second (FEV1) after treatment (246,248). However, in a phase-I study of persons with mild or moderate asthma who did not have influenza-like illness, 1 of 13 patients experienced bronchospasm after administration of zanamivir (246). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been reported. Certain patients had underlying airways disease (e.g., asthma or chronic obstructive pulmonary disease). Because of the risk for serious adverse events and because the efficacy has not been demonstrated among this population, zanamivir is not recommended for treatment for patients with underlying airway disease (246). If physicians decide to prescribe zanamivir to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should be used with caution under conditions of appropriate monitoring and supportive care, including the availability of short-acting bronchodilators (277). Patients with asthma or chronic obstructive pulmonary disease who use zanamivir are advised to 1) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and 2) stop using zanamivir and contact their physician if they experience difficulty breathing (246). No definitive evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza (277). Allergic reactions, including oropharyngeal or facial edema, have also been reported during postmarketing surveillance (246,253).\nIn clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone) (236)(237)(238)(239)(240)(241)253). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections. Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (246).\n\n# Oseltamivir\nNausea and vomiting were reported more frequently among adults receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%) (242,243,247,309). Among children treated with oseltamivir, 14.3% had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect (245), whereas a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (247). Similar types and rates of adverse events were reported in studies of oseltamivir prophylaxis (247). Nausea and vomiting might be less severe if oseltamivir is taken with food (247,309).\n\n# Use During Pregnancy\nNo clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester have been reported (134,135). However, both amantadine and rimantadine have been demonstrated in animal studies to be teratogenic and embryotoxic when administered at substantially high doses (286,288). Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these four drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus (see manufacturers' package inserts) (246,247,286,288).\n\n# Drug Interactions\nCareful observation is advised when amantadine is administered concurrently with drugs that affect CNS, including CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions (235). No clinically substantial interactions between rimantadine and other drugs have been identified.\nClinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically critical drug interactions have been predicted on the basis of in vitro data and data from studies using rats (246,310).\nLimited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (247,307).\nNo published data are available concerning the safety or efficacy of using combinations of any of these four influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral drugs, package inserts should be consulted.\n\n# Antiviral Drug-Resistant Strains of Influenza\nAmantadine-resistant viruses are cross-resistant to rimantadine and vice versa (311). Drug-resistant viruses can appear in approximately one third of patients when either amantadine or rimantadine is used for therapy (257,312,313). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace susceptible strains within 2-3 days of starting therapy (312,314). Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy (315,316); however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown. Amantadine-and rimantadine-resistant viruses are not more virulent or transmissible than susceptible viruses (317). The screening of epidemic strains of influenza A has rarely detected amantadine-and rimantadine-resistant viruses (312,318,319).\nPersons who have influenza A infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drugresistant viruses, including after 5-7 days of therapy (257). Such persons can benefit from therapy even when resistant viruses emerge.\nResistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (320)(321)(322)(323)(324)(325)(326)(327), but induction of resistance requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (328,329). Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (247,(330)(331)(332)(333). In clinical treatment studies using oseltamivir, 1.3% of posttreatment isolates from patients aged >13 years and 8.6% among patients aged 1-12 years had decreased susceptibility to oseltamivir (247). No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment iso-lates tested is limited (334) and the risk for emergence of zanamivir-resistant isolates cannot be quantified (246). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (331). Available diagnostic tests are not optimal for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being developed (334,335). Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted (336).\n\n# Sources of Information Regarding Influenza and Its Surveillance\nInformation regarding influenza surveillance, prevention, detection, and control is available at / weekly/fluactivity.htm. Surveillance information is available through the CDC Voice Information System (influenza update) at 888-232-3228 or CDC Fax Information Service at 888-232-3299. During October-May, surveillance information is updated at least every other week. In addition, periodic updates regarding influenza are published in the MMWR Weekly (). Additional information regarding influenza vaccine can be obtained by calling the CDC Immunization hotline at 800-232-2522 (English) or 800-232-0233 (Spanish). State and local health departments should be consulted concerning availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, and for reporting influenza outbreaks and receiving advice concerning outbreak control.\n\n# Additional Information Regarding Influenza Infection Control Among Specific Populations\nEach year, ACIP provides general, annually updated information regarding control and prevention of influenza. Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised persons, health-care personnel, hospitals, and travelers) are also available in the following publications:\n- CDC.\n\n# Advisory Committee on Immunization Practices\nMembership"},"raw_text":{"kind":"string","value":"depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction\nEpidemics of influenza typically occur during the winter months in temperate regions and have been responsible for an average of approximately 36,000 deaths/year in the United States during 1990-1999 (1). Influenza viruses also can cause pandemics, during which rates of illness and death from influenza-related complications can increase worldwide. Influenza viruses cause disease among all age groups (2)(3)(4). Rates of infection are highest among children, but rates of serious illness and death are highest among persons aged >65 years and persons of any age who have medical conditions that place them at increased risk for complications from influenza (2,(5)(6)(7).\nInfluenza vaccination is the primary method for preventing influenza and its severe complications. In this report from the Advisory Committee on Immunization Practices (ACIP), the primary target groups recommended for annual vaccination are 1) persons at increased risk for influenza-related complications (e.g., those aged >65 years, children aged 6-23 months, pregnant women, and persons of any age with certain chronic medical conditions); 2) persons aged 50-64 years because this group has an elevated prevalence of certain chronic medical conditions; and 3) persons who live with or care for persons at high risk (e.g., health-care workers and household contacts who have frequent contact with persons at high risk and who can transmit influenza to those persons at high risk). Vaccination is associated with reductions in influenza-related respiratory illness and physician visits among all age groups, hospitalization and death among persons at high risk, otitis media among children, and work absenteeism among adults (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Although influenza vaccination levels increased substantially during the 1990s, further improvements in vaccine coverage levels are needed, chiefly among persons aged <65 years who are at increased risk for influenza-related complications among all racial and ethnic groups, among blacks and Hispanics aged >65 years, among children aged 6-23 months, and among health-care workers. ACIP recommends using strategies to improve vaccination levels, including using reminder/recall systems and standing orders programs (19,20). Although influenza vaccination remains the cornerstone for the control and treatment of influenza, information on antiviral medications is also presented because these agents are an adjunct to vaccine.\n# Primary Changes and Updates in the Recommendations\nThe 2004 recommendations include four principal changes or updates:\n1. ACIP recommends that healthy children aged 6-23 months, and close contacts of children aged 0-23 months, be vaccinated against influenza (see Target Groups for Vaccination). \n# Influenza and Its Burden\n\n# Biology of Influenza\nInfluenza A and B are the two types of influenza viruses that cause epidemic human disease (21). Influenza A viruses are further categorized into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). Influenza B viruses are not categorized into subtypes. Since 1977, influenza A (H1N1) viruses, influenza A (H3N2) viruses, and influenza B viruses have been in global circulation. In 2001, influenza A (H1N2) viruses that probably emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses began circulating widely. Both influenza A and B viruses are further separated into groups on the basis of antigenic characteristics. New influenza virus variants result from frequent antigenic change (i.e., antigenic drift) resulting from point mutations that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses.\nA person's immunity to the surface antigens, including hemagglutinin, reduces the likelihood of infection and severity of disease if infection occurs (22). Antibody against one influenza virus type or subtype confers limited or no protection against another. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype (23). Frequent development of antigenic variants through antigenic drift is the virologic basis for seasonal epidemics and the reason for the usual incorporation of one or more new strains in each year's influenza vaccine.\n# Clinical Signs and Symptoms of Influenza\nInfluenza viruses are spread from person to person primarily through the coughing and sneezing of infected persons (21). The incubation period for influenza is 1-4 days, with an average of 2 days (24). Adults typically are infectious from the day before symptoms begin through approximately 5 days after illness onset. Children can be infectious for >10 days, and young children can shed virus for <6 days before their illness onset. Severely immunocompromised persons can shed virus for weeks or months (25)(26)(27)(28).\nUncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis) (29). Among children, otitis media, nausea, and vomiting are also commonly reported with influenza illness (30)(31)(32). Respiratory illness caused by influenza is difficult to distinguish from illness caused by other respiratory pathogens on the basis of symptoms alone (see Role of Laboratory Diagnosis). Reported sensitivities and specificities of clinical definitions for influenza-like illness in studies primarily among adults that include fever and cough have ranged from 63% to 78% and 55% to 71%, respectively, compared with viral culture (33,34). Sensitivity and predictive value of clinical definitions can vary, depending on the degree of co-circulation of other respiratory pathogens and the level of influenza activity (35). A study among older nonhospitalized patients determined that symptoms of fever, cough, and acute onset had a positive predictive value of 30% for influenza (36), whereas a study of hospitalized older patients with chronic cardiopulmonary disease determined that a combination of fever, cough, and illness of <7 days was 78% sensitive and 73% specific for influenza (37). However, a study among vaccinated older persons with chronic lung disease reported that cough was not predictive of influenza infection, although having a fever or feverishness was 68% sensitive and 54% specific for influenza infection (38).\nInfluenza illness typically resolves after a limited number of days for the majority of persons, although cough and malaise can persist for >2 weeks. Among certain persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a coinfection with other viral or bacterial pathogens (39). Young children with influenza infection can have initial symptoms mimicking bacterial sepsis with high fevers (40,41), and <20% of children hospitalized with influenza can have febrile seizures (31,42). Influenza infection has also been associated with encephalopathy, transverse myelitis, Reye syndrome, myositis, myocarditis, and pericarditis. (31,39,43,44).\n# Hospitalizations and Deaths from Influenza\nThe risks for complications, hospitalizations, and deaths from influenza are higher among persons aged >65 years, young children, and persons of any age with certain underlying health conditions (see Persons at Increased Risk for Complications) than among healthy older children and younger adults (1,6,8,(45)(46)(47)(48)(49)(50). Estimated rates of influenza-associated hospitalizations have varied substantially by age group in studies conducted during different influenza epidemics (Table 1).\nAmong children aged 0-4 years, hospitalization rates have ranged from approximately 500/100,000 children for those with high-risk medical conditions to 100/100,000 children for those without high-risk medical conditions (51)(52)(53)(54). Within the 0-4 year age group, hospitalization rates are highest among children aged 0-1 years and are comparable to rates reported among persons >65 years (53,54) (Table 1).\nDuring influenza epidemics from 1969-70 through 1994-95, the estimated overall number of influenza-associated hospitalizations in the United States ranged from approximately 16,000 to 220,000/epidemic. An average of approximately 114,000 influenza-related excess hospitalizations occurred per year, with 57% of all hospitalizations occurring among persons aged <65 years. Since the 1968 influenza A (H3N2) virus pandemic, the greatest numbers of influenza-associated hospitalizations have occurred during epidemics caused by type A (H3N2) viruses, with an estimated average of 142,000 influenza-associated hospitalizations per year (55).\nInfluenza-related deaths can result from pneumonia as well as from exacerbations of cardiopulmonary conditions and other chronic diseases. Older adults account for >90% of deaths attributed to pneumonia and influenza (1,50). In a recent study of influenza epidemics, approximately 19,000 influenza-associated pulmonary and circulatory deaths per influenza season occurred during 1976-1990, compared with approximately 36,000 deaths during 1990-1999 (1). Estimated rates of influenza-associated pulmonary and circulatory deaths/100,000 persons were 0.4-0.6 among persons aged 0-49 years, 7.5 among persons aged 50-64 years, and 98.3 among persons aged >65 years. In the United States, the number of influenza-associated deaths might be increasing in part because the number of older persons is increasing (56). In addition, influenza seasons in which influenza A (H3N2) viruses predominate are associated with higher mortality (57); influenza A (H3N2) viruses predominated in 90% of influenza seasons during 1990-1999, compared with 57% of seasons during 1976-1990 (1).\nDeaths from influenza are uncommon among children with and without high-risk conditions, but do occur (58,59). A study that modeled influenza-related deaths estimated that an average of 92 deaths occurred among children aged <5 years annually during the 1990's compared with 35,274 deaths among adults aged >50 years (1). Preliminary reports of laboratory-confirmed pediatric deaths during the 2003-04 influenza season indicated that among these 143 influenzarelated deaths (as of April 10, 2004), 58 (41%) were aged <2 years and, of those aged 2-17 years, 65 (45%) did not have an underlying medical condition traditionally considered to place a person at risk for influenza-related complications (unpublished data, CDC National Center for Infectious Diseases, 2004). Further information is needed regarding the risk of severe influenza-complications and optimal strategies for minimizing severe disease and death among children.\n# Options for Controlling Influenza\nIn the United States, the primary option for reducing the effect of influenza is immunoprophylaxis with vaccine. Inactivated (i.e., killed virus) influenza vaccine and live, attenuated influenza vaccine are available for use in the United States (see Recommendations for Using Inactivated and Live, Attenuated Influenza Vaccine). Vaccinating persons at high risk for complications and their contacts each year before seasonal increases in influenza virus circulation is the most effective means of reducing the effect of influenza. Vaccination coverage can be increased by administering vaccine to persons during hospitalizations or routine health-care visits before the influenza season, making special visits to physicians' offices or clinics unnecessary. When vaccine and epidemic strains are well-matched, achieving increased vaccination rates among persons living in closed settings (e.g., nursing homes and other chronic-care facilities) and among staff can reduce the risk for outbreaks by inducing herd immunity (13). Vaccination of health-care workers and other persons in close contact with persons at increased risk for severe influenza illness can also reduce transmission of influenza and subsequent influenzarelated complications. Antiviral drugs used for chemoprophylaxis or treatment of influenza are a key adjunct to vaccine (see Recommendations for Using Antiviral Agents for Influenza). However, antiviral medications are not a substitute for vaccination. viruses are a reassortant of influenza A (H1N1) and (H3N2) viruses, antibody directed against influenza A (H1N1) and influenza (H3N2) vaccine strains will provide protection against circulating influenza A (H1N2) viruses. Influenza viruses for both the inactivated and live attenuated influenza vaccines are initially grown in embryonated hens' eggs. Thus, both vaccines might contain limited amounts of residual egg protein. New Engl J Med 2000;342:232-9. § § Outcomes were for acute pulmonary conditions. Influenza-attributable hospitalization rates for children at high risk were not included in this study. ¶ ¶ Source: Barker WH, Mullooly JP. Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 1980;112:798-811. *** Outcomes were limited to hospitalizations in which either pneumonia or influenza was listed as the first condition on discharge records (Simonsen) or included anywhere in the list of discharge diagnoses (Barker). † † † Source: Simonsen L, Fukuda, K, Schonberger LB, Cox NJ. Impact of influenza epidemics on hospitalizations. J Infect Dis 2000;181:831-7. § § § Persons at high risk and not at high risk for influenza-related complications are combined. ¶ ¶ ¶ The low estimate is the average during influenza A(H1N1) or influenza B-predominate seasons, and the high estimate is the average during influenza A (H3N2)-predominate seasons.\n# Influenza Vaccine Composition\nFor the inactivated vaccine, the vaccine viruses are made noninfectious (i.e., inactivated or killed) (60). Subvirion and purified surface antigen preparations of the inactivated vaccine are available. Manufacturing processes differ by manufacturer. Manufacturers might use different compounds to inactivate influenza viruses and add antibiotics to prevent bacterial contamination. Package inserts should be consulted for additional information.\n# Thimerosal\nThimerosal, a mercury-containing compound, has been used as a preservative in vaccines since the 1930s and is used in multidose vials of inactivated influenza vaccine to reduce the likelihood of bacterial contamination. Although no scientific evidence indicates that thimerosal in vaccines leads to serious adverse events in vaccine recipients, in 1999, the U.S. Public Health Service and other organizations recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines to decrease total mercury exposure, chiefly among infants (61)(62)(63). Since mid-2001, vaccines routinely recommended for infants in the United States have been manufactured either without or with only trace amounts of thimerosal to provide a substantial reduction in the total mercury exposure from vaccines for children (64). Vaccines containing trace amounts of thimerosal have <1 mcg mercury/dose. In 1999, 15 of 28 vaccine products for which CDC had contracts did not contain thimerosal as a preservative. In 2004, 27 of 29 products under CDC contract do not contain thimerosal as a preservative.\nInfluenza Vaccines and Thimerosal. LAIV does not contain thimerosal. Thimerosal preservative-containing inactivated influenza vaccines, distributed in multidose containers in the United States, contain 25 mcg of mercury/0.5-mL dose (61,62). Inactivated influenza virus vaccines distributed in the United States as preservative-free vaccines in single-dose syringes contain only trace amounts of thimerosal as a residual from early manufacturing steps. Inactivated influenza vaccine that does not contain thimerosal as a preservative has <1 mcg mercury/0.5-mL dose or <0.5 mcg mercury/0.25-mL dose. This information is included in the package insert provided with each type of inactivated influenza virus vaccine.\nBeginning in 2004, influenza vaccine is part of the routine childhood immunization schedule. For the 2004-05 influenza season, 6-8 million single-dose syringes of inactivated influenza virus vaccine without thimerosal as a preservative probably will be available. This represents a substantial increase in the available amount of inactivated influenza vaccine without thimerosal as a preservative, compared with approximately 3.2 million doses that were available during the 2003-04 influenza season. Inactivated influenza vaccine without thimerosal as a preservative is available from two manufacturers. Chiron produces Fluvirin™, which is approved by the Food and Drug Administration (FDA) for persons aged >4 years. Fluvirin is marketed as a formulation with thimerosal as a preservative in multidose vials and as a formulation without thimerosal as a preservative in 0.5-mL unit dose syringes. Aventis Pasteur produces FluZone ® , which is FDA-approved for persons aged >6 months. FluZone containing thimerosal as a preservative is available in multidose vials. Preservative-free FluZone packaged as 0.25-mL unit dose syringes is available for use among persons aged 6-35 months. The total amount of inactivated influenza vaccine available without thimerosal as a preservative will be increased as manufacturing capabilities are expanded.\nThe risks of severe illness from influenza infection are elevated among both young children and pregnant women, and both groups benefit from vaccination by preventing illness and death from influenza. In contrast, no scientifically conclusive evidence exists of harm from exposure to thimerosal preservative-containing vaccine, whereas evidence is accumulating of lack of any harm resulting from exposure to such vaccines (61,65). Therefore, the benefits of influenza vaccination outweigh the theoretical risk, if any, for thimerosal exposure through vaccination. Nonetheless, certain persons remain concerned regarding exposure to thimerosal. The U.S. vaccine supply for infants and pregnant women is in a period of transition during which thimerosal in vaccines intended for these groups is being reduced by manufacturers as a feasible means of reducing an infant's total exposure to mercury because other environmental sources of exposure are more difficult or impossible to eliminate. Reductions in thimerosal in other vaccines have been achieved already and have resulted in substantially lowered cumulative exposure to thimerosal from vaccination among infants and children. For all of these reasons, persons recommended to receive inactivated influenza vaccine may receive either vaccine preparation, depending on availability. Supplies of inactivated influenza vaccines without thimerosal as a preservative will be increased for the 2004-05 influenza season compared with the 2003-04 season, and they will be included in CDC contracts to meet anticipated public demand in 2004.\n# Efficacy and Effectiveness of Inactivated Influenza Vaccine\nThe effectiveness of inactivated influenza vaccine depends primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the viruses in the vaccine and those in circulation. The majority of vaccinated children and young adults develop high postvaccination hemagglutination inhibition antibody titers (66)(67)(68).\n# MMWR May 28, 2004\nThese antibody titers are protective against illness caused by strains similar to those in the vaccine (67)(68)(69)(70).\nAdults Aged <65 Years. When the vaccine and circulating viruses are antigenically similar, influenza vaccine prevents influenza illness among approximately 70%-90% of healthy adults aged <65 years (9,12,71,72). Vaccination of healthy adults also has resulted in decreased work absenteeism and decreased use of health-care resources, including use of antibiotics, when the vaccine and circulating viruses are wellmatched (9)(10)(11)(12)72,73).\nChildren. Children aged as young as 6 months can develop protective levels of antibody after influenza vaccination (66,67,(74)(75)(76)(77), although the antibody response among children at high risk for influenza-related complications might be lower than among healthy children (78,79). In a randomized study among children aged 1-15 years, inactivated influenza vaccine was 77%-91% effective against influenza respiratory illness and was 44%-49%, 74%-76%, and 70%-81% effective against influenza seroconversion among children aged 1-5, 6-10, and 11-15 years, respectively (68). One study (80) reported a vaccine efficacy of 56% against influenza illness among healthy children aged 3-9 years, and another study (81) determined vaccine efficacy of 22%-54% and 60%-78% among children with asthma aged 2-6 years and 7-14 years, respectively. A 2-year randomized study of children aged 6-24 months determined that >89% of children seroconverted to all three vaccine strains during both years (82). During year 1, among 411 children, vaccine efficacy was 66% (95% confidence interval [CI] = 34% and 82%) against cultureconfirmed influenza (attack rates: 5.5% and 15.9% among vaccine and placebo groups, respectively). During year 2, among 375 children, vaccine efficacy was -7% (95% CI = -247% and 67%; attack rates: 3.6% and 3.3% among vaccine and placebo groups, respectively; the second year exhibited lower attack rates overall and was considered a mild season). However, no overall reduction in otitis media was reported (82). Other studies report that trivalent inactivated influenza vaccine decreases the incidence of influenza-associated otitis media among young children by approximately 30% (16,17).\nAdults Aged >65 Years. Older persons and persons with certain chronic diseases might develop lower postvaccination antibody titers than healthy young adults and thus can remain susceptible to influenza-related upper respiratory tract infection (83)(84)(85). A randomized trial among noninstitutionalized persons aged >60 years reported a vaccine efficacy of 58% against influenza respiratory illness, but indicated that efficacy might be lower among those aged >70 years (86). The vaccine can also be effective in preventing secondary complications and reducing the risk for influenza-related hospitalization and death among adults >65 years with and without high-risk medical conditions (e.g., heart disease and diabetes) (13)(14)(15)18,87). Among elderly persons not living in nursing homes or similar chronic-care facilities, influenza vaccine is 30%-70% effective in preventing hospitalization for pneumonia and influenza (15,88). Among older persons who do reside in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and deaths. Among this population, the vaccine can be 50%-60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death, although the effectiveness in preventing influenza illness often ranges from 30% to 40% (89)(90)(91).\n# Efficacy and Effectiveness of LAIV\nHealthy Children. A randomized, double-blind, placebocontrolled trial among 1,602 healthy children initially aged 15-71 months assessed the efficacy of trivalent LAIV against culture-confirmed influenza during two seasons (92,93). This trial included subsets of 238 healthy children (163 vaccinees and 75 placebo recipients) aged 60-71 months who received 2 doses and 74 children (54 vaccinees and 20 placebo recipients) aged 60-71 months who received a single dose during season one, and a subset of 544 children (375 vaccinees and 169 placebo recipients) aged 60-84 months during season two. Children who continued from season one to season two remained in the same study group. In season one, when vaccine and circulating virus strains were well-matched, efficacy was 93% for all participants, regardless of age, among persons receiving 2 doses of LAIV. Efficacy was 87% in the 60-71-month subset for those who received 2 doses, and was 91% in the subset for those who received 1 or 2 doses. In season two, when the A (H3N2) component was not well-matched between vaccine and circulating virus strains, efficacy was 86% overall and 87% among those aged 60-84 months. The vaccine was 92% efficacious in preventing culture-confirmed influenza during the twoseason study. Other results included a 27% reduction in febrile otitis media and a 28% reduction in otitis media with concomitant antibiotic use. Receipt of LAIV also resulted in decreased fever and otitis media among vaccine recipients who experienced influenza.\nHealthy Adults. A randomized, double-blind, placebocontrolled trial among 4,561 healthy working adults aged 18-64 years assessed multiple endpoints, including reductions in illness, absenteeism, health-care visits, and medication use during peak and total influenza outbreak periods (94). The study was conducted during the 1997-98 influenza season, when the vaccine and circulating A (H3N2) strains were not well-matched. The study did not include testing of viruses by a laboratory. During peak outbreak periods, no difference was identified between LAIV and placebo recipients experiencing any febrile episodes. However, vaccination was associated with reductions in severe febrile illnesses of 19% and febrile upper respiratory tract illnesses of 24%. Vaccination also was associated with fewer days of illness, fewer days of work lost, fewer days with health-care provider visits, and reduced use of prescription antibiotics and over-the-counter medications.\nAmong the subset of 3,637 healthy adults aged 18-49 years, LAIV recipients (n = 2,411) had 26% fewer febrile upperrespiratory illness episodes; 27% fewer lost work days as a result of febrile upper respiratory illness; and 18%-37% fewer days of health-care provider visits caused by febrile illness, compared with placebo recipients (n = 1,226). Days of antibiotic use were reduced by 41%-45% in this age subset.\nAnother randomized, double-blind, placebo-controlled challenge study among 92 healthy adults (LAIV, n = 29; placebo, n = 31; inactivated influenza vaccine, n = 32) aged 18-41 years assessed the efficacy of both LAIV and inactivated vaccine (95). The overall efficacy of LAIV and inactivated influenza vaccine in preventing laboratory-documented influenza from all three influenza strains combined was 85% and 71%, respectively, on the basis of experimental challenge by viruses to which study participants were susceptible before vaccination. The difference between the two vaccines was not statistically significant.\n# Cost-Effectiveness of Influenza Vaccine\nInfluenza vaccination can reduce both health-care costs and productivity losses associated with influenza illness. Economic studies of influenza vaccination of persons aged >65 years conducted in the United States have reported overall societal cost savings and substantial reductions in hospitalization and death (15,88,96). Studies of adults aged <65 years have reported that vaccination can reduce both direct medical costs and indirect costs from work absenteeism (8,(10)(11)(12)72,97). Reductions of 34%-44% in physician visits, 32%-45% in lost workdays (10,12), and 25% in antibiotic use for influenza-associated illnesses have been reported (12). One cost-effectiveness analysis estimated a cost of approximately $60-$4,000/illness averted among healthy persons aged 18-64 years, depending on the cost of vaccination, the influenza attack rate, and vaccine effectiveness against influenza-like illness (72). Another cost-benefit economic model estimated an average annual savings of $13.66/ person vaccinated (98). In the second study, 78% of all costs prevented were costs from lost work productivity, whereas the first study did not include productivity losses from influenza illness. Economic studies specifically evaluating the costeffectiveness of vaccinating persons aged 50-64 years are not available, and the number of studies that examine the economics of routinely vaccinating children with inactivated or live, attenuated vaccine are limited (8,(99)(100)(101)(102). However, in a study of inactivated vaccine that included all age groups, cost utility improved with increasing age and among those with chronic medical conditions (8). Among persons aged >65 years, vaccination resulted in a net savings per quality-adjusted life year (QALY) gained and resulted in costs of $23-$256/QALY among younger age groups. Additional studies of the relative costeffectiveness and cost utility of influenza vaccination among children and among adults aged <65 years are needed and should be designed to account for year-to-year variations in influenza attack rates, illness severity, and vaccine efficacy when evaluating the long-term costs and benefits of annual vaccination.\n# Vaccination Coverage Levels\nAmong persons aged >65 years, influenza vaccination levels increased from 33% in 1989 (103) to 66% in 1999 (104), surpassing the Healthy People 2000 objective of 60% (105). Vaccine coverage reached the highest levels recorded (68%) during the 1999-00 influenza season, using the percentage of adults reporting influenza vaccination during the past 12 months who participated in the National Health Interview Survey (NHIS) during the first and second quarters of each calendar year as a proxy measure of influenza vaccine coverage for the previous influenza season (104). Possible reasons for the increase in influenza vaccination levels among persons aged >65 years through the 1999-00 influenza season include 1) greater acceptance of preventive medical services by practitioners; 2) increased delivery and administration of vaccine by health-care providers and sources other than physicians; 3) new information regarding influenza vaccine effectiveness, cost-effectiveness, and safety; and 4) initiation of Medicare reimbursement for influenza vaccination in 1993 (8,14,15,89,90,106,107). Vaccine coverage increased more rapidly through the mid-1990s than during subsequent seasons (average annual percentage increase of 4% from 1988-89 to 1996-97 versus 1% from 1996-97 to 1999-00).\nEstimated national adult vaccine coverage for the 2001-02 season (Table 2), the most recent for which complete data are available, was 66% for adults aged >65 years and 34% for adults aged 50-64 years (104; unpublished data, CDC National Immunization Program, 2004). The estimated vaccination coverage among adults with high-risk conditions aged 18-49 years and 50-64 years was 23% and 44%, respectively, substantially lower than the Healthy People 2000 and 2010 objective of 60% (104,105,108). Continued annual monitoring is needed to determine the effects of vaccine supply delays, changes in influenza vaccination recommendations and target groups for vaccination, and other factors related to vaccination coverage among adults and children. The Healthy People 2010 objective is to achieve vaccination coverage for 90% of persons aged >65 years (108).\nReducing racial and ethnic health disparities, including disparities in vaccination coverage, is an overarching national goal (108). Although estimated influenza vaccination coverage for the 1999-00 season reached the highest levels recorded among older black, Hispanic, and white populations, vaccination levels among blacks and Hispanics continue to lag behind those among whites (104,109). Estimated influenza vaccination levels for 2001 among persons aged >65 years were 66% among non-Hispanic whites, 48% among non-Hispanic blacks, and 54% among Hispanics (109,110). Additional strategies are needed to achieve the Healthy People 2010 objectives among all racial and ethnic groups.\nIn 1997 and 1998, vaccination coverage estimates among nursing home residents were 64%-82% and 83%, respectively (111,112). The Healthy People 2010 goal is to achieve influenza vaccination of 90% among nursing home residents, an increase from the Healthy People 2000 goal of 80% (105,108).\nReported vaccination levels are low among children at increased risk for influenza complications. One study conducted among patients in health maintenance organizations reported influenza vaccination percentages ranging from 9% to 10% among children with asthma (113). A 25% vaccination level was reported among children with severe to moderate asthma who attended an allergy and immunology clinic (114). However, a study conducted in a pediatric clinic demonstrated an increase in the vaccination percentage of chil-dren with asthma or reactive airways disease from 5% to 32% after implementing a reminder/recall system (115). One study reported 79% vaccination coverage among children attending a cystic fibrosis treatment center (116). Increasing vaccination coverage among persons who have high-risk conditions and are aged <65 years, including children at high risk, is the highest priority for expanding influenza vaccine use.\nAnnual vaccination is recommended for health-care workers. Nonetheless, NHIS reported vaccination coverage of only 34% and 38% among health-care workers in the 1997 and 2002 surveys, respectively (117,118; unpublished data, CDC National Immunization Program, 2004) (Table 2). Vaccination of health-care workers has been associated with reduced work absenteeism (9) and fewer deaths among nursing home patients (119,120).\nLimited information is available regarding use of influenza vaccine among pregnant women. Among women aged 18-44 years without diabetes responding to the 2001 Behavioral Risk Factor Surveillance System, those reporting they were pregnant were less likely to report influenza vaccination during the past 12 months (13.7%) than those not pregnant (16.8%) (121). Only 12% of pregnant women reported vaccination according to 2002 NHIS data, excluding pregnant women who reported diabetes, heart disease, lung disease, and other selected high-risk conditions (unpublished data, CDC National Immunization Program, 2004) (Table 2). Although * As recommended by the Advisory Committee on Immunization Practices. † CI = Confidence interval. § Persons categorized as being at high risk for influenza-related complications self-reported one or more of the following: 1) ever being told by a physician they had diabetes, emphysema, coronary heart disease, angina, heart attack, or other heart condition; 2) having a diagnosis of cancer in the past 12 months (excluding nonmelanoma skin cancer) or ever being told by a physician they have lymphoma, leukemia, or blood cancer in the past 12 months; 3) being told by a physician they have chronic bronchitis or weak or failing kidneys; or 4) reporting an asthma episode or attack in the past 12 months. ¶ Aged 18-44 years, pregnant at the time of the survey and without high-risk conditions. ** Adults were classified as health-care workers if they were currently employed in a health-care occupation or in a health-care industry setting, on the basis of standard occupation and industry categories recoded in groups by CDC's National Center for Health Statistics. † † Interviewed adult in each household containing at least one of the following: a child aged <2 years, an adult aged >65 years, or any person aged 2-64 years at high risk (see previous footnote § ).\nnot directly measuring influenza vaccination among women who were past the first trimester of pregnancy during influenza season, these data indicate low compliance with the ACIP recommendations for pregnant women. In a study of influenza vaccine acceptance by pregnant women, 71% who were offered the vaccine chose to be vaccinated (122). However, a 1999 survey of obstetricians and gynecologists determined that only 39% administered influenza vaccine to obstetric patients, although 86% agreed that pregnant women's risk for influenzarelated morbidity and mortality increases during the last two trimesters (123).\nRecent data indicate that self-report of influenza vaccination among adults, compared with extraction from the medical record, is both sensitive and specific. Patient self-reports should be accepted as evidence of influenza vaccination in clinical practice (124). However, information on the validity of parents' reports of pediatric influenza vaccination is not yet available.\n# Recommendations for Using Inactivated and Live, Attenuated Influenza Vaccines\nBoth the inactivated influenza vaccine and LAIV can be used to reduce the risk of influenza. LAIV is only approved for use among healthy persons aged 5-49 years. Inactivated influenza vaccine is approved for persons aged >6 months, including those with high-risk conditions (see following sections on inactivated influenza vaccine and live, attenuated influenza vaccine).\n# Target Groups for Vaccination\n\n# Persons at Increased Risk for Complications\nVaccination with inactivated influenza vaccine is recommended for the following persons who are at increased risk for complications from influenza:\n• (125).\n# Persons Aged 50-64 Years\nVaccination is recommended for persons aged 50-64 years because this group has an increased prevalence of persons with high-risk conditions. In 2000, approximately 42 million persons in the United States were aged 50-64 years, of whom 12 million (29%) had one or more high-risk medical conditions (125). Influenza vaccine has been recommended for this entire age group to increase the low vaccination rates among persons in this age group with high-risk conditions (see preceding section). Age-based strategies are more successful in increasing vaccine coverage than patient-selection strategies based on medical conditions. Persons aged 50-64 years without high-risk conditions also receive benefit from vaccination in the form of decreased rates of influenza illness, decreased work absenteeism, and decreased need for medical visits and medication, including antibiotics (9)(10)(11)(12). Further, 50 years is an age when other preventive services begin and when routine assessment of vaccination and other preventive services has been recommended (126,127).\n# Persons Who Can Transmit Influenza to Those at High Risk\nPersons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. Decreasing transmission of influenza from caregivers and household contacts to persons at high risk might reduce influenza-related deaths among persons at high risk. Evidence from two studies indicates that vaccination of healthcare personnel is associated with decreased deaths among nursing home patients (119,120). Health-care workers should be vaccinated against influenza annually. Facilities that employ heath-care workers are strongly encouraged to provide vaccine to workers by using approaches that maximize immuni-zation rates. This will protect health-care workers, their patients, and communities, and will improve prevention, patient safety, and reduce disease burden. Health-care workers' influenza immunization rates should be regularly measured and reported. Although rates of health-care worker vaccination are typically <40%, with moderate effort, organized campaigns can attain higher rates of vaccination among this population (118).\nThe following groups should be vaccinated:\n• physicians, nurses, and other personnel in both hospital and outpatient-care settings, including medical emergency response workers (e.g., paramedics and emergency medical technicians); • employees of nursing homes and chronic-care facilities who have contact with patients or residents; • employees of assisted living and other residences for persons in groups at high risk; • persons who provide home care to persons in groups at high risk; and • household contacts (including children) of persons in groups at high risk. In addition, because children aged 0-23 months are at increased risk for influenza-related hospitalization (52-54), vaccination is recommended for their household contacts and out-of-home caregivers, particularly for contacts of children aged 0-5 months, because influenza vaccines have not been approved by FDA for use among children aged <6 months (see Healthy Young Children).\nHealthy persons aged 5-49 years in these groups who are not contacts of severely immunosuppressed persons (see Live, Attenuated Influenza Vaccine Recommendations) can receive either LAIV or inactivated influenza vaccine. All other persons in this group should receive inactivated influenza vaccine.\n# Additional Information Regarding Vaccination of Specific Populations Pregnant Women\nInfluenza-associated excess deaths among pregnant women were documented during the pandemics of 1918-19 and 1957-58 (128)(129)(130)(131). Case reports and limited studies also indicate that pregnancy can increase the risk for serious medical complications of influenza (132)(133)(134)(135)(136). An increased risk might result from 1) increases in heart rate, stroke volume, and oxygen consumption; 2) decreases in lung capacity; and 3) changes in immunologic function during pregnancy. A study of the effect of influenza during 17 interpandemic influenza seasons demonstrated that the relative risk for hospitalization for selected cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4 during weeks 14-20 of gestation to 4.7 during weeks 37-42, in comparison with women who were 1-6 months postpartum (137). Women in their third trimester of pregnancy were hospitalized at a rate (i.e., 250/100,000 pregnant women) comparable with that of nonpregnant women who had high-risk medical conditions. Researchers estimate that an average of 1-2 hospitalizations can be prevented for every 1,000 pregnant women vaccinated.\nBecause of the increased risk for influenza-related complications, women who will be pregnant during the influenza season should be vaccinated. Vaccination can occur in any trimester. One study of influenza vaccination of >2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine (138).\n# Healthy Young Children\nStudies indicate that rates of hospitalization are higher among young children than older children when influenza viruses are in circulation (51)(52)(53)139,140). The increased rates of hospitalization are comparable with rates for other groups considered at high risk for influenza-related complications. However, the interpretation of these findings has been confounded by co-circulation of respiratory syncytial viruses, which are a cause of serious respiratory viral illness among children and which frequently circulate during the same time as influenza viruses (141)(142)(143). Two recent studies have attempted to separate the effects of respiratory syncytial viruses and influenza viruses on rates of hospitalization among children who do not have high-risk conditions (52,53). Both studies reported that otherwise healthy children aged <2 years, and possibly children aged 2-4 years, are at increased risk for influenza-related hospitalization compared with older healthy children (Table 1). Among the Tennessee Medicaid population during 1973-1993, healthy children aged 6 months-<3 years had rates of influenza-associated hospitalization comparable with or higher than rates among children aged 3-14 years with high-risk conditions (Table 1) (52,54). Another Tennessee study reported a hospitalization rate per year of 3-4/1,000 healthy children aged <2 years for laboratory-confirmed influenza (32).\nBecause children aged 6-23 months are at substantially increased risk for influenza-related hospitalizations, ACIP recommends vaccination of all children in this age group (144). ACIP continues to recommend influenza vaccination of persons aged >6 months who have high-risk medical conditions.\nThe current inactivated influenza vaccine is not approved by FDA for use among children aged <6 months, the pediatric group at greatest risk for influenza-related complications (52). Vaccinating their household contacts and out-of-home caregivers might decrease the probability of influenza infection among these children.\nBeginning in March 2003, the group of children eligible for influenza vaccine coverage under the Vaccines for Children (VFC) program was expanded to include all VFCeligible children aged 6-23 months and VFC-eligible children aged 2-18 years who are household contacts of children aged 0-23 months (145).\n# Persons Infected with HIV\nLimited information is available regarding the frequency and severity of influenza illness or the benefits of influenza vaccination among persons with HIV infection (146,147). However, a retrospective study of young and middle-aged women enrolled in Tennessee's Medicaid program determined that the attributable risk for cardiopulmonary hospitalizations among women with HIV infection was higher during influenza seasons than during the peri-influenza periods. The risk for hospitalization was higher for HIV-infected women than for women with other well-recognized high-risk conditions, including chronic heart and lung diseases (148). Another study estimated that the risk for influenza-related death was 9.4-14.6/10,000 persons with acquired immunodeficiency syndrome (AIDS) compared with 0.09-0.10/10,000 among all persons aged 25-54 years and 6.4-7.0/10,000 among persons aged >65 years (149). Other reports indicate that influenza symptoms might be prolonged and the risk for complications from influenza increased for certain HIVinfected persons (150)(151)(152).\nInfluenza vaccination has been demonstrated to produce substantial antibody titers against influenza among vaccinated HIV-infected persons who have minimal AIDS-related symptoms and high CD4 + T-lymphocyte cell counts (153)(154)(155)(156). A limited, randomized, placebo-controlled trial determined that influenza vaccine was highly effective in preventing symptomatic, laboratory-confirmed influenza infection among HIV-infected persons with a mean of 400 CD4 + T-lymphocyte cells/mm 3 ; a limited number of persons with CD4 + T-lymphocyte cell counts of <200 were included in that study (147). A nonrandomized study among HIV-infected persons determined that influenza vaccination was most effective among persons with >100 CD4 + cells and among those with <30,000 viral copies of HIV type-1/mL (152). Among persons who have advanced HIV disease and low CD4 + T-lymphocyte cell counts, influenza vaccine might not induce protective antibody titers (155,156); a second dose of vaccine does not improve the immune response in these persons (156,157).\nOne study determined that HIV RNA (ribonucleic acid) levels increased transiently in one HIV-infected person after influenza infection (158). Studies have demonstrated a transient (i.e., 2-4 week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (155,159). Other studies using similar laboratory techniques have not documented a substantial increase in the replication of HIV (160)(161)(162)(163). Deterioration of CD4 + T-lymphocyte cell counts or progression of HIV disease have not been demonstrated among HIVinfected persons after influenza vaccination compared with unvaccinated persons (156,164). Limited information is available concerning the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza infection or influenza vaccination (146,165). Because influenza can result in serious illness, and because influenza vaccination can result in the production of protective antibody titers, vaccination will benefit HIV-infected persons, including HIV-infected pregnant women.\n# Breastfeeding Mothers\nInfluenza vaccine does not affect the safety of mothers who are breastfeeding or their infants. Breastfeeding does not adversely affect the immune response and is not a contraindication for vaccination.\n# Travelers\nThe risk for exposure to influenza during travel depends on the time of year and destination. In the tropics, influenza can occur throughout the year. In the temperate regions of the Southern Hemisphere, the majority of influenza activity occurs during April-September. In temperate climate zones of the Northern and Southern Hemispheres, travelers also can be exposed to influenza during the summer, especially when traveling as part of large organized tourist groups (e.g., on cruise ships) that include persons from areas of the world where influenza viruses are circulating (166,167). Persons at high risk for complications of influenza who were not vaccinated with influenza vaccine during the preceding fall or winter should consider receiving influenza vaccine before travel if they plan to\n• travel to the tropics,\n• travel with organized tourist groups at any time of year, or • travel to the Southern Hemisphere during April-September.\nNo information is available regarding the benefits of revaccinating persons before summer travel who were already vaccinated in the preceding fall. Persons at high risk who receive the previous season's vaccine before travel should be revaccinated with the current vaccine the following fall or winter. Persons aged >50 years and others at high risk should consult with their physicians before embarking on travel during the summer to discuss the symptoms and risks for influenza and May 28, 2004 the advisability of carrying antiviral medications for either prophylaxis or treatment of influenza.\n# General Population\nIn addition to the groups for which annual influenza vaccination is recommended, physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza (the vaccine can be administered to children >6 months), depending on vaccine availability (see Influenza Vaccine Supply). Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics.\n# Comparison of LAIV with Inactivated Influenza Vaccine\nBoth inactivated influenza vaccine and LAIV are available to reduce the risk of influenza infection and illness. However, the vaccines also differ in key ways (Table 3).\n# Major Similarities\nLAIV and inactivated influenza vaccine contain strains of influenza viruses that are antigenically equivalent to the annually recommended strains: one influenza A (H3N2) virus, one A (H1N1) virus, and one B virus. Each year, one or more virus strains might be changed on the basis of global surveillance for influenza viruses and the emergence and spread of new strains. Viruses for both vaccines are grown in eggs. Both vaccines are administered annually to provide optimal protection against influenza infection (Table 3).\n# Major Differences\nInactivated influenza vaccine contains killed viruses, whereas LAIV contains attenuated viruses still capable of replication. LAIV is administered intranasally by sprayer, whereas inactivated influenza vaccine is administered intramuscularly by injection. LAIV is more expensive than inactivated influenza vaccine. LAIV is approved for use only among healthy persons aged 5-49 years; inactivated influenza vaccine is approved for use among persons aged >6 months, including those who are healthy and those with chronic medical conditions (Table 3).\n# Inactivated Influenza Vaccine Recommendations Persons Who Should Not Be Vaccinated with Inactivated Influenza Vaccine\nInactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Prophylactic use of antiviral agents is an option for preventing influenza among such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications from influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information regarding vaccine components is located in package inserts from each manufacturer. Persons with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis.\n# Dosage\nDosage recommendations vary according to age group (Table 4). Among previously unvaccinated children aged <9 years, 2 doses administered >1 month apart are recommended for satisfactory antibody responses. If possible, the second dose should be administered before December. If a child aged <9 years receiving vaccine for the first time does not receive a second dose of vaccine within the same season, only 1 dose of vaccine should be administered the following season. Two doses are not required at that time. Among adults, studies have indicated limited or no improvement in antibody response when a second dose is administered during the same season (168)(169)(170). Even when the current influenza vaccine contains one or more antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines during the year after vaccination (171,172). Vaccine prepared for a previous influenza season should not be administered to provide protection for the current season.\n# Route\nThe intramuscular route is recommended for influenza vaccine. Adults and older children should be vaccinated in the deltoid muscle. A needle length >1 inch can be considered for these age groups because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults and older children (173).\nInfants and young children should be vaccinated in the anterolateral aspect of the thigh (64). ACIP recommends a needle length of 7/8-1 inch for children aged <12 months for intramuscular vaccination into the anterolateral thigh. When injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8-1.25 inches is recommended (64).\n# Side Effects and Adverse Reactions\nWhen educating patients regarding potential side effects, clinicians should emphasize that 1) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza; and 2) coincidental respiratory disease unrelated to influenza vaccination can occur after vaccination.\n# Local Reactions\nIn placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts <2 days (12,(174)(175)(176). These local reactions typically are mild and rarely inter-fere with the person's ability to conduct usual daily activities. One blinded, randomized, cross-over study among 1,952 adults and children with asthma, demonstrated that only body aches were reported more frequently after inactivated influenza vaccine (25.1%) than placebo-injection (20.8%) (177). One study (79) reported 20%-28% of children with asthma aged 9 months-18 years with local pain and swelling and another study (77) reported 23% of children aged 6 months-4 years with chronic heart or lung disease had local reactions. A different study (76) reported no difference in local reactions among 53 children aged 6 months-6 years with high-risk medical conditions or among 305 healthy children aged 3-12 years in a placebo-controlled trial of inactivated influenza vaccine. In a study of 12 children aged 5-32 months, no substantial local or systemic reactions were noted (178).\n# Systemic Reactions\nFever, malaise, myalgia, and other systemic symptoms can occur after vaccination with inactivated vaccine and most often affect persons who have had no prior exposure to the * Populations at high risk from complications of influenza infection include persons aged >65 years; residents of nursing homes and other chronic-care facilities that house persons with chronic medical conditions; adults and children with chronic disorders of the pulmonary or cardiovascular systems; adults and children with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression; children and adolescents receiving long-term aspirin therapy (at risk for developing Reye syndrome after wild-type influenza infection); pregnant women; and children aged 6-23 months. † No data are available regarding effect on safety or efficacy. § Inactivated influenza vaccine coadministration has been evaluated systematically only among adults with pneumococcal polysaccharide vaccine. \n# Yes\nYes influenza virus antigens in the vaccine (e.g., young children) (179,180). These reactions begin 6-12 hours after vaccination and can persist for 1-2 days. Recent placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (12,(174)(175)(176).\nLess information from published studies is available for children, compared with adults. However, in a randomized crossover study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age group (177). An analysis of 215,600 children aged <18 years and 8,476 children aged 6-23 months enrolled in one of five health maintenance organizations reported no increase in biologically plausible medically attended events during the 2 weeks after inactivated influenza vaccination, compared with control periods 3-4 weeks before and after vaccination (181). In a study of 791 healthy children (68), postvaccination fever was noted among 11.5% of children aged 1-5 years, 4.6% among children aged 6-10 years, and 5.1% among children aged 11-15 years. Among children with high-risk medical conditions, one study of 52 children aged 6 months-4 years reported fever among 27% and irritability and insomnia among 25% (77); and a study among 33 children aged 6-18 months reported that one child had irritability and one had a fever and seizure after vaccination (182). No placebo comparison was made in these studies. However, in pediatric trials of A/New Jersey/76 swine influenza vaccine, no difference was reported between placebo and split-virus vaccine groups in febrile reactions after injection, although the vaccine was associated with mild local tenderness or erythema (76).\nLimited data regarding potential adverse events after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). During January 1, 1991-January 23, 2003, VAERS received 1,072 reports of adverse events among children aged <18 years, including 174 reports of adverse events among children aged 6-23 months. The number of influenza vaccine doses received by children during this time period is unknown. The most frequently reported events among children were fever, injection-site reactions, and rash (unpublished data, CDC, 2003). Because of the limitations of spontaneous reporting systems, determining causality for specific types of adverse events, with the exception of injection-site reactions, is usually not possible by using VAERS data alone.\nHealth-care professionals should promptly report all clinically significant adverse events after influenza vaccination of children to VAERS, even if the health-care professional is not certain that the vaccine caused the event. The Institute of Medicine has specifically recommended reporting of potential neurologic complications (e.g., demyelinating disorders such as Guillain-Barré [GBS] syndrome), although no evidence exists of a causal relationship between influenza vaccine and neurologic disorders in children.\nImmediate -presumably allergic -reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination (183). These reactions probably result from hypersensitivity to certain vaccine components; the majority of reactions probably are caused by residual egg protein. Although current influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have had hives or swelling of the lips or tongue, or who have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma or other allergic responses to egg protein, might also be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Protocols have been published for safely administering influenza vaccine to persons with egg allergies (184)(185)(186). Immunogenicity and side effects of split-and whole-virus vaccines are similar among adults when vaccines are administered at the recommended dosage. § For adults and older children, the recommended site of vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. ¶ Two doses administered at least 1 month apart are recommended for children aged <9 years who are receiving influenza vaccine for the first time.\nHypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity (187,188). When reported, hypersensitivity to thimerosal usually has consisted of local, delayed hypersensitivity reactions (187).\n# Guillain-Barré Syndrome\nThe 1976 swine influenza vaccine was associated with an increased frequency of GBS (189,190). Among persons who received the swine influenza vaccine in 1976, the rate of GBS was <10 cases/1 million persons vaccinated. The risk for influenza vaccine-associated GBS is higher among persons aged >25 years than persons <25 years (189). Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. Obtaining strong epidemiologic evidence for a possible limited increase in risk is difficult for such a rare condition as GBS, which has an annual incidence of 10-20 cases/1 million adults (191). More definitive data probably will require using other methodologies (e.g., laboratory studies of the pathophysiology of GBS).\nDuring three of four influenza seasons studied during 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated but were not statistically significant in any of these studies (192)(193)(194). However, in a study of the 1992-93 and 1993-94 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0-2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately 1 additional case of GBS/1 million persons vaccinated. The combined number of GBS cases peaked 2 weeks after vaccination (195). Thus, investigations to date indicate no substantial increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976), and that, if influenza vaccine does pose a risk, it is probably slightly more than one additional case/1 million persons vaccinated. Cases of GBS after influenza infection have been reported, but no epidemiologic studies have documented such an association (196,197). Substantial evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni, as well as upper respiratory tract infections are associated with GBS (191,(198)(199)(200).\nEven if GBS were a true side effect of vaccination in the years after 1976, the estimated risk for GBS of approximately 1 additional case/1 million persons vaccinated is substantially less than the risk for severe influenza, which can be prevented by vaccination among all age groups, especially persons aged >65 years and those who have medical indications for influenza vaccination (Table 1) (see Hospitalizations and Deaths from Influenza). The potential benefits of influenza vaccina-tion in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for experiencing vaccine-associated GBS. The average case fatality ratio for GBS is 6% and increases with age (191,201). No evidence indicates that the case fatality ratio for GBS differs among vaccinated persons and those not vaccinated.\nThe incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (192,202). Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown; therefore, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination is prudent. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. Although data are limited, for the majority of persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination.\n# Live, Attenuated Influenza Vaccine Recommendations Background\nDescription and Action Mechanisms. LAIVs have been in development since the 1960s in the United States, where they have been evaluated as mono-, bi-, and trivalent formulations (203)(204)(205)(206)(207). The LAIV licensed for use in the United States beginning in 2003 is produced by MedImmune, Inc. (Gaithersburg, Maryland; http://www.medimmune.com) and marketed under the name FluMist™. It is a live, trivalent, intranasally administered vaccine that is • attenuated, producing mild or no signs or symptoms related to influenza virus infection; • temperature-sensitive, a property that limits the replication of the vaccine viruses at 38 º C-39 º C, and thus restricts LAIV viruses from replicating efficiently in human lower airways; and • cold-adapted, replicating efficiently at 25 º C, a temperature that is permissive for replication of LAIV viruses, but restrictive for replication of different wild-type viruses. In animal studies, LAIV viruses replicate in the mucosa of the nasopharynx, inducing protective immunity against viruses included in the vaccine, but replicate inefficiently in the lower airways or lungs.\nThe first step in developing an LAIV was the derivation of two stably attenuated master donor viruses (MDV), one for type A and one for type B influenza viruses. The two MDVs each acquired the cold-adapted, temperature-sensitive, attenuated phenotypes through serial passage in viral culture conducted at progressively lower temperatures. The vaccine viruses in LAIV are reassortant viruses containing genes from these MDVs that confer attenuation, temperature sensitivity, and cold adaptation and genes from the recommended contemporary wild-type influenza viruses, encoding the surface antigens hemagglutinin (HA) and neuraminidase (NA). Thus, MDVs provide the stably attenuated vehicles for presenting influenza HA and NA antigens, to which the protective antibody response is directed, to the immune system. The reassortant vaccine viruses are grown in embryonated hens' eggs. After the vaccine is formulated and inserted into individual sprayers for nasal administration, the vaccine must be stored at -15 º C or colder.\nThe immunogenicity of the approved LAIV has been assessed in multiple studies (96,(208)(209)(210)(211)(212)(213), which included approximately 100 children aged 5-17 years, and approximately 300 adults aged 18-49 years. LAIV virus strains replicate primarily in nasopharyngeal epithelial cells. The protective mechanisms induced by vaccination with LAIV are not completely understood but appear to involve both serum and nasal secretory antibodies. No single laboratory measurement closely correlates with protective immunity induced by LAIV.\nShedding and Transmission of Vaccine Viruses. Available data indicate that both children and adults vaccinated with LAIV can shed vaccine viruses for >2 days after vaccination, although in lower titers than typically occur with shedding of wild-type influenza viruses. Shedding should not be equated with person-to-person transmission of vaccine viruses, although, in rare instances, shed vaccine viruses can be transmitted from vaccinees to nonvaccinated persons.\nOne unpublished study in a child care center setting assessed transmissibility of vaccine viruses from 98 vaccinated to 99 unvaccinated subjects, all aged 8-36 months. Eighty percent of vaccine recipients shed one or more virus strains, with a mean of 7.6 days' duration (214). One vaccine type influenza type B isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The type B isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype, and it possessed the same genetic sequence as a virus shed from a vaccine recipient in the same children's play group. The placebo recipient from whom the influenza type B vaccine virus was isolated did not exhibit symptoms that were different from those experienced by vaccine recipients. The estimated probability of acquiring vac-cine virus after close contact with a single LAIV recipient in this child care population was 0.58%-2.4%.\nOne study assessing shedding of vaccine viruses in 20 healthy vaccinated adults aged 18-49 years demonstrated that the majority of shedding occurred within the first 3 days after vaccination, although one subject was noted to shed virus on day 7 after vaccine receipt. No subject shed vaccine viruses >10 days after vaccination. Duration or type of symptoms associated with receipt of LAIV did not correlate with duration of shedding of vaccine viruses. Person-to-person transmission of vaccine viruses was not assessed in this study (215).\nStability of Vaccine Viruses. In clinical trials, viruses shed by vaccine recipients have been phenotypically stable. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt (216). Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes.\n# Using Live, Attenuated Influenza Vaccine\nLAIV is an option for vaccination of healthy persons aged 5-49 years, including persons in close contact with groups at high risk and those wanting to avoid influenza. Possible advantages of LAIV include its potential to induce a broad mucosal and systemic immune response, its ease of administration, and the acceptability of an intranasal rather than intramuscular route of administration.\n# Persons Who Should Not Be Vaccinated with LAIV\nThe following populations should not be vaccinated with LAIV:\n• \n# Close Contacts of Persons at High Risk for Complications from Influenza\nClose contacts of persons at high risk for complications from influenza should receive influenza vaccine to reduce transmission of wild-type influenza viruses to persons at high risk. Use of inactivated influenza vaccine is preferred for vaccinating household members, health-care workers, and others who have close contact with severely immunosuppressed persons (e.g., patients with hematopoietic stem cell transplants) during those periods in which the immunosuppressed person requires care in a protective environment. The rationale for not using LAIV among health-care workers caring for such patients is the theoretical risk that a live, attenuated vaccine virus could be transmitted to the severely immunosuppressed person and cause disease. No preference exists for inactivated influenza vaccine use by health-care workers or other persons who have close contact with persons with lesser degrees of immunosuppression (e.g., persons with diabetes, persons with asthma taking corticosteroids, or persons infected with human immunodeficiency virus), and no preference exists for inactivated influenza vaccine use by health-care workers or other healthy persons aged 5-49 years in close contact with all other groups at high risk.\nIf a health-care worker receives LAIV, that worker should refrain from contact with severely immunosuppressed patients as described previously for 7 days after vaccine receipt. Hospital visitors who have received LAIV should refrain from contact with severely immunosuppressed persons for 7 days after vaccination; however, such persons need not be excluded from visitation of patients who are not severely immunosuppressed.\n# Personnel Who May Administer LAIV\nLow-level introduction of vaccine viruses into the environment is likely unavoidable when administering LAIV. The risk of acquiring vaccine viruses from the environment is unknown but likely to be limited. Severely immunosuppressed persons should not administer LAIV. However, other persons at high risk for influenza complications may administer LAIV. These include persons with underlying medical conditions placing them at high risk or who are likely to be at risk, including pregnant women, persons with asthma, and persons aged >50 years.\n# LAIV Dosage and Administration\nLAIV is intended for intranasal administration only and should not be administered by the intramuscular, intradermal, or intravenous route. LAIV must be stored at -15 º C or colder. LAIV should not be stored in a frost-free freezer (because the temperature might cycle above -15 º C), unless a manufacturer-supplied freezer box is used. LAIV must be thawed before administration. This can be accomplished by holding an individual sprayer in the palm of the hand until thawed, with subsequent immediate administration. Alternatively, the vaccine can be thawed in a refrigerator and stored at 2 º C-8 º C for <24 hours before use. Vaccine should not be refrozen after thawing. LAIV is supplied in a prefilled singleuse sprayer containing 0.5 mL of vaccine. Approximately 0.25 mL (i.e., half of the total sprayer contents) is sprayed into the first nostril while the recipient is in the upright position. An attached dose-divider clip is removed from the sprayer to administer the second half of the dose into the other nostril. If the vaccine recipient sneezes after administration, the dose should not be repeated.\nLAIV should be administered annually according to the following schedule:\n• Children aged 5-8 years previously unvaccinated at any time with either LAIV or inactivated influenza vaccine should receive 2 doses † of LAIV separated by 6-10 weeks. • Children aged 5-8 years previously vaccinated at any time with either LAIV or inactivated influenza vaccine should receive 1 dose of LAIV. They do not require a second dose. • Persons aged 9-49 years should receive 1 dose of LAIV. LAIV can be administered to persons with minor acute illnesses (e.g., diarrhea or mild upper respiratory tract infection with or without fever). However, if clinical judgment indicates nasal congestion is present that might impede delivery of the vaccine to the nasopharyngeal mucosa, deferral of administration should be considered until resolution of the illness. Whether concurrent administration of LAIV with other vaccines affects the safety or efficacy of either LAIV or the simultaneously administered vaccine is unknown. In the absence of specific data indicating interference, following the ACIP general recommendations for immunization is prudent (64). Inactivated vaccines do not interfere with the immune response to other inactivated vaccines or to live vaccines. An inactivated vaccine can be administered either simultaneously or at any time before or after LAIV. Two live vaccines not administered on the same day should be administered >4 weeks apart when possible.\n# LAIV and Use of Influenza Antiviral Medications\nThe effect on safety and efficacy of LAIV coadministration with influenza antiviral medications has not been studied.\n# MMWR May 28, 2004\nHowever, because influenza antivirals reduce replication of influenza viruses, LAIV should not be administered until 48 hours after cessation of influenza antiviral therapy, and influenza antiviral medications should not be administered for 2 weeks after receipt of LAIV.\n# LAIV Storage\nLAIV must be stored at -15 º C or colder. LAIV should not be stored in a frost-free freezer because the temperature might cycle above -15 º C, unless a manufacturer-supplied freezer box or other strategy is used. LAIV can be thawed in a refrigerator and stored at 2 º C-8 º C for <24 hours before use. It should not be refrozen after thawing. Additional information is available at Wyeth Product Quality (1-800-411-0086) or at http:// www.FluMist.com.\n# Side Effects and Adverse Reactions\nTwenty prelicensure clinical trials assessed the safety of the approved LAIV. In these combined studies, approximately 28,000 doses of the vaccine were administered to >20,000 subjects. A subset of these trials were randomized, placebocontrolled studies in which >4,000 healthy children aged 5-17 years and >2,000 healthy adults aged 18-49 years were vaccinated. The incidence of adverse events possibly complicating influenza (e.g., pneumonia, bronchitis, bronchiolitis, or central nervous system events) was not statistically different among LAIV and placebo recipients aged 5-49 years.\nChildren. Signs and symptoms reported more often among vaccine recipients than placebo recipients included runny nose or nasal congestion (20%-75%), headache (2%-46%), fever (0%-26%), and vomiting (3%-13%), abdominal pain (2%), and myalgias (0%-21%) (208,211,213,(217)(218)(219). These symptoms were associated more often with the first dose and were self-limited. In a subset of healthy children aged 60-71 months from one clinical trial (92,93), certain signs and symptoms were reported more often among LAIV recipients after the first dose (n = 214) than placebo recipients (n = 95) (e.g., runny nose, 48.1% versus 44.2%; headache, 17.8% versus 11.6%; vomiting, 4.7% versus 3.2%; myalgias, 6.1% versus 4.2%), but these differences were not statistically significant. Unpublished data from a study including subjects aged 1-17 years indicated an increase in asthma or reactive airways disease in the subset aged 12-59 months. Because of this, LAIV is not approved for use among children aged <60 months.\nAdults. Among adults, runny nose or nasal congestion (28%-78%), headache (16%-44%), and sore throat (15%-27%) have been reported more often among vaccine recipients than placebo recipients (94,220,221). In one clinical trial (94), among a subset of healthy adults aged 18-49 years, signs and symptoms reported more frequently among LAIV recipi-ents (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (13.9% versus 10.8%); runny nose (44.5% versus 27.1%); sore throat (27.8% versus 17.1%); chills (8.6% versus 6.0%); and tiredness/weakness (25.7% versus 21.6%).\nSafety Among Groups at High Risk from Influenza-Related Morbidity. Until additional data are acquired, persons at high risk for experiencing complications from influenza infection (e.g., immunocompromised patients; patients with asthma, cystic fibrosis, or chronic obstructive pulmonary disease; or persons aged >65 years) should not be vaccinated with LAIV. Protection from influenza among these groups should be accomplished by using inactivated influenza vaccine.\nSerious Adverse Events. Serious adverse events among healthy children aged 5-17 years or healthy adults aged 18-49 years occurred at a rate of <1%. Surveillance should continue for adverse events that might not have been detected in previous studies. Health-care professionals should promptly report all clinically significant adverse events after LAIV administration to VAERS, as recommended for inactivated influenza vaccine.\n# Recommended Vaccines for Different Age Groups\nWhen vaccinating children aged 6 months-3 years, healthcare providers should use inactivated influenza vaccine that has been approved by FDA for this age group. Inactivated influenza vaccine from Aventis Pasteur, Inc., (FluZone splitvirus) is approved for use among persons aged >6 months. Inactivated influenza vaccine from Chiron (Fluvirin) is labeled in the United States for use only among persons aged >4 years because data to demonstrate efficacy among younger persons have not been provided to FDA. Live, attenuated influenza vaccine from MedImmune (FluMist) is approved for use by healthy persons aged 5-49 years (Table 5).\n# Timing of Annual Influenza Vaccination\nThe annual supply of inactivated influenza vaccine and the timing of its distribution cannot be guaranteed in any year. Information regarding the supply of 2004-05 vaccine might not be available until late summer or early fall 2004. To allow vaccine providers to plan for the upcoming vaccination season, taking into account the yearly possibility of vaccine delays or shortages and the need to ensure vaccination of persons at high risk and their contacts, ACIP recommends that vaccine campaigns conducted in October focus their efforts primarily on persons at increased risk for influenza complications and their contacts, including health-care workers. Campaigns conducted in November and later should continue to vaccinate persons at high risk and their contacts, but also vaccinate other persons who wish to decrease their risk for influenza infection. Vaccination efforts for all groups should continue into December and beyond. CDC and other public health agencies will assess the vaccine supply on a continuing basis throughout the manufacturing period and will make recommendations in the summer preceding the 2004-05 influenza season regarding the need for tiered timing of vaccination of different risk groups.\n# Vaccination in October and November\nThe optimal time to vaccinate is usually during October-November. ACIP recommends that vaccine providers focus their vaccination efforts in October and earlier primarily on persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6-23 months), household contacts of persons at high risk (including out-of-home caregivers and household contacts of children aged 0-23 months), and health-care workers. Vaccination of children aged <9 years who are receiving vaccine for the first time should also begin in October or earlier because those persons need a booster dose 1 month after the initial dose. Efforts to vaccinate other persons who wish to decrease their risk for influenza infection should begin in November; however, if such persons request vaccination in October, vaccination should not be deferred. Materials to assist providers in prioritizing early vaccine are available at http://www.cdc.gov/flu/professionals/vaccination/index.htm (see also Travelers in this report).\n# Timing of Organized Vaccination Campaigns\nPersons planning substantial organized vaccination campaigns should consider scheduling these events after mid-October because the availability of vaccine in any location cannot be ensured consistently in early fall. Scheduling campaigns after mid-October will minimize the need for cancel-lations because vaccine is unavailable. Campaigns conducted before November should focus efforts on vaccination of persons aged >50 years, persons aged <50 years at increased risk for influenza-related complications (including children aged 6-23 months), health-care workers, and household contacts of persons at high-risk (including children aged 0-23 months) to the extent feasible.\n# Vaccination in December and Later\nAfter November, many persons who should or want to receive influenza vaccine remain unvaccinated. In addition, substantial amounts of vaccine have remained unused during three of the past four influenza seasons. To improve vaccine coverage, influenza vaccine should continue to be offered in December and throughout the influenza season as long as vaccine supplies are available, even after influenza activity has been documented in the community. In the United States, seasonal influenza activity can begin to increase as early as October or November, but influenza activity has not reached peak levels in the majority of recent seasons until late December-early March (Table 6). Therefore, although the timing of influenza activity can vary by region, vaccine administered after November is likely to be beneficial in the majority of influenza seasons. Adults develop peak antibody protection against influenza infection 2 weeks after vaccination (222,223).\n# Vaccination Before October\nTo avoid missed opportunities for vaccination of persons at high risk for serious complications, such persons should be offered vaccine beginning in September during routine healthcare visits or during hospitalizations, if vaccine is available. In facilities housing older persons (e.g., nursing homes), vaccination before October typically should be avoided because antibody levels in such persons can begin to decline within a limited time after vaccination (224). In addition, children aged <9 years who have not been previously vaccinated and who need 2 doses before the start of the influenza season can receive their first dose in September or earlier.\n# Strategies for Implementing Vaccination Recommendations in Health-Care Settings\nSuccessful vaccination programs combine publicity and education for health-care workers and other potential vaccine recipients, a plan for identifying persons at high risk, use of reminder/recall systems, and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine, including use of standing orders programs (19,225). Using standing orders programs is recommended for long-term-care facilities (e.g., nursing homes and skilled nursing facilities), hospitals, and home health agencies to ensure the administration of recommended vaccinations for adults (226). Standing orders programs for both influenza and pneumococcal vaccination should be conducted under the supervision of a licensed practitioner according to a physicianapproved facility or agency policy by health-care personnel trained to screen patients for contraindications to vaccination, administer vaccine, and monitor for adverse events. The Centers for Medicare and Medicaid Services (CMS) has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to Medicare and Medicaid patients in hospitals, long-term-care facilities, and home health agencies (226). To the extent allowed by local and state law, these facilities and agencies may implement standing orders for influenza and pneumococcal vaccination of Medicare-and Medicaid-eligible patients. Other settings (e.g., outpatient facilities, managed care organizations, assisted living facilities, correctional facilities, pharmacies, and adult workplaces) are encouraged to introduce standing orders programs as well (20). Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following sections.\n# Outpatient Facilities Providing Ongoing Care\nStaff in facilities providing ongoing medical care (e.g., physicians' offices, public health clinics, employee health clinics, hemodialysis centers, hospital specialty-care clinics, and outpatient rehabilitation programs) should identify and label the medical records of patients who should receive vaccination. Vaccine should be offered during visits beginning in September and throughout the influenza season. The offer of vaccination and its receipt or refusal should be documented in the medical record. Patients for whom vaccination is recommended and who do not have regularly scheduled visits dur-ing the fall should be reminded by mail, telephone, or other means of the need for vaccination.\n# Outpatient Facilities Providing Episodic or Acute Care\nBeginning each September, acute health-care facilities (e.g., emergency rooms and walk-in clinics) should offer vaccinations to persons for whom vaccination is recommended or provide written information regarding why, where, and how to obtain the vaccine. This written information should be available in languages appropriate for the populations served by the facility.\n# Nursing Homes and Other Residential Long-Term-Care Facilities\nDuring October and November each year, vaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility or anytime afterwards. All residents should be vaccinated at one time, preceding the influenza season. Residents admitted through March after completion of the facility's vaccination program should be vaccinated at the time of admission.\n# Acute-Care Hospitals\nPersons of all ages (including children) with high-risk conditions and persons aged >50 years who are hospitalized at any time during September-March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. In one study, 39%-46% of adult patients hospitalized during the winter with influenza-related diagnoses had been hospitalized during the preceding autumn (227). Thus, the hospital serves as a setting in which persons at increased risk for subsequent hospitalization can be identified and vaccinated. However, vaccination of persons at high risk during or after their hospitalizations is often not done. In a study of hospitalized Medicare patients, only 31.6% were vaccinated before admission, 1.9% during admission, and 10.6% after admission (228). Using standing orders in hospitals increases vaccination rates among hospitalized persons (229).\n# Visiting Nurses and Others Providing Home Care to Persons at High Risk\nBeginning in September, nursing-care plans should identify patients for whom vaccination is recommended, and vaccine should be administered in the home, if necessary. Caregivers and other persons in the household (including children) should be referred for vaccination.\n# Other Facilities Providing Services to Persons Aged >50 Years\nBeginning in October, such facilities as assisted living housing, retirement communities, and recreation centers should offer unvaccinated residents and attendees vaccination on-site before the influenza season. Staff education should emphasize the need for influenza vaccine.\n# Health-Care Personnel\nBeginning in October each year, health-care facilities should offer influenza vaccinations to all personnel, including night and weekend staff. Particular emphasis should be placed on providing vaccinations to persons who care for members of groups at high risk. Efforts should be made to educate healthcare personnel regarding the benefits of vaccination and the potential health consequences of influenza illness for themselves and their patients. All health-care personnel should be provided convenient access to influenza vaccine at the work site, free of charge, as part of employee health programs (118).\n# Influenza Vaccine Supply\nDuring the 2002-03 season, approximately 95 million doses of influenza vaccine were produced, but 12 million doses went unused and had to be destroyed. During the 2003-04 season, approximately 87 million doses of vaccine were produced. During that season, shortages of vaccine were noted in multiple regions of the United States after an unprecedented demand for vaccine lasted longer into the season than usual, caused in part by increased media attention to influenza. On the basis of early projections, manufacturers anticipate production of 90-100 million doses of vaccine for the 2004-05 season.\nInfluenza vaccine delivery delays or vaccine shortages remain possible in part because of the inherent critical time constraints in manufacturing the vaccine given the annual updating of the influenza vaccine strains. Steps being taken to address possible future delays or vaccine shortages include identification and implementation of ways to expand the influenza vaccine supply and improvement of targeted delivery of vaccine to groups at high risk when delays or shortages are expected.\n# Future Directions\nACIP plans to review new vaccination strategies for improving prevention and control of influenza, including the possibility of expanding recommendations for use of influenza vaccines. In addition, strategies for regularly monitoring vaccine effectiveness will be reviewed.\n# Recommendations for Using Antiviral Agents for Influenza\nAntiviral drugs for influenza are an adjunct to influenza vaccine for controlling and preventing influenza. However, these agents are not a substitute for vaccination. Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir.\nAmantadine and rimantadine are chemically related antiviral drugs known as adamantanes with activity against influenza A viruses but not influenza B viruses. Amantadine was approved in 1966 for chemoprophylaxis of influenza A (H2N2) infection and was later approved in 1976 for treatment and chemoprophylaxis of influenza type A virus infections among adults and children aged >1 year. Rimantadine was approved in 1993 for treatment and chemoprophylaxis of influenza A infection among adults and prophylaxis among children. Although rimantadine is approved only for chemoprophylaxis of influenza A infection among children, certain specialists in the management of influenza consider it appropriate for treatment of influenza A among children (230).\nZanamivir and oseltamivir are chemically related antiviral drugs known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for treating uncomplicated influenza infections. Zanamivir is approved for treating persons aged >7 years, and oseltamivir is approved for treatment for persons aged >1 year. In 2000, oseltamivir was approved for chemoprophylaxis of influenza among persons aged >13 years.\nThe four drugs differ in pharmacokinetics, side effects, routes of administration, approved age groups, dosages, and costs. An overview of the indications, use, administration, and known primary side effects of these medications is presented in the following sections. Information contained in this report might not represent FDA approval or approved labeling for the antiviral agents described. Package inserts should be consulted for additional information.\n# Role of Laboratory Diagnosis\nAppropriate treatment of patients with respiratory illness depends on accurate and timely diagnosis. Early diagnosis of influenza can reduce the inappropriate use of antibiotics and provide the option of using antiviral therapy. However, because certain bacterial infections can produce symptoms similar to influenza, bacterial infections should be considered and appropriately treated, if suspected. In addition, bacterial infections can occur as a complication of influenza.\nInfluenza surveillance information and diagnostic testing can aid clinical judgment and help guide treatment decisions. The accuracy of clinical diagnosis of influenza on the basis of symptoms alone is limited because symptoms from illness caused by other pathogens can overlap considerably with influenza (29,33,34). Influenza surveillance by state and local health departments and CDC can provide information regarding the presence of influenza viruses in the community. Surveillance can also identify the predominant circulating types, subtypes, and strains of influenza.\nDiagnostic tests available for influenza include viral culture, serology, rapid antigen testing, polymerase chain reaction (PCR) and immunofluorescence (24). Sensitivity and specificity of any test for influenza might vary by the laboratory that performs the test, the type of test used, and the type of specimen tested. Among respiratory specimens for viral isolation or rapid detection, nasopharyngeal specimens are typically more effective than throat swab specimens (231). As with any diagnostic test, results should be evaluated in the context of other clinical information available to health-care providers.\nCommercial rapid diagnostic tests are available that can be used by laboratories in outpatient settings to detect influenza viruses within 30 minutes (24,232). These rapid tests differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types. Different tests can detect 1) only influenza A viruses; 2) both influenza A and B viruses, but not distinguish between the two types; or 3) both influenza A and B and distinguish between the two. The types of specimens acceptable for use (i.e., throat swab, nasal wash, or nasal swab) also vary by test. The specificity and, in particular, the sensitivity of rapid tests are lower than for viral culture and vary by test (233,234). Because of the lower sensitivity of the rapid tests, physicians should consider confirming negative tests with viral culture or other means. Further, when interpreting results of a rapid influenza test, physicians should consider the positive and negative predictive values of the test in the context of the level of influenza activity in their community. Package inserts and the laboratory performing the test should be consulted for more details regarding use of rapid diagnostic tests. Additional information concerning diagnostic testing is located at http://www.cdc. gov/flu/professionals/labdiagnosis.htm.\nDespite the availability of rapid diagnostic tests, collecting clinical specimens for viral culture is critical, because only culture isolates can provide specific information regarding circulating influenza subtypes and strains. This information is needed to compare current circulating influenza strains with vaccine strains, to guide decisions regarding influenza treatment and chemoprophylaxis, and to formulate vaccine for the coming year. Virus isolates also are needed to monitor the emergence of antiviral resistance and the emergence of novel influenza A subtypes that might pose a pandemic threat.\n# Indications for Use Treatment\nWhen administered within 2 days of illness onset to otherwise healthy adults, amantadine and rimantadine can reduce the duration of uncomplicated influenza A illness, and zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day, compared with placebo (72,(235)(236)(237)(238)(239)(240)(241)(242)(243)(244)(245)(246)(247)(248)(249). More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A infection than for treatment of influenza B infection (250)(251)(252)(253)(254)(255)(256)(257)(258)(259)(260)(261)(262)(263)(264)(265)(266). However, in vitro data and studies of treatment among mice and ferrets (267)(268)(269)(270)(271)(272)(273)(274), in addition to clinical studies, have documented that zanamivir and oseltamivir have activity against influenza B viruses (241,(245)(246)(247)275,276).\nData are limited regarding the effectiveness of the four antiviral agents in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these four antiviral drugs is principally based on studies of patients with uncomplicated influenza (277). Data are limited and inconclusive concerning the effectiveness of amantadine, rimantadine, zanamivir, and oseltamivir for treatment of influenza among persons at high risk for serious complications of influenza (27,235,237,238,240,241,248,(250)(251)(252)(253)(254). One study assessing oseltamivir treatment primarily among adults reported a reduction in complications necessitating antibiotic therapy compared with placebo (255). Fewer studies of the efficacy of influenza antivirals have been conducted among pediatric populations (235,238,244,245,251,256,257). One study of oseltamivir treatment documented a decreased incidence of otitis media among children (245). Inadequate data exist regarding the safety and efficacy of any of the influenza antiviral drugs for use among children aged <1 year (234).\nTo reduce the emergence of antiviral drug-resistant viruses, amantadine or rimantadine therapy for persons with influenza A illness should be discontinued as soon as clinically warranted, typically after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with either zanamivir or oseltamivir is 5 days.\n# Chemoprophylaxis\nChemoprophylactic drugs are not a substitute for vaccination, although they are critical adjuncts in preventing and controlling influenza. Both amantadine and rimantadine are indicated for chemoprophylaxis of influenza A infection, but not influenza B. Both drugs are approximately 70%-90% effective in preventing illness from influenza A infection (72,235,251). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and development of protective antibody against circulating influenza viruses. Therefore, certain persons who take these drugs will develop protective immune responses to circulating influenza viruses. Amantadine and rimantadine do not interfere with the antibody response to the vaccine (235). Both drugs have been studied extensively among nursing home populations as a component of influenza outbreak-control programs, which can limit the spread of influenza within chronic care institutions (235,250,(258)(259)(260).\nAmong the neuraminidase inhibitor antivirals, zanamivir and oseltamivir, only oseltamivir has been approved for prophylaxis, but community studies of healthy adults indicate that both drugs are similarly effective in preventing febrile, laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%) (261,262,278). Both antiviral agents have also been reported to prevent influenza illness among persons administered chemoprophylaxis after a household member was diagnosed with influenza (263,275,278). Experience with prophylactic use of these agents in institutional settings or among patients with chronic medical conditions is limited in comparison with the adamantanes (247,253,254,(264)(265)(266). One 6-week study of oseltamivir prophylaxis among nursing home residents reported a 92% reduction in influenza illness (247,279). Use of zanamivir has not been reported to impair the immunologic response to influenza vaccine (246,280). Data are not available regarding the efficacy of any of the four antiviral agents in preventing influenza among severely immunocompromised persons.\nWhen determining the timing and duration for administering influenza antiviral medications for prophylaxis, factors related to cost, compliance, and potential side effects should be considered. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost-effective, one study of amantadine or rimantadine prophylaxis reported that the drugs should be taken only during the period of peak influenza activity in a community (281).\nPersons at High Risk Who Are Vaccinated After Influenza Activity Has Begun. Persons at high risk for complications of influenza still can be vaccinated after an outbreak of influenza has begun in a community. However, development of antibodies in adults after vaccination takes approximately 2 weeks (222,223). When influenza vaccine is administered while influenza viruses are circulating, chemoprophylaxis should be considered for persons at high risk during the time from vaccination until immunity has developed. Children aged <9 years who receive influenza vaccine for the first time can require 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose).\nPersons Who Provide Care to Those at High Risk. To reduce the spread of virus to persons at high risk during community or institutional outbreaks, chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who have frequent contact with persons at high risk. Persons with frequent contact include employees of hospitals, clinics, and chronic-care facilities, household members, visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of influenza that might not be controlled by the vaccine, chemoprophylaxis should be considered for all such persons, regardless of their vaccination status.\nPersons Who Have Immune Deficiencies. Chemoprophylaxis can be considered for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons infected with HIV, chiefly those with advanced HIV disease. No published data are available concerning possible efficacy of chemoprophylaxis among persons with HIV infection or interactions with other drugs used to manage HIV infection. Such patients should be monitored closely if chemoprophylaxis is administered.\nOther Persons. Chemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Chemoprophylaxis can also be offered to persons who wish to avoid influenza illness. Health-care providers and patients should make this decision on an individual basis.\n# Control of Influenza Outbreaks in Institutions\nUsing antiviral drugs for treatment and prophylaxis of influenza is a key component of influenza outbreak control in institutions. In addition to antiviral medications, other outbreak-control measures include instituting droplet precautions and establishing cohorts of patients with confirmed or suspected influenza, re-offering influenza vaccinations to unvaccinated staff and patients, restricting staff movement between wards or buildings, and restricting contact between ill staff or visitors and patients (282)(283)(284) (for additional information regarding outbreak control in specific settings, see Additional Information Regarding Influenza Infection Control Among Specific Populations).\nThe majority of published reports concerning use of antiviral agents to control influenza outbreaks in institutions are based on studies of influenza A outbreaks among nursing home populations where amantadine or rimantadine were used (235,250,(258)(259)(260)281). Less information is available concerning use of neuraminidase inhibitors in influenza A or B institutional outbreaks (253,254,266,279,285). When confirmed or suspected outbreaks of influenza occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. In these situations, having preapproved orders from physicians or plans to obtain orders for antiviral medications on short notice can substantially expedite administration of antiviral medications.\nWhen outbreaks occur in institutions, chemoprophylaxis should be administered to all residents, regardless of whether they received influenza vaccinations during the previous fall, and should continue for a minimum of 2 weeks. If surveillance indicates that new cases continue to occur, chemoprophylaxis should be continued until approximately 1 week after the end of the outbreak. The dosage for each resident should be determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza that is not well-matched by the vaccine.\nIn addition to nursing homes, chemoprophylaxis also can be considered for controlling influenza outbreaks in other closed or semiclosed settings (e.g., dormitories or other settings where persons live in close proximity). For example, chemoprophylaxis with rimantadine has been used successfully to control an influenza A outbreak aboard a large cruise ship (167).\nTo limit the potential transmission of drug-resistant virus during outbreaks in institutions, whether in chronic or acutecare settings or other closed settings, measures should be taken to reduce contact as much as possible between persons taking antiviral drugs for treatment and other persons, including those taking chemoprophylaxis (see Antiviral Drug-Resistant Strains of Influenza).\n# Dosage\nDosage recommendations vary by age group and medical conditions (Table 7).\n# Children\nAmantadine. Use of amantadine among children aged <1 year has not been adequately evaluated. The FDA-approved dosage for children aged 1-9 years for treatment and prophylaxis is 4.4-8.8 mg/kg body weight/day, not to exceed 150 mg/day. Although further studies are needed to determine the optimal dosage for children aged 1-9 years, physicians should consider prescribing only 5 mg/kg body weight/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children aged >10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is advisable (252).\nRimantadine. Rimantadine is approved for prophylaxis among children aged >1 year and for treatment and prophylaxis among adults. Although rimantadine is approved only for prophylaxis of infection among children, certain specialists in the management of influenza consider it appropriate for treatment among children (230). Use of rimantadine among children aged <1 year has not been adequately evaluated. Rimantadine should be administered in 1 or 2 divided doses at a dosage of 5 mg/kg body weight/day, not to exceed 150 mg/day for children aged 1-9 years. The approved dosage for children aged >10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg body weight/day, regardless of age, is recommended (286).\nZanamivir. Zanamivir is approved for treatment among children aged >7 years. The recommended dosage of zanamivir for treatment of influenza is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart) (246).\nOseltamivir. Oseltamivir is approved for treatment among persons aged >1 year and for chemoprophylaxis among persons aged >13 years. Recommended treatment dosages for children vary by the weight of the child: the dosage recommendation for children who weigh <15 kg is 30 mg twice a day; for children weighing >15-23 kg, the dosage is 45 mg twice a day; for those weighing >23-40 kg, the dosage is 60 mg twice a day; and for children weighing >40 kg, the dosage is 75 mg twice a day. The treatment dosage for persons aged >13 years is 75 mg twice daily. For children aged >13 years, the recommended dose for prophylaxis is 75 mg once a day (247).\n# Persons Aged >65 Years\nAmantadine. The daily dosage of amantadine for persons aged >65 years should not exceed 100 mg for prophylaxis or treatment, because renal function declines with increasing age. For certain older persons, the dose should be further reduced.\nRimantadine. Among older persons, the incidence and severity of central nervous system (CNS) side effects are substantially lower among those taking rimantadine at a dosage of 100 mg/day than among those taking amantadine at dosages adjusted for estimated renal clearance (287). However, chronically ill older persons have had a higher incidence of CNS and gastrointestinal symptoms and serum concentra- (235). For prophylaxis among persons aged >65 years, the recommended dosage is 100 mg/day. For treatment of older persons in the community, a reduction in dosage to 100 mg/day should be considered if they experience side effects when taking a dosage of 200 mg/day. For treatment of older nursing home residents, the dosage of rimantadine should be reduced to 100 mg/day (286).\nZanamivir and Oseltamivir. No reduction in dosage is recommended on the basis of age alone.\n# Persons with Impaired Renal Function\nAmantadine. A reduction in dosage is recommended for patients with creatinine clearance <50 mL/min/1.73m 2 . Guidelines for amantadine dosage on the basis of creatinine clearance are located in the package insert. Because recommended dosages on the basis of creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully for adverse reactions. If necessary, further reduction in the dose or discontinuation of the drug might be indicated because of side effects. Hemodialysis contributes minimally to amantadine clearance (288,289).\nRimantadine. A reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance <10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including older persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance (290).\nZanamivir. Limited data are available regarding the safety and efficacy of zanamivir for patients with impaired renal function. Among patients with renal failure who were administered a single intravenous dose of zanamivir, decreases in renal clearance, increases in half-life, and increased systemic exposure to zanamivir were observed (246,291). However, a limited number of healthy volunteers who were administered high doses of intravenous zanamivir tolerated systemic levels of zanamivir that were substantially higher than those resulting from administration of zanamivir by oral inhalation at the recommended dose (292,293). On the basis of these considerations, the manufacturer recommends no dose adjustment for inhaled zanamivir for a 5-day course of treatment for patients with either mild to moderate or severe impairment in renal function (246).\nOseltamivir. Serum concentrations of oseltamivir carboxylate (GS4071), the active metabolite of oseltamivir, increase with declining renal function (247,294). For patients with creatinine clearance of 10-30 mL/min (247), a reduction of the treatment dosage of oseltamivir to 75 mg once daily and in the prophylaxis dosage to 75 mg every other day is recommended. No treatment or prophylaxis dosing recommendations are available for patients undergoing routine renal dialysis treatment.\n# Persons with Liver Disease\nAmantadine. No increase in adverse reactions to amantadine has been observed among persons with liver disease. Rare instances of reversible elevation of liver enzymes among patients receiving amantadine have been reported, although a specific relation between the drug and such changes has not been established (295).\nRimantadine. A reduction in dosage to 100 mg/day is recommended for persons with severe hepatic dysfunction.\nZanamivir and Oseltamivir. Neither of these medications has been studied among persons with hepatic dysfunction.\n# Persons with Seizure Disorders\nAmantadine. An increased incidence of seizures has been reported among patients with a history of seizure disorders who have received amantadine (296). Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.\nRimantadine. Seizures (or seizure-like activity) have been reported among persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine (297). The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated.\nZanamivir and Oseltamivir. Seizure events have been reported during postmarketing use of zanamivir and oseltamivir, although no epidemiologic studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.\n# Route\nAmantadine, rimantadine, and oseltamivir are administered orally. Amantadine and rimantadine are available in tablet or syrup form, and oseltamivir is available in capsule or oral suspension form (298,299). Zanamivir is available as a dry powder that is self-administered via oral inhalation by using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of correct use of this device (246).\n# Pharmacokinetics Amantadine\nApproximately 90% of amantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion (258,(300)(301)(302)(303). Thus, renal clearance of amantadine is reduced substantially among persons with renal insufficiency, and dosages might need to be decreased (see Dosage) (Table 7).\n# Rimantadine\nApproximately 75% of rimantadine is metabolized by the liver (251). The safety and pharmacokinetics of rimantadine among persons with liver disease have been evaluated only after single-dose administration (251,304). In a study of persons with chronic liver disease (the majority with stabilized cirrhosis), no alterations in liver function were observed after a single dose. However, for persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease (286).\nRimantadine and its metabolites are excreted by the kidneys. The safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration (251,290). Further studies are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages for patients with renal insufficiency. In a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that among healthy persons of the same age (290). Hemodialysis did not contribute to drug clearance. In studies of persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher than those among control patients without renal disease who were the same weight, age, and sex (286,305).\n# Zanamivir\nIn studies of healthy volunteers, approximately 7%-21% of the orally inhaled zanamivir dose reached the lungs, and 70%-87% was deposited in the oropharynx (246,306). Approximately 4%-17% of the total amount of orally inhaled zanamivir is systemically absorbed. Systemically absorbed zanamivir has a half-life of 2.5-5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in the feces (246,293).\n# Oseltamivir\nApproximately 80% of orally administered oseltamivir is absorbed systemically (294). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxy-late has a half-life of 6-10 hours and is excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway (247,307). Unmetabolized oseltamivir also is excreted in the urine by glomerular filtration and tubular secretion (308).\n# Side Effects and Adverse Reactions\nWhen considering use of influenza antiviral medications (i.e., choice of antiviral drug, dosage, and duration of therapy), clinicians must consider the patient's age, weight, and renal function (Table 7); presence of other medical conditions; indications for use (i.e., prophylaxis or therapy); and the potential for interaction with other medications.\n# Amantadine and Rimantadine\nBoth amantadine and rimantadine can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day. However, incidence of CNS side effects (e.g., nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine (308). In a 6-week study of prophylaxis among healthy adults, approximately 6% of participants taking rimantadine at a dosage of 200 mg/day experienced one or more CNS symptoms, compared with approximately 13% of those taking the same dosage of amantadine and 4% of those taking placebo (308). A study of older persons also demonstrated fewer CNS side effects associated with rimantadine compared with amantadine (287). Gastrointestinal side effects (e.g., nausea and anorexia) occur among approximately 1%-3% of persons taking either drug, compared with 1% of persons receiving the placebo (308).\nSide effects associated with amantadine and rimantadine are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week, despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures) (288,296). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among older persons who have been taking amantadine as prophylaxis at a dosage of 200 mg/day (258). Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects (Table 7). In acute overdosage of amantadine, CNS, renal, respiratory, and cardiac toxicity, including arrhythmias, have been reported (288). Because rimantadine has been marketed for a shorter period than amantadine, its safety among certain patient populations (e.g., chronically ill and older persons) has been evaluated less frequently. Because amantadine has anticholinergic effects and might cause mydriasis, it should not be used among patients with untreated angle closure glaucoma (288).\n# Zanamivir\nIn a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease where study medication was administered after use of a B2-agonist, 13% of patients receiving zanamivir and 14% of patients who received placebo (inhaled powdered lactose vehicle) experienced a >20% decline in forced expiratory volume in 1 second (FEV1) after treatment (246,248). However, in a phase-I study of persons with mild or moderate asthma who did not have influenza-like illness, 1 of 13 patients experienced bronchospasm after administration of zanamivir (246). In addition, during postmarketing surveillance, cases of respiratory function deterioration after inhalation of zanamivir have been reported. Certain patients had underlying airways disease (e.g., asthma or chronic obstructive pulmonary disease). Because of the risk for serious adverse events and because the efficacy has not been demonstrated among this population, zanamivir is not recommended for treatment for patients with underlying airway disease (246). If physicians decide to prescribe zanamivir to patients with underlying chronic respiratory disease after carefully considering potential risks and benefits, the drug should be used with caution under conditions of appropriate monitoring and supportive care, including the availability of short-acting bronchodilators (277). Patients with asthma or chronic obstructive pulmonary disease who use zanamivir are advised to 1) have a fast-acting inhaled bronchodilator available when inhaling zanamivir and 2) stop using zanamivir and contact their physician if they experience difficulty breathing (246). No definitive evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza (277). Allergic reactions, including oropharyngeal or facial edema, have also been reported during postmarketing surveillance (246,253).\nIn clinical treatment studies of persons with uncomplicated influenza, the frequencies of adverse events were similar for persons receiving inhaled zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone) (236)(237)(238)(239)(240)(241)253). The most common adverse events reported by both groups were diarrhea; nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and ear, nose, and throat infections. Each of these symptoms was reported by <5% of persons in the clinical treatment studies combined (246).\n# Oseltamivir\nNausea and vomiting were reported more frequently among adults receiving oseltamivir for treatment (nausea without vomiting, approximately 10%; vomiting, approximately 9%) than among persons receiving placebo (nausea without vomiting, approximately 6%; vomiting, approximately 3%) (242,243,247,309). Among children treated with oseltamivir, 14.3% had vomiting, compared with 8.5% of placebo recipients. Overall, 1% discontinued the drug secondary to this side effect (245), whereas a limited number of adults who were enrolled in clinical treatment trials of oseltamivir discontinued treatment because of these symptoms (247). Similar types and rates of adverse events were reported in studies of oseltamivir prophylaxis (247). Nausea and vomiting might be less severe if oseltamivir is taken with food (247,309).\n# Use During Pregnancy\nNo clinical studies have been conducted regarding the safety or efficacy of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only two cases of amantadine use for severe influenza illness during the third trimester have been reported (134,135). However, both amantadine and rimantadine have been demonstrated in animal studies to be teratogenic and embryotoxic when administered at substantially high doses (286,288). Because of the unknown effects of influenza antiviral drugs on pregnant women and their fetuses, these four drugs should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus (see manufacturers' package inserts) (246,247,286,288).\n# Drug Interactions\nCareful observation is advised when amantadine is administered concurrently with drugs that affect CNS, including CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions (235). No clinically substantial interactions between rimantadine and other drugs have been identified.\nClinical data are limited regarding drug interactions with zanamivir. However, no known drug interactions have been reported, and no clinically critical drug interactions have been predicted on the basis of in vitro data and data from studies using rats (246,310).\nLimited clinical data are available regarding drug interactions with oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine by glomerular filtration and tubular secretion via the anionic pathway, a potential exists for interaction with other agents excreted by this pathway. For example, coadministration of oseltamivir and probenecid resulted in reduced clearance of oseltamivir carboxylate by approximately 50% and a corresponding approximate twofold increase in the plasma levels of oseltamivir carboxylate (247,307).\nNo published data are available concerning the safety or efficacy of using combinations of any of these four influenza antiviral drugs. For more detailed information concerning potential drug interactions for any of these influenza antiviral drugs, package inserts should be consulted.\n# Antiviral Drug-Resistant Strains of Influenza\nAmantadine-resistant viruses are cross-resistant to rimantadine and vice versa (311). Drug-resistant viruses can appear in approximately one third of patients when either amantadine or rimantadine is used for therapy (257,312,313). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace susceptible strains within 2-3 days of starting therapy (312,314). Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy (315,316); however, the frequency with which resistant viruses are transmitted and their effect on efforts to control influenza are unknown. Amantadine-and rimantadine-resistant viruses are not more virulent or transmissible than susceptible viruses (317). The screening of epidemic strains of influenza A has rarely detected amantadine-and rimantadine-resistant viruses (312,318,319).\nPersons who have influenza A infection and who are treated with either amantadine or rimantadine can shed susceptible viruses early in the course of treatment and later shed drugresistant viruses, including after 5-7 days of therapy (257). Such persons can benefit from therapy even when resistant viruses emerge.\nResistance to zanamivir and oseltamivir can be induced in influenza A and B viruses in vitro (320)(321)(322)(323)(324)(325)(326)(327), but induction of resistance requires multiple passages in cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be induced with fewer passages in cell culture (328,329). Development of viral resistance to zanamivir and oseltamivir during treatment has been identified but does not appear to be frequent (247,(330)(331)(332)(333). In clinical treatment studies using oseltamivir, 1.3% of posttreatment isolates from patients aged >13 years and 8.6% among patients aged 1-12 years had decreased susceptibility to oseltamivir (247). No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of posttreatment iso-lates tested is limited (334) and the risk for emergence of zanamivir-resistant isolates cannot be quantified (246). Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported (331). Available diagnostic tests are not optimal for detecting clinical resistance to the neuraminidase inhibitor antiviral drugs, and additional tests are being developed (334,335). Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted (336).\n# Sources of Information Regarding Influenza and Its Surveillance\nInformation regarding influenza surveillance, prevention, detection, and control is available at http://www.cdc.gov/flu/ weekly/fluactivity.htm. Surveillance information is available through the CDC Voice Information System (influenza update) at 888-232-3228 or CDC Fax Information Service at 888-232-3299. During October-May, surveillance information is updated at least every other week. In addition, periodic updates regarding influenza are published in the MMWR Weekly (http://www.cdc.gov/mmwr). Additional information regarding influenza vaccine can be obtained by calling the CDC Immunization hotline at 800-232-2522 (English) or 800-232-0233 (Spanish). State and local health departments should be consulted concerning availability of influenza vaccine, access to vaccination programs, information related to state or local influenza activity, and for reporting influenza outbreaks and receiving advice concerning outbreak control.\n# Additional Information Regarding Influenza Infection Control Among Specific Populations\nEach year, ACIP provides general, annually updated information regarding control and prevention of influenza. Other reports related to controlling and preventing influenza among specific populations (e.g., immunocompromised persons, health-care personnel, hospitals, and travelers) are also available in the following publications:\n• CDC. \n# Advisory Committee on Immunization Practices\nMembership"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":287,"cells":{"id":{"kind":"string","value":"7419f776406ce1fca8ddeb54f33dad174d54cc7a"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"These guidelines update previous CDC recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) in the United States. The most notable changes in these guidelines reflect both the findings of clinical trials that evaluated new drug regimens for treating and preventing TB among HIV-infected persons and recent advances in the use of antiretroviral therapy. In September 1997, when CDC convened a meeting of expert consultants to discuss current information about HIV-related TB, special emphasis was given to issues related to coadministration of TB therapy and antiretroviral therapy and how to translate this information into management guidelines. Thus, these guidelines are based on the following scientific principles: restores immune function. Adding to CDC's current recommendations for administering isoniazid preventive therapy to HIV-infected persons with positive tuberculin skin tests and to HIV-infected persons who were exposed to patients with infectious TB, this report also describes in detail the use of new shortcourse (i.e., 2 months) multidrug regimens (e.g., a rifamycin, such as rifampin or rifabutin, combined with pyrazinamide) to prevent TB in persons with HIV infection. A continuing education component for U.S. physicians and nurses is included.#\n- Early diagnosis and effective treatment of TB among HIV-infected patients are critical for curing TB, minimizing the negative effects of TB on the course of HIV, and interrupting the transmission of Mycobacterium tuberculosis to other persons in the community.\n- All HIV-infected persons at risk for infection with M. tuberculosis must be carefully evaluated and, if indicated, administered therapy to prevent the progression of latent infection to active TB disease and avoid the complications associated with HIV-related TB.\n- All HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy, because most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies. However, the use of rifampin with protease inhibitors or nonnucleoside reverse transcriptase inhibitors is contraindicated.\nIdeally, the management of TB among HIV-infected patients taking antiretroviral drugs requires a) directly observed therapy, b) availability of experienced and coordinated TB/HIV care givers, and in most situations, c) use of a TB treatment regimen that includes rifabutin instead of rifampin. Because alternatives to the use of rifampin for antituberculosis treatment are now available, the previously recommended practice of stopping protease inhibitor therapy to allow the use of rifampin for TB treatment is no longer recommended for patients with HIV-related TB. The use of rifabutin-containing antituberculosis regimens should always include an assessment of the patient's response to treatment to decide the appropriate duration of therapy (i.e., 6 months or 9 months). Physicians and patients also should be aware that paradoxical reactions might occur during the course of TB treatment when antiretroviral therapy\n\n# INTRODUCTION\nThese guidelines update previous CDC recommendations for treating and preventing active tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) (1)(2)(3). The most notable changes in these guidelines reflect both the recent advances in the use of antiretroviral therapy and the findings of clinical trials that evaluated new drug regimens for the treatment and prevention of TB among HIV-infected persons. Antiretroviral therapy is discussed in the context of TB treatment only; more detailed information about antiretroviral therapy is published elsewhere (4 ).\nIn September 1997, CDC convened a meeting of expert consultants who reviewed and considered background information about HIV-related TB in the United States and the scientific principles of therapy for both diseases (Part I of this report). The consultants then used this review as the basis for updating the recommendations for HIV-infected patients with TB (Part II). During their review of the scientific principles of therapy, the expert consultants focused on epidemiologic and clinical interactions between Mycobacterium tuberculosis infection and HIV infection, considering the frequency of coexisting TB and HIV infection and rates of drug-resistant TB among patients infected with HIV in the United States; the copathogenicity of TB and HIV disease; the potential for a poorer outcome of TB therapy and paradoxical reactions to TB treatment among HIV-infected patients; drug interactions between rifampin used for TB therapy and agents commonly used in antiretroviral therapy; use of TB treatment regimens that do not contain rifampin; and results of clinical trials of therapies to prevent TB among HIV-infected persons. Thus, in addition to CDC's current recommendations, these new guidelines include information about the following topics:\n- directly observed therapy for all patients with HIV-related TB;\n- rifabutin-containing antituberculosis regimens (or a streptomycin-based alternative regimen that does not contain rifamycin) for treating TB among patients taking antiretroviral drugs that have interactions with rifampin;\n- monitoring responses to antituberculosis treatment to decide about the appropriate duration of TB therapy;\n- occurrence and management of paradoxical reactions during TB treatment, when immune function is restored because of antiretroviral therapy;\n- use of 9 months of isoniazid daily or twice weekly for the treatment of M. tuberculosis infection; 2 MMWR October 30, 1998\n- short-course multidrug therapy for latent M. tuberculosis infection; and\n- special considerations that apply to children and pregnant women with HIVrelated TB.\nHealth-care professionals need to be familiar with these new guidelines to ensure the use of the most effective management strategies for TB patients infected with HIV, while concurrently promoting optimal antiretroviral therapy for these patients. To help clinicians make informed treatment decisions based on the most current research results, the expert consultants have given each recommendation an evidence-based rating similar to the ratings used in previously issued guidelines (4,5 ). However, these recommendations are not intended to substitute for the judgment of an expert physician. When possible, the treatment of TB in HIV-infected persons should be directed by (or done in consultation with) a physician with extensive experience in the care of patients with TB and HIV disease. The implementation of these recommendations will help prevent cases of drug-resistant TB, reduce TB treatment failures, and diminish the adverse effects that TB has on HIV replication. Moreover, these guidelines will contribute to efforts to control TB and eliminate it from the United States by minimizing the likelihood of M. tuberculosis transmission, which will prevent the occurrence of new cases of TB.\nIn future years, health-care professionals can expect changes in the recommendations regarding the therapeutic options used to prevent and treat TB among patients infected with HIV. These changes will reflect the availability of new antiretroviral and antituberculosis agents, new information about existing agents, and subsequent changes in CDC's guidelines for the use of antiretroviral therapy for persons infected with HIV. Multiple copies of this report and all updates are available from the Office of Communications, National Center for HIV, STD, and TB Prevention, CDC, 1600 Clifton Road, Mail Stop E-06, Atlanta, GA 30333. The report also is posted on the CDC Division of TB Elimination Internet website at and the MMWR website at . Readers should consult these sources regularly for updates in the guidelines.\n\n# PART I. BACKGROUND AND SCIENTIFIC RATIONALE\n\n# Frequency of Coexisting TB and HIV Infection and Disease in the United States\nIn the United States, epidemiologic evidence indicates that the HIV epidemic contributed substantially to the increased numbers of TB cases in the late 1980s and early 1990s (6,7 ). Overlap between the acquired immunodeficiency syndrome (AIDS) and TB epidemics continues to result in increases in TB morbidity. Analysis of national HIV-related TB surveillance data is limited by incomplete reporting of HIV status for persons with TB. As an alternative, state health department personnel have compared TB and AIDS registries to help estimate the proportion of persons reported with TB who are also infected with HIV. In the most recent comparison conducted by the 50 states and Puerto Rico, 14% of persons with TB in 1993-1994 (27% among those aged 25-44 years) also appeared in the AIDS registry (8 ). This proportion of TB patients with AIDS is believed to be a minimum estimate for the United States and might represent an increase in the proportion of TB patients identified as having TB and AIDS in 1990 (9%) (6 ). During 1993-1994, most persons with TB and AIDS (80%) were found in eight reporting areas: New York City, California, Florida, Georgia, Illinois, New Jersey, New York, and Texas (8 ).\nIn prospective epidemiologic studies, investigators have estimated that the annual rate of TB disease among untreated, tuberculin skin-test (TST)-positive, HIV-infected persons in the United States ranges from 1.7 to 7.9 TB cases per 100 person-years (Table 1) (9-11 ). The variability observed in these studies mirrors the differences in TB prevalence observed for different U.S. populations (i.e., the highest case rate was found in a study of a New York City population of intravenous drug users at a time when the incidence of TB was high and increasing ; and the lowest case rate was evident in a community-based cohort of persons enrolled in a study of the pulmonary complications of HIV infection at a time and in a population in which the incidence of TB was relatively low ). However, in all of these studies, the rate of TB disease among HIV-infected, TST-positive persons was approximately 4-26 times higher than the rate among comparable HIV-infected, TST-negative persons, and it was approximately 200-800 times higher than the rate of TB estimated for the U.S. population overall (0.01%) (12 ). Therefore, activities to control and eliminate TB in the United States must include aggressive efforts to identify HIV-infected persons with latent\n\n# TABLE 1. Annual rates- of tuberculosis among persons with human imunodeficiency virus infection, by tuberculin skin-test (TST) status -selected years and U.S. areas Location and source\n\n# Rate among persons with positive TSTs\n\n# Rate among persons with negative TSTs\nRate ratio New York City Selwyn et al., 1989 (9 ) 7.9 0. TB infection and to provide them with therapy to prevent progression to active TB disease.\n\n# Rates of Drug-Resistant TB Among HIV-Infected Persons in the United States\nResistance to antituberculosis drugs is an important consideration for some HIVinfected persons with TB. According to the results of a study of TB cases reported to CDC from 1993 through 1996, the risk of drug-resistant TB was higher among persons with known HIV infection compared with others (13 ). During this 4-year period, among U.S.-born persons aged 25-44 years with TB, HIV test results were reported as positive for 32% of persons, negative for 23%, and unknown for 45%. Using univariate analysis that excluded patients known to have had a previous episode of TB, investigators found that patients known to be HIV seropositive had a significantly higher rate of resistance to all first-line antituberculosis drugs, compared with HIV-seronegative patients and patients with unknown HIV serostatus (Table 2). Moreover, using a multivariate model that included age, history of previous TB, birth country, residence in New York City, and race/ethnicity, the investigators confirmed HIV-positive serostatus as a risk factor for resistance to at least isoniazid, for both isoniazid and rifampin resistance (multidrug-resistant TB) and for rifampin monoresistance (TB resistant to rifampin only). In some areas of the United States with a low level of occurrence of MDR TB, however, differences in MDR TB related to HIV status have not been found (8 ). Reasons for the increased risk for TB drug resistance among HIV-seropositive persons might reflect a higher proportion of TB disease resulting from recently acquired M. tuberculosis infection (14,15 ) and thus an increased risk of disease caused by drug-resistant strains in areas with high community and institutional transmission of drug-resistant strains of M. tuberculosis (16 ). Several well-described outbreaks of † The patient's Mycobacterium tuberculosis isolate had resistance to at least the specified drug but may have had resistance to other drugs as well. § The differences in drug-resistance rates among patients with TB known to be HIV-seropositive, compared with those known to be HIV-seronegative or of unknown status, are statistically significant (Chi-square test statistic, p<0.05). ¶ These figures were calculated for patients with M. tuberculosis isolates tested for isoniazid and rifampin always and streptomycin sometimes. Monoresistant isolates were resistant to rifampin but susceptible to the other first-line drugs tested. Source: CDC, National Tuberculosis Surveillance System. nosocomially transmitted MDR TB, primarily affecting persons with AIDS, support this association (17)(18)(19)(20)(21).\nIn the past decade, reports have increased of TB caused by strains of M. tuberculosis resistant to rifampin only, and growing evidence has indicated that this rare event is associated with HIV coinfection (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). In retrospective studies, nonadherence with TB therapy has been associated with acquired rifampin monoresistance (22)(23)(24); and among a small number of patients, the use of rifabutin as prophylaxis for Mycobacterium avium complex was associated with the development of rifamycin resistance (31 ). However, the occurrence of TB relapse with acquired rifampin monoresistance also has been documented among patients with TB who initially had rifampin-susceptible isolates and who were treated with a rifampin-containing TB regimen by directly observed therapy (DOT) (30,32 ). The mechanisms involved in the development of acquired rifampin monoresistance are not clearly understood but could involve the persistence of actively multiplying mycobacteria in patients with severe cellular immunodeficiency, selective antituberculosis drug malabsorption, and inadequate tissue penetration of drugs.\nThus, of critical importance for HIV-infected persons is implementation of TB prevention and control strategies such as a) appropriate use of therapy for latent M. tuberculosis infection, b) early diagnosis and effective treatment of active TB (i.e., administering four-drug antituberculosis regimens by DOT to all coinfected patients), and c) prompt compliance with requirements for reporting TB cases and drug-susceptibility test results. Implementing these strategies for persons coinfected with HIV will not only help reduce new cases of TB in general; it also could decrease further transmission of drug-resistant strains and new cases of drug-resistant TB.\n\n# Copathogenicity of TB and HIV Disease\nHuman immunodeficiency virus type 1 (HIV-1) and M. tuberculosis are two intracellular pathogens that interact at the population, clinical, and cellular levels. Initial studies of HIV-1 and TB emphasized the impact of HIV-1 on the natural progression of TB, but mounting immunologic and virologic evidence now indicates that the host immune response to M. tuberculosis enhances HIV replication and might accelerate the natural progression of HIV infection (33 ). Therefore, the interaction between these two pathogens has important implications for the prevention and treatment of TB among HIV-infected persons. Studies of the immune response in persons with TB disease support the biologic plausibility of copathogenesis in dually infected persons. The initial interaction between the host immune system and M. tuberculosis occurs in the alveolar macrophages that present mycobacterial antigens to antigen-specific CD4+ T cells (34 ). These T cells release interferon-gamma, a cytokine that acts at the cellular level to activate macrophages and enhance their ability to contain mycobacterial infection. The activated macrophages also release proinflammatory cytokines, such as tumor necrosis factor and interleukin (IL)-1, cytokines that enhance viral replication in monocyte cell lines in vitro (35)(36)(37)(38). The mycobacteria and their products also enhance viral replication by inducing nuclear factor kappa-B, the cellular factor that binds to promoter regions of HIV (39,40 ).\nWhen TB disease develops in an HIV-infected person, the prognosis is often poor, though it depends on the person's degree of immunosuppression and response to appropriate antituberculosis therapy (41)(42)(43). The 1-year mortality rate for treated, HIV-related tuberculosis ranges from 20% to 35% and shows little variation between cohorts from industrialized and developing countries (44)(45)(46)(47)(48)(49). The observed mortality rate for HIV-infected persons with TB is approximately four times greater than the rate for TB patients not infected with HIV (44,46,49,50 ). Although the cause of death in the initial period of therapy can be TB (46 ), death after the induction phase of antituberculosis therapy usually is attributed to complications of HIV other than TB (45,51,52 ). Epidemiologic data suggest that active TB accelerates the natural progression of HIV infection. In a retrospective cohort study of HIV-infected women from Zaire, investigators estimated the relative risk of death to be 2.7 among women with active TB compared with those without TB (53 ). In a retrospective cohort study of HIV-infected subjects from the United States, active TB was associated with an increased risk for opportunistic infections and death (54 ). The risk of death, or hazard rate, for persons with HIV-related TB follows a bimodal distribution, peaking within the first 3 months of antituberculosis therapy and then again after 1 year (48 ); the reasons for this distribution are not clear but might relate to the impact of TB on HIV disease progression. The observation that active TB increases deaths associated with HIV infection has been corroborated in studies of three independent cohorts in Europe (55)(56)(57).\nEarly in the HIV epidemic, researchers postulated that the immune activation resulting from concurrent infection with parasitic or bacterial pathogens might alter the natural progression of HIV infection (58 ). Subsequent observations have demonstrated that immune activation from TB enhances both systemic and local HIV replication. In some patients with active TB, the plasma HIV RNA level rises substantially before TB is diagnosed (59 ). Moreover, TB treatment alone leads to reductions in the viral load in these dually infected patients. TB and HIV also interact in the lungs, the site of primary infection with M. tuberculosis. In a recently published study of HIVinfected patients with TB, researchers found that the viral load was higher in the bronchoalveolar lavage fluid from the affected versus the unaffected lung and was correlated with levels of tumor necrosis factor in bronchoalveolar fluid (60 ). Researchers used V3 loop viral sequences to construct a phylogenetic tree and observed that the HIV quasispecies from the affected lung differed from those in the plasma within the same patient. These data suggest that pulmonary TB might act as a potent stimulus for the cellular-level replication of HIV. In summary, recent research findings have improved clinicians' understanding of how HIV affects the natural progression of TB and how TB affects the clinical course of HIV disease, and these findings support the recommendation for prevention, early recognition, and effective treatment for both diseases.\n\n# TB Therapy Outcomes Among Patients with HIV-Related TB\nAmong patients treated for TB, early clinical response to therapy and the time in which M. tuberculosis sputum cultures convert from positive to negative appear to be similar for those with HIV infection and those without HIV infection (30,61,62 ). However, the data are less clear about whether rates of TB relapse (recurrence of TB following successful completion of treatment) differ among patients with or without HIV infection (63 ). Current CDC and American Thoracic Society guidelines recommend a 6-month treatment regimen for drug-susceptible TB disease for patients coinfected with HIV (2 ) but suggest prolonged treatment for patients who have a delayed clinical and bacteriologic response to antituberculosis therapy. Some experts have suggested that to ensure an optimal antituberculosis treatment outcome, all patients with HIV-related TB should be treated with a longer course of therapy (i.e., 9 months), regardless of evidence of early response to therapy (64,65 ).\nTo make a recommendation on duration of therapy for HIV-related TB, expert consultants at the September 1997 CDC meeting considered the results of prospective studies that ascertained the posttreatment relapse rate following 6-month TB therapy regimens among patients with HIV infection (Table 3) (29,30,49,66,67 ). Differences in the study designs, including those pertaining to eligibility for enrollment in the study and to the definition of TB relapse, limited the analysis of combined results from the five studies. Despite this limitation, the expert consultants were able to make the following observations: a) the studies had a posttreatment follow-up duration that ranged from 8 to 22 months (median duration: 18 months); b) in three studies (30,49,67 ), investigators found that 6-month TB regimens were associated with a clinically acceptable (≤5.4%) TB relapse rate; and c) in two studies (29,66 ), researchers found a high (≥9%) TB relapse rate associated with the use of 6-month TB regimens.\nIn the Zaire study (66 ), TB patients coinfected with HIV had almost twofold higher posttreatment relapse rates than patients not infected with HIV who received the same TB treatment regimen; however, the authors did not investigate whether the relapses were the result of a recurrence of disease with the same strain of M. tuberculosis or reinfection (new disease) with a different strain. In the other study (29 ), which enrolled HIV-seropositive patients from 21 different sites in the United States, in all three patients who relapsed, the strain of M. tuberculosis isolated during the relapse episode matched, by DNA fingerprint, the strain of M. tuberculosis that was isolated during the initial episode of TB; this finding ruled out the possibility of reinfection.\nThe expert consultants who reviewed the available data agreed that short-course (i.e., 6-month) regimens should be used for the treatment of HIV-related pansusceptible TB (i.e., susceptible to all first-line antituberculosis drugs) in the United States, where patients are usually treated with DOT and where response to antituberculosis daily induction regimen followed by a continuation regimen of 4-month intermittent isoniazid and rifampin.\nThe exceptions are that a) ethambutol was not used during the induction phase in Côte d'Ivoire, and b) half of patients in one of the U.S. studies (30 ) received levofloxacin in addition to the other four drugs during the induction phase. During the continuation phase, patients in Côte d'Ivoire received drugs daily, patients in Haiti received drugs three times a week, and patients in all other studies received drugs twice a week. † Also in this study, 51 comparable patients with HIV-related TB were randomly assigned to a treatment arm in which the duration of the continuation phase was prolonged from 4 months to 7 months. The cultureconfirmed posttreatment relapse rate (2%) in this study arm was not significantly different from the rate in the 6-month study arm (p=1.00); however, an isolate was not available for DNA fingerprinting.\ndrugs can be monitored. This approach limits the use of lengthier multidrug antituberculosis therapies to the minimum possible number of patients with TB and HIV disease. Some experts believe the risk of TB treatment failure is increased among patients with advanced HIV-related immunosuppression and therefore advocate greater caution (or longer duration of therapy) when treating such patients for TB. The available data do not permit CDC to make a definitive recommendation regarding this issue. However, the experts recommended that clinicians treating TB in patients with HIV infection should consider the factors that increase a person's risk for a poor clinical outcome (e.g., lack of adherence to TB therapy, delayed conversion of M. tuberculosis sputum cultures from positive to negative, and delayed clinical response) when deciding the total duration of TB therapy.\n\n# Paradoxical Reactions Associated with Initiation of Antiretroviral Therapy During the Course of TB Therapy\nThe temporary exacerbation of TB symptoms and lesions after initiation of antituberculosis therapy -known as a paradoxical reaction -has been described as a rare occurrence (68)(69)(70)(71)(72)(73)(74) attributed to causes such as recovery of the patient's delayed hypersensitivity response and an increase in exposure and reaction to mycobacterial antigens after bactericidal antituberculosis therapy is initiated (75 ). Recently, a similar phenomenon was reported among patients with HIV-related TB (76 ). These reactions appear to be related more often to the concurrent administration of antiretroviral and antituberculosis therapy and occur with greater frequency than do paradoxical reactions associated primarily with the administration of antituberculosis therapy. Patients with paradoxical reactions can have hectic fevers, lymphadenopathy (sometimes severe), worsening of chest radiographic manifestations of TB (e.g., miliary infiltrates, pleural effusions), and worsening of original tuberculous lesions (e.g., cutaneous and peritoneal). However, these reactions are not associated with changes in M. tuberculosis bacteriology (i.e., no change from negative to positive culture and smear), and patients generally feel well and have no signs of toxicity.\nIn a prospective study, paradoxical reactions were more common among 33 patients with HIV-related TB who received TB treatment and combination antiretroviral therapy (36%) than among 55 patients not infected with HIV who received antituberculosis drugs alone (2%) and among 28 HIV-infected patients (historical control patients during pre-zidovudine era) who received antituberculosis drugs alone (7%) (76 ). Furthermore, among patients treated for both diseases, the paradoxical reactions were more temporally related to the initiation of combination antiretroviral therapy (mean +/-standard deviation : 15 +/-11 days afterward) than to the initiation of antituberculosis treatment (mean SD: 109 +/-72 days afterward). Researchers investigated potential causes for these symptoms and lesions (i.e., TB treatment failure, antituberculosis drug resistance, nonadherence with TB therapy, drug fever, development of conditions not related to TB or HIV) but considered such causes unlikely because these evaluations produced negative results, and TB was cured in patients who remained on unmodified antituberculosis regimens. Among patients in this study who received combination antiretroviral therapy, which usually included a protease inhibitor, the paradoxical reactions corresponded with a concurrent drop in HIV viral loads after antiretroviral therapy began and, in all but one patient, occurred while peripheral blood CD4+ T-cell counts were <200 cells/µL (76 ). In the historical control group (i.e., patients who were treated for TB but not for HIV), two (7%) of the 28 patients had a paradoxical reaction after antituberculosis therapy was initiated. This finding indicates that treatment of TB alone might sometimes decrease HIV viral load substantially and improve immune function (40,59,68,76 ).\nAfter reviewing information about paradoxical reactions occurring during the course of TB therapy, expert consultants at the September 1997 CDC meeting concluded that exacerbation of TB signs and symptoms in patients with HIV-related TB can occur soon after combination antiretroviral therapy is initiated. Clinicians should always conduct a thorough investigation to eliminate other etiologies before making a diagnosis of paradoxical treatment reaction. For patients with paradoxical reactions, rarely are changes in antituberculosis or antiretroviral therapy needed. If the lymphadenopathy or other lesions are severe, one option is to continue with appropriate antituberculosis therapy and administer short-term steroids that suppress the enhanced immune response.\nIn the prospective study (76 ), despite having low CD4+ T-cell counts, six (86%) of seven TB patients who were initially tuberculin skin-test (TST)-negative had positive TST results after combination antiretroviral therapy was started. The reaction sizes of postantiretroviral TSTs ranged from 7 to 67 mm of induration. Clinicians must be aware of the potential public health and clinical implications of restored TST reactivity among persons who have not been diagnosed with active TB but who might be latently infected with M. tuberculosis. Persons previously known to have negative TST results might benefit from repeat tuberculin testing if they have evidence of restored immune function after antiretroviral therapy is initiated, because TB preventive therapy is recommended for TST-positive HIV-infected persons.\n\n# Considerations for TB Therapy for HIV-Infected Patients Treated with Antiretroviral Agents Drug Interactions Between Rifamycins Used for TB Therapy and Antiretroviral Drugs Used for HIV Therapy\nWidely used antiretroviral drugs available in the United States include protease inhibitors (saquinavir, indinavir, ritonavir, and nelfinavir) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, delavirdine, and efavirenz). Protease inhibitors and NNRTIs have substantive interactions with the rifamycins (rifampin, rifabutin, and rifapentine) used to treat mycobacterial infections (3,77 ). These drug interactions principally result from changes in the metabolism of the antiretroviral agents and the rifamycins secondary to induction or inhibition of the hepatic cytochrome CYP450 enzyme system (78,79 ). Rifamycin-related CYP450 induction decreases the blood levels of drugs metabolized by CYP450. For example, if protease inhibitors are administered with rifampin (a potent CYP450 inducer), blood concentrations of the protease inhibitors (all of which are metabolized by CYP450) decrease markedly, and most likely the antiretroviral activity of these agents declines as well. Conversely, if ritonavir (a potent CYP450 inhibitor) is administered with rifabutin, blood concentrations of rifabutin increase markedly, and most likely rifabutin toxicity increases as well.\nOf the available rifamycins, rifampin is the most potent CYP450 inducer; rifabutin has substantially less activity as an inducer; and rifapentine, a newer rifamycin, has intermediate activity as an inducer (80)(81)(82). The four currently approved protease inhibitors and amprenavir (141W94, an investigational agent in Phase III clinical trials) are all, in differing degrees, inhibitors of CYP450 (83,84 ). The rank order of the agents in terms of potency in inhibiting CYP450 is ritonavir (the most potent); amprenavir, indinavir, and nelfinavir (with approximately equal potencies); and saquinavir (the least potent). The magnitude of the effects of coadministering rifamycins and protease inhibitors has been evaluated in limited pharmacokinetic studies (Table 4) (85)(86)(87)(88)(89)(90)(91). The three approved NNRTIs have diverse effects on CYP450: nevirapine is an inducer, delavirdine is an inhibitor, and efavirenz is both an inducer and an inhibitor. The magnitude of the effects of coadministering rifamycins and NNRTIs has also been evaluated in pharmacokinetic studies or has been predicted on the basis of what is known about their potential for inducing or inhibiting CYP450 (Table 5) (92)(93)(94)(95)(96).\nIn contrast to the protease inhibitors and the NNRTIs, the other class of antiretroviral agents available, nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not metabolized by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the glucuronidation of zidovudine and thus slightly decreases the serum concentration of zidovudine (97)(98)(99)(100). The effect of this interaction probably is not clinically important, and the concurrent use of NRTIs and rifamycins is not contraindicated (77 ). Also, no contraindication exists for the use of NRTIs, NNRTIs, and protease inhibitors with isoniazid, pyrazinamide, ethambutol, or streptomycin. These first-line antituberculosis medications, in contrast to the rifamycins, are not CYP450 inducers.\n\n# Coadministration of Antituberculosis and Antiretroviral Therapies\nAccording to 1998 U.S. Department of Health and Human Services guidelines on the use of antiretroviral agents among HIV-infected adults and adolescents (4 ), to improve the length and quality of patients' lives, all persons with symptomatic HIV infection should be offered antiretroviral therapy. HIV-infected patients with TB fall in this category. When used appropriately, combinations of potent antiretroviral agents can effect prolonged suppression of HIV replication and reduce the inherent tendency of HIV to generate drug-resistant viral strains. However, as antiretroviral therapeutic regimens have become increasingly effective, they also have become increasingly complex in themselves as well as in the problems they cause for the treatment of other HIV-associated diseases.\nAt present, regimens that include two NRTIs combined with a potent protease inhibitor (or, as an alternative, combined with an NNRTI) are the preferred choice for combination antiretroviral therapy for the majority of patients. Each of the antiretroviral drug combination regimens must be used according to optimum schedules and doses (4 ) because the potential for resistant mutations of HIV decreases if serum concentrations of the multiple antiretroviral drugs are maintained steadily. Because rifampin markedly lowers the blood levels of these drugs and is likely to result in suboptimal antiretroviral therapy, the use of rifampin to treat active TB in a patient who is taking a protease inhibitor or an NNRTI is always contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome enzymes than is rifampin and, when used in appropriately modified doses, might not be associated with a clinically significant reduction of protease inhibitors or nevirapine (Table 6). Thus, the substitution of rifabutin for rifampin in TB treatment regimens has been proposed as a practical - Effects are expressed as a percentage change in AUC of the concomitant treatment relative to that of the drug-alone treatment. No data are available regarding the magnitude of these bidirectional interactions when rifamycins are administered two or three times a week instead of daily. † Predicted effect based on knowledge of metabolic pathways for the two drugs.\n\n# TABLE 6. Feasibility of using different antiretroviral drugs and rifabutin\n\n# Antiretroviral agent\n\n# Can be used in combination with rifabutin? Comments\nSaquinavir (soft-gel formulation)\nProbably Use of the soft-gel formulation (Fortovase™) in higher-than-usual doses might allow adequate serum concentrations of this drug despite concurrent use of rifabutin.- However, the pharmacokinetic data for this combination are limited in comparison with other protease inhibitors. Because of the expected low bioavailability of the hard-gel formulation (Invirase™) the concurrent use of this agent with rifabutin is not recommended.\n\n# Ritonavir\nNo Ritonavir increases concentrations of rifabutin by 35-fold and results in increased rates of toxicity (arthralgia, uveitis, skin discoloration, and leukopenia). These adverse events have been noted in studies of high-dose rifabutin therapy, when rifabutin is administered with clarithromycin (another CYP450 inhibitor) -an indication that these events might result from high serum concentrations of rifabutin.\n\n# Indinavir\n\n# Yes\nData from drug interaction studies (unpublished report, Merck Research Laboratories, West Point, PA, 1998) suggest that the dose of indinavir should be increased from 800 mg every 8 hours to 1,200 mg every 8 hours if used in combination with rifabutin.*\n\n# Nelfinavir\nYes Some clinical experts suggest that the dose of nelfinavir should be increased from 750 mg three times a day to 1,000 mg three times a day if used in combination with rifabutin.*\n\n# Amprenavir\n\n# Probably\nThe drug interactions between amprenavir and rifabutin (and thus potential for rifabutin toxicity) are reported to be similar to those of ritonavir with rifabutin. However, potential advantages of using this combination are that a) rifabutin has a minimal effect on reducing the levels of amprenavir and b) even though it has not been studied, rifabutin toxicity is not expected if the daily dose of rifabutin is reduced when used in combination with amprenavir.\n\n# NRTIs †\nYes Not expected to have clinically significant interaction.\n\n# Nevirapine\nYes Not known whether nevirapine or rifabutin dose adjustments are necessary when these drugs are used together.*\n\n# Delavirdine\nNo Not recommended on the basis of marked decreases in concentrations of delavirdine when administered with rifamycins.\n\n# Efavirenz\nProbably Newly approved agent. Preliminary drug interaction studies suggest that when rifabutin is used concurrently with efavirenz, the dose of rifabutin for both daily and twice weekly administration should be increased from 300 mg to 450 mg.\n*Daily dose of rifabutin should be reduced from 300 mg to 150 mg if used in combination with amprenavir, nelfinavir, or indinavir. It is unknown whether the dose of rifabutin should be reduced if used in combination with saquinavir (Fortovase™) or nevirapine. † Nucleoside reverse transcriptase inhibitiors, including zidovudine, didanosine, zalcitabine, stavudine, and lamivudine. choice for patients who are also undergoing therapy with protease inhibitors (with the exception of ritonavir or hard-gel capsule saquinavir ) or with the NNRTIs nevirapine or efavirenz (but not delavirdine ). Currently, more clinical and pharmacokinetic data are available on the use of indinavir or nelfinavir with rifabutin than on the use of amprenavir or soft-gel saquinavir (Fortovase™) with rifabutin. Rifapentine is not recommended as a substitute for rifampin because its safety and effectiveness have not been established for the treatment of patients with HIV-related TB. As an alternative to the use of rifamycin for the treatment of TB, the use of streptomycin-based regimens that do not contain rifamycin can be considered for the treatment of TB in patients undergoing antiretroviral therapy with protease inhibitors or NNRTIs.\n\n# Use of Rifabutin-Based Regimens for the Treatment of HIV-Related TB\nAt present, TB drug regimens that include rifabutin instead of rifampin appear to offer the best alternative for the treatment of active TB among patients taking antiretroviral therapies that include protease inhibitors or NNRTIs. This recommendation is based on findings from studies of equivalent in vitro antituberculosis activity of rifabutin and rifampin (104,105 ) and the results of three clinical trials (106)(107)(108). These trials demonstrated that 6-month rifabutin-containing regimens (at a daily dose of either 150 mg or 300 mg) were as effective and as safe as similar control regimens containing rifampin for the treatment of TB (Table 7). The smallest (n=49) of these three trials was conducted in Uganda (108 ) and is the only one to include HIVcoinfected patients (who were not undergoing antiretroviral therapy at the time of the study). This study indicated that 81% of patients taking a TB treatment regimen containing daily rifabutin converted their sputum from M. tuberculosis positive to negative after 2 months of treatment, compared with a 48% sputum conversion rate among patients taking a TB regimen containing daily rifampin (p<0.05). However, when the researchers controlled for differences in baseline characteristics (a greater proportion of patients in the rifampin group had cavitary disease), they found no difference in the time to sputum conversion between the two study groups.\nStudies are under way to evaluate the use of rifabutin administered daily (at a dose of 150 mg) or twice a week (at a dose of 300 mg) for the treatment of TB in HIV-infected patients who take protease inhibitors. Physicians at a state tuberculosis hospital in Florida have treated or consulted on the treatment of approximately 30 HIV-infected patients who received a protease inhibitor while undergoing treatment for TB with rifabutin. Patients have been treated for TB primarily with administration of rifabutin (150 mg daily) as part of four-drug therapy for 2-4 weeks, followed by rifabutin (300 mg twice weekly) as part of four-drug therapy to complete 8 weeks of induction, and then a continuation phase consisting of twice-weekly isoniazid and rifabutin (300 mg) to complete 6 months of treatment. To date, patients treated with this regimen have not experienced clinically significant increases in rifabutin serum levels, have had a minimal incidence of adverse reactions from rifabutin (one patient developed a case of uveitis), and have had a good clinical response to TB and HIV therapies. Approximately 80% of the patients attained sputum conversion by the second month of treatment, most have attained and maintained suppression of HIV replication, and no TB relapses have occurred with up to 1 year of posttreatment follow-up (David Ashkin, M.D., and Masahiro Narita, M.D., A.G. Holley State Tuberculosis Hospital, Lantana, Florida, personal communication, 1998).\nIn previous reports, CDC and the American Thoracic Society jointly recommended the use of rifampin-containing short-course regimens for the initial treatment of HIVrelated TB (2 ). The inclusion of rifampin in regimens to treat TB was supported by data collected from approximately 90 controlled clinical trials conducted from 1968 to 1988 (109 ). Excluding rifampin from the TB treatment regimen was not recommended because regimens not containing rifampin a) had not been proven to have acceptable efficacy (i.e., have been associated with higher rates of TB treatment failure and death and with slower bacteriologic responses to therapy leading to potential increases in the likelihood of M. tuberculosis transmission) and b) require prolonging duration of therapy from 6 months to 12-15 months. Presently, available data suggest that rifabutin in short-course (i.e., 6 months) multidrug regimens to treat TB provides the same benefits as the use of rifampin. Three additional reasons support the use of rifabutin for treating HIV-related TB: a) observations suggest that rifabutin might be more reliably absorbed than rifampin in patients with advanced HIV disease (110,111 ); b) the use of rifabutin appears to have been better tolerated in patients with rifampininduced hepatotoxicity (David Ashkin, M.D., and Masahiro Narita, M.D., A.G. Holley State Tuberculosis Hospital, Lantana, Florida, personal communication, 1998); and c) the use of rifabutin might lessen the possibility of interactions with other medications commonly prescribed for patients with HIV infection (e.g., azole antifungal drugs, anticonvulsant agents, and methadone) (77 ).\n\n# Use of Alternative TB Treatment Regimens that Contain Minimal or No Rifamycin\nTB treatment regimens that contain no rifamycins have been proposed as an alternative for patients who take protease inhibitors or NNRTIs. Several clinical trials conducted in Hong Kong and Africa by the British Medical Research Council and published from 1974 through 1984 provide information about nonrifamycin and minimal-rifamycin regimens for the treatment of TB in patients who were not likely to be infected with HIV (Table 8) (112)(113)(114)(115). Most of these studies demonstrated high relapse rates when regimens not containing streptomycin were used and when the duration of therapy was less than 9 months. However, in a large (n=404) randomized controlled clinical trial in Hong Kong that evaluated the use of six TB treatment regimens consisting of streptomycin, isoniazid, and pyrazinamide either daily, three times a week, or two times a week for 6 or 9 months (112 ), almost all patients treated with any of the study regimens achieved rapid sputum conversions (86%-94% of patients converted within 3 months of therapy). In this study, the 30-month posttreatment follow-up relapse rates were high (18%-24%) among patients treated with 6-month regimens, but the relapse rates among patients treated with 9-month regimens (5%-6%) were similar to the relapse rates expected following the use of rifampin-based TB treatments. Thus, the expert consultants who developed these guidelines concluded that treatment of TB without rifamycin always requires longer-duration (at least 9 months) regimens that include streptomycin (or an injectable antituberculosis drug such as capreomycin, amikacin, or kanamycin) (63 ). However, these TB regimens have not been studied among patients with HIV infection. Streptomycin is highly bactericidal against M. tuberculosis, but it is rarely used in the United States to treat drug-susceptible TB because of problems associated with its administration by injection that can be intensified in patients with low body mass or wasting and because of potential ototoxicity and nephrotoxicity. The associated potential toxicities and increased duration of therapy and the patient's difficulty in adhering to an injectable-drug-based TB regimen can compromise the effectiveness of streptomycin-based TB regimens, and these limitations should be considered by physicians and patients.\n\n# Treatment of Latent M. tuberculosis Infection in Patients with HIV Infection Scientific Rationale\nPreventive therapy for TB is essential to controlling and eliminating TB in the United States (116,117 ). Treatment for HIV-infected persons who are latently infected with M. tuberculosis is an important part of this strategy and is also an important personal health intervention because of the serious complications associated with active TB in HIV-infected persons (118)(119)(120). Expert consultants attending the September 1997 CDC meeting and additional consultants attending a September 1998 meeting sponsored by the American Thoracic Society and CDC considered findings from multiple studies (121)(122)(123)(124)(125)(126)(127)(128)(129)(130) before developing recommendations about the optimal duration of isoniazid preventive therapy regimens; frequency of administration (intermittency) of preventive therapy; new short-course multidrug regimens; and preventive therapy for anergic HIV-infected adults with a high risk of M. tuberculosis infection.\nA key difference in most preventive therapy trials conducted before and after the beginning of the HIV epidemic is that the earlier trials focused on 12-month regimens of isoniazid, whereas five of seven trials (122)(123)(124)(125)(126) conducted in HIV-infected populations assessed 6-month regimens of isoniazid (Table 9). Four of these 6-month isoniazid regimens (122)(123)(124)(125) were chosen for study on the basis of the operational feasibility of providing therapy in countries with limited resources where preventive therapy programs were not available; the fifth study (126 ), a U.S. trial conducted among anergic patients, used a 6-month regimen because of the absence of previous data about optimal duration of therapy for TST-negative, HIV-infected patients. Despite these variations, the expert consultants concluded that the findings from these different preventive therapy studies should apply to most persons with latent M. tuberculosis infection, regardless of their HIV serostatus, because similar levels of protection have been observed when identical preventive therapy regimens have been administered to persons infected with HIV and those not infected.\n\n# Optimal Duration of Isoniazid Regimens for Treatment of Latent M. tuberculosis Infection\nThe American Thoracic Society and CDC have previously recommended a regimen of 12 months of isoniazid alone for treatment of latent M. tuberculosis infection in HIV-infected adults (2 ). The recommended duration of TB preventive therapy for persons not infected with HIV was a minimum of 6 months. When considering the optimal duration of isoniazid preventive therapy, the consultants reviewed findings from two studies conducted in populations not known to be infected with HIV (128,129 ). One of these studies, a controlled trial conducted in seven European countries, compared the efficacy of three durations (3, 6, and 12 months) of isoniazid preventive treatment for TST-positive persons with stable, fibrotic lesions on chest radiographs (128 ). In this study, compliant patients who received medication for 12 months had better protection against TB (93%) than those who received medication for 6 months (69%). The other study was conducted among the Inuits in the Bethel area of Alaska, where participants received 0-24 months of isoniazid preventive therapy (129 ). In an assessment of observed posttherapy case rates of TB relative to the amount of isoniazid ingested (expressed as a percentage of a 12-month regimen), researchers found that higher amounts of therapy corresponded with lower TB rates among participants who had received 0-9 months of isoniazid therapy; after 9 months of therapy, participants had no additional benefits in terms of decreased TB case rates.\nFour studies of HIV-infected persons have evaluated 6-month and 12-month regimens of daily isoniazid (121,123,125,127 ). Both of the studies that evaluated a 6-month regimen included a placebo comparison group and demonstrated reductions in the incidence of TB among persons in the treatment group -70% in Uganda (123 ) and 75% in Kenya (125 ). A study of the 12-month regimen (121 ), which was conducted in Haiti and also included a placebo comparison group, demonstrated an 83% reduction in the incidence of TB among persons in the treatment group. A multicenter trial conducted in the United States, Mexico, Brazil, and Haiti (127 ) demonstrated that the magnitude of protection obtained from a regimen of isoniazid administered daily for 12 months was similar to that obtained from a regimen of rifampin and pyrazinamide administered daily for 2 months. Isoniazid preventive therapy regimens of 6 and 12 months' duration have not been compared with each other in the same study conducted among HIV-infected persons. In summary, these data indicate that a) the optimal duration of isoniazid preventive therapy should be >6 months to provide the maximum degree of protection against TB; b) therapy for 9 months appears to be sufficient; c) therapy for >12 months does not appear to provide additional protection.\n\n# Frequency of Administering Isoniazid Preventive Therapy\nTwo clinical trials (122,124 ) have evaluated 6-month twice-weekly isoniazid regimens for the prevention of active TB in HIV-infected persons (Table 9). Participants enrolled in the twice-weekly 6-month isoniazid arm of a study conducted in Zambia had a 40% reduction in the rate of TB compared with persons who took a placebo for 6 months (124 ). The findings of a trial conducted in Haiti (122 ) suggest that the magnitude of protection obtained from isoniazid administered twice a week for 6 months is equivalent to that obtained from rifampin and pyrazinamide regimens administered twice a week for 2 months. Preventive therapy trials that include twice-weekly isoniazid regimens for >6 months or comparisons of the same drugs administered daily versus intermittently have not been conducted. However, in a Baltimore demonstration project in which isoniazid was administered twice a week (10-15 mg/kg, with a maximum dose of 900 mg) to a cohort of injecting-drug users under directly observed preventive therapy (DOPT), the findings support the efficacy of twice-weekly isoniazid preventive therapy (130 ). Twice-weekly regimens with DOPT were used in Baltimore because the project staff expected that supervised delivery of therapy would enhance adherence with and completion of the preventive therapy regimen. Thus, the available data suggest that the protection obtained from isoniazid preventive therapy regimens should be the same whether the drug is administered daily or twice a week.\n\n# Short-Course Multidrug Regimens for TB Preventive Therapy\nFour clinical trials (122)(123)(124)127 ) conducted among HIV-infected populations have evaluated courses of preventive therapy that are shorter than 6 months and that include rifampin in combination with isoniazid or pyrazinamide (Table 9). The largest and most recent of these trials was a multicenter, randomized TB prevention study conducted from 1992 through 1998 (127 ). Researchers found identical rates of TB (1.2 per 100 person-years) in two groups of TST-positive, HIV-infected persons: those who primarily self-administered isoniazid daily for 12 months and those who primarily self-administered rifampin and pyrazinamide daily for 2 months. Both study groups had similar adverse events and mortality rates; persons taking rifampin and pyrazinamide for 2 months were significantly more likely (80%) to complete therapy than were persons taking isoniazid for 12 months (68%) (p<0.001). Two other trials conducted in Haiti and Zambia (122,124 ) have also evaluated regimens of rifampin and pyrazinamide for the prevention of TB but have not included comparison arms of 12month isoniazid regimens. The study in Haiti ( 122) compared patients receiving rifampin and pyrazinamide administered twice a week for 2 months with patients receiving isoniazid twice a week for 6 months; in both arms of the study, one of the twice-weekly doses was administered by DOPT. Investigators observed no difference in TB risk or mortality among participants enrolled in the two treatment arms (122 ). The placebo-controlled trial in Zambia demonstrated comparable protection from 3 months of rifampin and pyrazinamide versus 6 months of isoniazid; both regimens were self-administered twice a week (124 ). In the multicenter trial (127 ) and in the Haiti and Zambia studies (122,124 ), regimens that included rifampin and pyrazinamide were well tolerated. In a study conducted in Uganda (123 ), investigators observed no statistically significant reduction in TB rates but a high rate of toxicity and drug intolerance among persons who took three drugs (isoniazid, rifampin, and pyrazinamide) daily for 3 months compared with persons who took a placebo (Table 9); 3 months of daily self-administered rifampin and isoniazid provided protection similar to that of 6 months of daily self-administered isoniazid. Thus, short-course multidrug regimens (i.e., two drugs for 2-3 months) have been shown to be effective for the prevention of active TB in HIV-infected persons. The use of three drugs for preventive therapy, however, can be associated with unacceptably high rates of toxicity, and the use of a 3-month regimen of rifampin and isoniazid is not being considered for use in the United States. Available data indicate that in the United States, a regimen of rifampin and pyrazinamide administered daily for 2 months is a reasonable treatment option for HIV-infected adults with latent M. tuberculosis infection. The available data do not permit CDC to make a definitive statement regarding the intermittent (i.e., twice a week) administration of a 2-month regimen of rifampin and pyrazinamide.\n\n# Preventive Therapy for Anergic HIV-Infected Adults with a High Risk of Latent M. tuberculosis Infection\nIsoniazid preventive therapy has not been found to be useful or cost-effective in preventing TB when administered to anergic, HIV-infected persons (123,126 ) (Table 9). The anergic subjects who received isoniazid in the Uganda trial had a statistically insignificant (17%) reduction in the rate of TB (2.5 cases per 100 person-years) compared with patients in the placebo group (3.1 cases per 100 person-years) (123 ). Similarly, anergic HIV-infected persons with a high risk for tuberculous infection who were enrolled in a U.S. multicenter trial and treated with isoniazid daily for 6 months had a rate of TB (0.4 cases per 100 person-years) that was 50% less than, but not statistically different from, the rate observed among patients treated with placebo (0.9 cases per 100 person-years) (126 ). In both of these studies, HIV-infected persons with anergy tolerated isoniazid well, as suggested by the low rates of adverse reactions and high rates of therapy completion. These study findings do not support the routine use of preventive therapy in anergic, HIV-infected persons. Preventive therapy for TST-negative, HIV-infected persons also has not been proven effective (121,124, 125 ) (Table 9); however, some experts recommend primary preventive therapy (to prevent M. tuberculosis infection) for TST-negative or anergic HIV-infected residents of institutions that pose an ongoing high risk for exposure to M. tuberculosis (e.g., prisons, jails, homeless shelters).\n\n# Implications of Results of TB Preventive Therapy Trials\nThe effects of TB preventive therapy on mortality and progression of HIV infection appear to be limited, with the exception that such therapy can protect against the development of TB disease and its associated consequences. Moreover, the duration of this protective effect has not been clearly established for HIV-infected persons. Despite these limitations and uncertainties, preventive therapy is recommended because its benefits in preventing TB disease are thought to be greater than the risks of serious treatment-related adverse events, and such therapy benefits society by helping to prevent the spread of infection to other persons in the community.\nThe implementation of TB preventive therapy programs should be facilitated by the use of newly recommended short-course multidrug regimens and twice-weekly isoniazid regimens, especially among patients for whom DOPT is feasible. Because of the drug interactions between rifampin and protease inhibitors or NNRTIs, the use of shorter regimens containing rifampin is contraindicated for patients taking these antiretroviral drugs. Although preventive therapy trials evaluating rifabutin use among TST-positive, HIV-infected persons have not been conducted, the expert consultants reviewed available data and agreed that the use of rifabutin instead of rifampin is valid on the basis of the same scientific principles that support the use of rifabutin for the treatment of active TB.\n\n# PART II. RECOMMENDATIONS\nThis section of the report provides clinicians with recommendations for diagnosing, treating, and preventing TB among persons coinfected with HIV while concurrently promoting optimal antiretroviral care for these patients. The recommendations reflect the current state of knowledge regarding the use of antiretroviral agents, but this field of science is rapidly evolving. As new antiretroviral agents and new data regarding existing agents alter therapeutic options and preferences for antiretroviral therapy, these changes might affect future recommendations for the treatment of TB infection and disease among patients coinfected with HIV and the treatment of HIV infection among persons with TB. Expert consultants updated these recommendations after a September 1997 CDC meeting, where they reviewed and considered available information about the scientific principles of therapy for TB and HIV.\nTo help clinicians make informed treatment decisions based on the most current research results, the expert consultants have given the recommendations evidencebased ratings (general recommendations have no rating). The ratings include a letter and a Roman numeral (Table 10), similar to the ratings used in previously issued guidelines (4,5 ). The letter indicates the strength of the recommendation, and the Roman numeral indicates the nature of the evidence supporting the recommendation. Thus, clinicians can use the ratings to differentiate between recommendations based on data from clinical trials versus those based on the opinions of experts familiar with the relevant clinical practice and scientific rationale for such practice (when clinical trial data are not available). However, these recommendations are not intended to substitute for the judgment of an expert physician. Management of HIV-related TB disease is complex, and clinical and public health consequences associated with treatment failure are serious. When possible, treatment of TB among HIV-infected persons should be directed by, or conducted in consultation with, a physician with extensive experience in the care of patients with these two diseases.\nThe objectives of implementing these recommendations are to reduce TB treatment failures, prevent drug-resistant TB, and diminish the adverse effects that TB has on HIV replication. Moreover, these guidelines contribute to efforts to control and eliminate TB from the United States by minimizing the likelihood of M. tuberculosis transmission, which will prevent the occurrence of new cases of TB. Multiple copies of this report and all updates are available from the Office of Communications, National\n\n# Active Tuberculosis Clinical and Public Health Principles\nPrompt initiation of effective antituberculosis treatment increases the probability that a patient with HIV infection who develops TB will be cured of this disease (45,131 ). TB treatment also quickly renders patients noninfectious (30 ), with the resulting reduction in the amount of M. tuberculosis transmitted to others, and it minimizes the patient's risk of death resulting from TB (41)(42)(43)132 ). Therefore, clinicians must immediately and thoroughly investigate the possibility of TB when a patient infected with HIV has symptoms consistent with TB. Persons suspected of having current TB disease should immediately be started on appropriate treatment, ideally with directly observed therapy (DOT) (133)(134)(135), and placed in TB isolation as necessary (136,137 ). Patients with TB and unknown HIV-infection status should be counseled and offered HIV testing. HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy. Most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies (4 ).\nHealth-care providers, administrators, and TB controllers must strive to promote coordinated care for patients with TB and HIV and remove existing barriers to information-sharing between TB control programs and HIV/AIDS programs. TB control programs are responsible for setting TB treatment standards for physicians in the community, promoting the awareness and use of recommended TB infection-control practices, and enforcing state and local health department requirements concerning TB case notification and early reporting of drug-susceptibility test results. Because of the complexity of managing HIV-related TB disease and the serious public health consequences of mismanagement, care for persons with HIV-related TB should be provided by, or in consultation with, experts in the management of both TB and HIV disease.\n\n# Diagnosis of HIV-Related Tuberculosis\nThe typical signs and symptoms of pulmonary TB are cough with or without fever, night sweats, weight loss, and upper-lobe infiltrates with or without cavitation on chest x-rays. The diagnosis of TB for some HIV-infected patients might be difficult because TB in an immunocompromised host can be associated with atypical symptoms, a lack of typical symptoms, and a paucity of findings in chest x-rays (138-140 ). Among persons with AIDS, the diagnosis of TB also can be complicated by the presence of other pulmonary infections such as Pneumocystis carinii pneumonia and Mycobacterium avium complex disease and by the occurrence of TB in extrapulmonary sites. For patients with unusual clinical and radiographic findings, the starting point for diagnosing active TB often is a positive tuberculin skin test (TST). All patients with positive TSTs should be evaluated to rule out active TB (see Diagnosis of M. tuberculosis Infection Among HIV-Infected Persons).\n\n# Medical Evaluation of Patients Suspected of Having Active TB\n\n# Management of HIV-Infected Patients with Active TB Coadministration of TB Treatment and Antiretroviral Therapy\nThe following management strategies are for patients with HIV-related pulmonary TB a) who are not known to have or who do not have risk factors for multidrugresistant TB and b) for whom antiretroviral therapy is appropriate. When they first receive care for active TB disease, some patients might already be receiving antiretroviral therapy, whereas other patients might be newly diagnosed with HIV infection (Figure 1). For these newly diagnosed patients, in addition to the currently established recommendations for the immediate initiation of antituberculosis therapy, recently published guidelines (4 ) recommend the use of antiretroviral therapy. When treatments for HIV and TB disease are begun simultaneously, the optimal setting is one with experienced and coordinated care givers as well as accessible resources to provide a continuum of medical services (e.g., a reliable source of medications and social, psychosocial, and nutritional services). *Coadministration of rifabutin with ritonavir, saquinavir (Invirase™), or delavirdine is not recommended.\n\n# FIGURE 1. Recommended management strategies for patients with human immunodeficiency virus (HIV) infection and tuberculosis (TB) OBJECTIVE\nThe objective of this MMWR is to inform the reader of recommendations and guidelines for the diagnosis, treatment, and prevention of tuberculosis (TB) among patients with human immunodeficiency virus (HIV). These recommendations and guidelines are based on a meeting of expert consultants convened in September 1997 by CDC. These recommendations should guide clinical practice and policy development related to appropriate management of patients with or at risk for HIV-related TB. Upon completion of this educational activity, the reader should possess a clear working knowledge of the diagnosis, treatment, and prevention of TB among patients with HIV.\n\n# ACCREDITATION Continuing Medical Education (CME) Credit:\nThis activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) by CDC. CDC is accredited by the ACCME to provide continuing medical education for physicians. CDC awards 2.0 hours of category 1 credit toward the AMA Physician's Recognition Award for this activity.\n\n# Continuing Nursing Education (CNE) Credit:\nThis activity for 2.4 contact hours is provided by CDC, which is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC) Commission on Accreditation.\n\n# EXPIRATION -October 30, 1999\nThe response form must be completed and returned electronically, by fax, or by mail, postmarked no later than one year from the publication date of this report, for eligibility to receive continuing education credit.\n\n# INSTRUCTIONS\n\n# Recommendations and Reports\nTo receive continuing education credit, please answer all of the following questions:\n1. Which of the following statements are true? (Indicate all that are true.)\nA. Human immunodeficiency virus (HIV) infection accelerates the natural progression of tuberculosis (TB).\nB. Active TB accelerates the natural progression of HIV infection and disease.\nC. The mortality rate for HIV-infected persons with TB is four times greater than the rate for TB patients not infected with HIV.\nD. The toxicity associated with isoniazid TB preventive therapy significantly outweighs this therapy's benefits in preventing active TB in an HIV-infected person.\n2. Which of the following strategies are recommended for patients with TB taking protease inhibitors for HIV therapy? (Indicate all that are true.)\nA. Stop protease inhibitor therapy to allow the use of rifampin for TB treatment.\nB. Use an antituberculosis treatment regimen that includes rifabutin instead of rifampin.\nC. Ensure that experienced and coordinated TB/HIV care givers are available. D. Provide therapy for TB that is directly observed.\n\n# Which of the following strategies are recommended for HIV-infected patients with active TB\n? (Indicate all that are true.)\nA. Immediately and simultaneously begin treatment regimens that include a protease inhibitor for HIV therapy and drugs other than rifampin for antituberculosis therapy.\nB. Immediately and simultaneously begin treatment regimens that include a protease inhibitor for HIV therapy and rifampin for antituberculosis therapy.\nC. For patients who start antiretroviral therapy with a protease inhibitor, plan a 2-week period between the last dose of rifampin and the first dose of protease inhibitor.\nD. For patients who are not on antiretroviral therapy when TB is diagnosed, plan to start antiretroviral therapy at the end of the induction phase of TB therapy (8 weeks) or when TB therapy is completed.\n\n# When rifabutin is administered with indinavir, nelfinavir, or amprenavir, the recommended dosage of rifabutin is: (Choose the one correct answer.)\nA. 300 mg daily or 150 mg twice weekly.\nB. 300 mg daily or 300 mg twice weekly.\nC. 150 mg daily or 300 mg twice weekly.\nD. 150 mg daily or 150 mg twice weekly.\n\n# A paradoxical reaction during the course of TB and HIV treatment . . . (Indicate all that are true.)\nA. is a temporary exacerbation of symptoms and signs of TB in some patients who have restored immune function because of effective antiretroviral therapy.\nB. is always associated with a positive Mycobacterium tuberculosis culture.\nC. if suspected, calls for evaluating the patient to rule out other causes of the signs and symptoms (e.g., antituberculosis treatment failure).\nD. might require hospitalization and possibly time-limited use of corticosteroids (e.g., prednisone therapy) if the patient has severe or life-threatening clinical manifestations.\n6. When administered with rifamycins, which of the following drugs might require a dosage adjustment, the use of alternative therapies, or other changes because of drug interaction? (Indicate all that are true.) The following questions will assess your perceptions of the readability and applicability of the material.\nAnswer guide for questions 1-9\nA B C D E F 2. A B C D E F 3. A B C D E F 4. A B C D E F 5. A B C D E F 6. A B C D E F 7. A B C D E F 8. A B C D E F 9. A B C D E F 10. A B C D E F 11. A B C D E F 12. A B C D E F 13. A B C D E F 14. A B C D E F 15. A B C D E F 16. A B C D E F\nDetach or photocopy. Because of drug interactions, the use of rifampin to treat TB is not recommended for patients who a) will start treatment with an antiretroviral regimen that includes a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor (NNRTI) at the same time they begin treatment for TB (4 ) or b) have established HIV infection that is being maintained on such an antiretroviral regimen when TB is newly diagnosed and needs to be treated. Thus, two TB treatment options are currently recommended for these patients: a) a rifabutin-based regimen or b) an alternative nonrifamycin regimen that includes streptomycin (see Treatment Options for Patients with HIV Infection and Drug-Susceptible Pulmonary TB and Figure 1). Using a rifampin-based TB treatment regimen continues to be recommended for patients with HIV infection a) who have not started antiretroviral therapy, when both the patient and the clinician agree that waiting to start such therapy would be prudent or b) for whom antiretroviral management does not include a protease inhibitor or an NNRTI (4 ) (Figure 1).\n\n# BOX 1. Components of the medical evaluation for human immunodeficiency virus-infected patients suspected of having tuberculosis\nThe medical evaluation should include the following questions and assessments:\n\n# Medical History\n- Ask all patients about their history of tuberculosis (TB) treatment. If the patient has previously received treatment, care providers must determine the antituberculosis drugs used, duration of treatment, history of adverse reactions, reasons for discontinuation of treatment, history of adherence with treatment, and previous antituberculosis drugsusceptibility test results.\n- Question all patients about the following risk factors for drug-resistant TB: a) previous treatment for TB, especially if it was incomplete; b) previous residence in a country outside the United States where drug-resistant TB is common; c) close contact with a person who has drug-resistant TB or multidrug-resistant TB; and d) previous residence in an institution (i.e., hospital, prison, homeless shelter) with documented transmission of a drug-resistant strain of TB.\n- Ask all patients about their history of antiretroviral therapy and their history of therapies to prevent opportunistic infections. If the patient has previously or is currently receiving these treatments, care providers should determine the drugs used, duration of treatment, history of adverse reactions, and reasons for discontinuation of treatment if treatment ended.\n- Ask female patients whether they might be pregnant. Women of childbearing potential with menses more than 2 weeks late should receive a pregnancy test. (See TB Treatment for HIV-Infected Pregnant Women.)\n- When clinical specimens for culture and susceptibility testing cannot be obtained from patients (e.g., young children, patients with skeletal or meningeal TB), the culture and drug-susceptibility results of the Mycobacterium tuberculosis strain isolated from the infecting source-patient should be investigated and reviewed if available so that TB treatment for the current patient can be tailored appropriately. (See TB Treatment for HIV-Infected Children.)\n- If necessary, perform a Mantoux-method tuberculin skin test (TST) to help diagnose culture-negative TB.\nWhen determining the time to begin antiretroviral therapy for patients who are acutely ill with TB, clinicians and patients need to consider the existing clinical issues (e.g., drug interactions and toxicities, ability to adhere to two complex treatment regimens, and laboratory abnormalities). A staggered initiation of antituberculosis and antiretroviral treatments for patients not currently on antiretroviral therapy might promote greater adherence to the TB and HIV treatment regimens and reduce the associated drug toxicity of both regimens. This strategy might include starting antiretroviral therapy either at the end of the 2-month induction phase of TB therapy or after TB therapy is completed. When a decision is made to delay initiation of antiretroviral therapy, clinicians should monitor the patient's condition by measuring\n\n# BOX 1. Components of the medical evaluation for human immunodeficiency virus-infected patients suspected of having tuberculosis -Continued Chest X-Ray Examination\n- Perform a chest x-ray examination. HIV-related immunosuppression reduces the inflammatory reaction and cavitation of pulmonary lesions, and therefore HIV-infected patients with pulmonary TB can have atypical findings or normal chest x-rays. Children younger than age 5 years should undergo both a posterior-anterior and a lateral chest x-ray. All other persons should receive a posterior-anterior chest x-ray; additional chest x-ray examinations should be performed at the physician's discretion. Pregnant women who are being evaluated for active TB disease should undergo a chest x-ray (with the appropriate shielding) without delay, even during the first trimester of pregnancy. Patients suspected of having extrapulmonary TB should undergo a chest x-ray to rule out pulmonary TB.\n\n# Laboratory Tests\n- Collect smears for acid-fast bacilli, cultures, and drug susceptibilities from expectorated or induced sputum samples on 3 consecutive days, preferably in the mornings. Children who are unable to produce sputum spontaneously or who cannot use the sputum induction machine should be admitted to the hospital for early morning gastric aspirates on 3 consecutive, separate days.\n- Obtain a complete blood cell count, including platelets.\n- Conduct chemistry panel tests, especially for liver enzyme levels (serum glutamic oxalacetic transaminase or aspartate aminotransferase and serum glutamic pyruvic transaminase or alanine aminotransferase ); total bilirubin; uric acid; blood urea nitrogen; and creatinine.\n\n# Other Procedures\n- Perform a baseline visual acuity exam and test for red-green color perception for all patients who will be receiving ethambutol.\n- Perform baseline audiometry tests if an aminoglycoside (e.g, streptomycin, amikacin, kanamycin) or capreomycin will be administered.\n- Perform as necessary procedures such as bronchoscopies and bronchoalveolar lavage; biopsies and aspirates (e.g, of peripheral lymph nodes, visceral lymph nodes, liver, and bone marrow); mycobacterial culturing of nonrespiratory clinical specimens (e.g., blood, urine, pleural fluid); and radiologic evaluations other than chest x-rays (e.g., computerized tomographies, magnetic resonance imaging). plasma HIV RNA levels (viral load) and CD4+ T-cell counts and assessing the HIVassociated clinical condition at least every 3 months (4), because such information will assist in decisions regarding the timing for initiating such therapy. For some patients, switching from a rifampin-based TB regimen to either a rifabutin-based or a nonrifamycin-based TB regimen will be necessary if the decision is made to start antiretroviral therapy before completion of antituberculosis therapy. Clinicians and patients should be aware that the potent effect of rifampin as a CYP450 inducer (77,80), which lowers the serum concentration of protease inhibitors and NNRTIs, continues up to at least 2 weeks following the discontinuation of rifampin. Thus, they should consider planning for a 2-week period between the last dose of rifampin and the first dose of protease inhibitors or NNRTIs (see TB Drug Interaction and Absorption and Table 1A of Appendix).\n\n# Treatment Options for Patients with HIV Infection and Drug-Susceptible Pulmonary TB A.II\nDOT and other strategies that promote adherence to therapy should be used for all patients with HIV-related TB.\n\n# A.II\nFor patients who are receiving therapy with protease inhibitors or NNRTIs, the initial phase of a 6-month TB regimen consists of isoniazid, rifabutin, pyrazinamide, and ethambutol. These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment consists of isoniazid and rifabutin administered daily or twice a week for 4 months (see Six-month RFB-based therapy in Table 1A of Appendix).\n\n# B.II\nFor patients for whom the use of rifamycins is limited or contraindicated for any reason (e.g., intolerance to rifamycins, patient/clinician decision not to combine antiretroviral therapy with rifabutin), the initial phase of a 9-month TB regimen consists of isoniazid, streptomycin,- pyrazinamide, and ethambutol administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment consists of isoniazid, streptomycin,- and pyrazinamide administered 2-3 times a week for 7 months (see Nine-month SM-based therapy in Table 1A of Appendix). A.I For patients who are not candidates for antiretroviral therapy, or for those patients for whom a decision is made not to combine the initiation of antiretroviral therapy with TB therapy, the preferred option continues to be a 6-month regimen that consists of isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin). These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by 2-3-times-perweek dosing for 6 weeks, to complete the 2-month induction phase. The *Every effort should be made to continue administering streptomycin for the total duration of treatment or for at least 4 months after culture conversion (approximately 6-7 months from the start of treatment). Some experts suggest that in situations in which streptomycin is not included in the regimen for all of the recommended 9 months, ethambutol should be added to the regimen to replace streptomycin, and the duration of treatment should be prolonged from 9 months to 12 months. Alternatives to streptomycin are the injectable drugs amikacin, kanamycin, and capreomycin.\nsecond phase of treatment consists of a) isoniazid and rifampin administered daily or 2-3 times a week for 4 months. Isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) also can be administered three times a week for 6 months (see Six-month RIF-based therapy in Table 1A of Appendix). D.II TB regimens consisting of isoniazid, ethambutol, and pyrazinamide (i.e., three-drug regimens that do not contain a rifamycin, an aminoglycoside , or capreomycin) should generally not be used for the treatment of patients with HIV-related TB; if these regimens are used for the treatment of TB, the minimum duration of therapy should be 18 months (or 12 months after documented culture conversion). A.II Pyridoxine (vitamin B 6 ) (25-50 mg daily or 50-100 mg twice weekly) should be administered to all HIV-infected patients who are undergoing TB treatment with isoniazid, to reduce the occurrence of isoniazid-induced side effects in the central and peripheral nervous system. E.II Because CDC's most recent recommendations for the use of antiretroviral therapy strongly advise against interruptions of therapy,- and because alternative TB treatments that do not contain rifampin are available, previous antituberculosis therapy options that involved stopping protease inhibitor therapy to allow the use of rifampin (Option I and Option II ) are no longer recommended.\n\n# Medications and Doses for Treatment of TB\nNo rating When rifabutin is used concurrently with indinavir, nelfinavir, or amprenavir, the recommended daily dose of rifabutin should be decreased from 300 mg to 150 mg (Table 2A of Appendix). No rating The dose of rifabutin recommended for twice-weekly administration is 300 mg, and this dose recommendation does not change if rifabutin is used concurrently with indinavir, nelfinavir, or amprenavir (Table 2A of Appendix). No rating Preliminary drug interaction studies suggest that when rifabutin is used concurrently with efavirenz, the dose of rifabutin for both daily and twiceweekly administration should be increased from 300 mg to 450 mg. No rating Three-times-per-week administration of rifabutin used in combination with antiretroviral therapy has not been studied, and thus a recommendation for adjustment of dosages cannot currently be made. No rating Experts do not know whether the daily dose of rifabutin should be reduced when this drug is used concurrently with either soft-gel saquinavir (Fortovase ™ ) or nevirapine. No rating No modifications in the usually recommended doses of isoniazid, ethambutol, pyrazinamide, or streptomycin (Table 2A of Appendix) are necessary if these drugs are used concurrently with protease inhibitors, NNRTIs, or nucleoside reverse transcriptase inhibitors (NRTIs).\n*To minimize the emergence of drug-resistant HIV strains, if any antiretroviral medication must be temporarily discontinued for any reason, clinicians and patients should be aware of the theoretical advantage of stopping all antiretroviral agents simultaneously, rather than continuing the administration of one or two of these agents alone (4).\nNo rating The safety and effectiveness of rifapentine (Priftin ® ), a rifamycin newly approved by the U.S. Food and Drug Administration for the treatment of pulmonary tuberculosis, have not been established for patients infected with HIV. Administration of rifapentine to patients with HIV-related TB is not currently recommended.\n\n# Duration of TB Treatment\nA.II\nThe minimum duration of short-course rifabutin-containing TB treatment regimens is 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12 The final decision on the duration of therapy should consider the patient's response to treatment. For patients with delayed response to treatment (see Box 2), the duration of rifamycin-based regimens should be prolonged from 6 months to 9 months (or to 4 months after culture conversion is documented).\n\n# A.II\nThe minimum duration of nonrifamycin, streptomycin-based TB treatment regimens is 9 months, to complete a) at least 60 induction doses (one dose per day for 2 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12-18 induction doses (two to three doses per week for 6 weeks) plus either 60 continuation doses (two doses per week for 30 weeks) or 90 continuation doses (three doses per week for 30 weeks).\n\n# A.II\nWhen making the final decision on the duration of therapy, clinicians should consider the patient's response to treatment. For patients with delayed response to treatment (see Box 2), the duration of streptomycinbased regimens should be prolonged from 9 months to 12 months (or to 6 months after culture conversion is documented).\n\n# A.III\nInterruptions in therapy because of drug toxicity or other reasons should be taken into consideration when calculating the end-of-therapy date for individual patients. Completion of therapy is based on total number of medication doses administered and not on duration of therapy alone. A.III Reinstitution of therapy for patients with interrupted TB therapy might require a continuation of the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) *Three-times-per-week rifabutin regimens, used in combination with antiretroviral therapy, have not been studied.\n\n# BOX 2. Components of the monthly medical evaluation for human immunodeficiency virus-infected patients undergoing treatment for active tuberculosis\nFor patients infected with human immunodeficiency virus (HIV) who are undergoing treatment for active tuberculosis (TB), clinicians should include the following components in the monthly evaluation:\n- Once a month, evaluate symptoms and signs of TB (response to treatment) by conducting a) a physical examination (the nature and extent of this evaluation will depend on the patient's symptoms and the site of disease) and b) for patients with pulmonary TB, an examination by smear and culture of an expectorated or induced sputum specimen until cultures are no longer positive for Mycobacterium tuberculosis.\n- Perform as necessary for individual patients laboratory tests such as: complete blood cell count, platelet count, and tests for serum glutamic oxalacetic transaminase or aspartate aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase or alanine aminotransferase (SGPT/ALT), alkaline phosphatase, total bilirubin, uric acid, blood urea nitrogen, and creatinine.\n- To assist in the decision about the duration of TB treatment, investigate the possibility of a delayed response to treatment (Table 1A of Appendix). Delayed response to treatment should be suspected (and in most cases treatment duration should be prolonged) if by the end of the 2-month induction phase of therapy, patients a) continue to be culture-positive for M. tuberculosis or b) do not experience resolution of signs or symptoms of TB or do experience progression of signs or symptoms of TB (e.g., persistent fever, progressive weight loss, or increase in size of lymph nodes, abscesses, or other tuberculous lesions, none of which can be accounted for by a disease other than TB). (See Duration of TB Treatment.)\n- Some factors potentially associated with TB treatment failure are a large mycobacterial load and extensive lung cavitation at baseline, nonadherence with the drug regimen (even among patients assumed to be on DOT), inappropriately low medication doses, and impaired absorption of drugs. Immediately institute corrective measures for those factors amenable to intervention.\n- Because patients with HIV-infection often are treated with multiple drugs in addition to antituberculosis drugs, at each visit, review all medications that the patient is taking and assess any change in medications for potential drug interactions with TB medications. Efforts to manage these potential problems related to drug interactions require the coordinated efforts of care givers for HIV and TB disease. (See TB Drug Interaction and Absorption.)\n- Because several antituberculosis drugs have hepatotoxicity as a potential side effect (Table 2A of Appendix), advise all persons taking TB medications about the symptoms consistent with hepatitis (e.g., anorexia, nausea, vomiting, abdominal pain, jaundice) and instruct them to discontinue all TB medications immediately and seek medical attention promptly if they exhibit such symptoms. These patients usually will need an examination by a physician, liver function tests, and a planned strategy for restarting TB treatment.\n- If ethambutol is administered, perform a monthly visual acuity exam and test for redgreen color perception.\n- If streptomycin is administered, perform audiometry and renal function tests as needed.\n-r a complete renewal of the regimen. In either situation, when therapy is resumed after an interruption of ≥2 months, sputum samples (or other clinical samples as appropriate) should be taken for smear, culture, and drug-susceptibility testing.\n\n# Management of the Coadministration of TB and HIV Therapies, Including the Potential for Paradoxical Reactions\nWhen antituberculosis treatment has been started, all patients should be monitored for response to antituberculosis therapy, drug-related toxicity, and drug interactions. Detailed recommendations for managing antiretroviral therapy are published elsewhere (4 ), and consultation with experts in this area is highly recommended.\nThe frequency and type of most TB medication side effects are similar among TB patients with and without HIV infection (30,65,67 ). When caring for HIV-infected persons, clinicians must be aware of the following problems that can result from the administration of TB medications: a) patients might have a higher predisposition toward isoniazid-related peripheral neuropathy; b) evaluation of dermatologic reactions related to TB medications might be complicated because HIV-infected patients are subject to several dermatologic diseases related to HIV disease or to medications used for other treatment or prophylaxis reasons; and c) patients undergoing concurrent therapy with rifabutin and protease inhibitors or NNRTIs are at risk for rifabutin toxicity associated with increased serum concentrations of this drug. The reported adverse events associated with rifabutin toxicity include arthralgias, uveitis, and leukopenia (86,(101)(102)(103). Detailed recommendations for managing these adverse reactions are published elsewhere and should be consulted (2,64 ).\nParadoxical reactions -temporary exacerbation of symptoms, signs, or radiographic manifestations of TB (e.g., recurrence of fever, enlarged lymph nodes, appearance of cavitation in previously normal chest x-ray) among patients who have experienced a good clinical and bacteriologic response to antituberculosis therapyhave been reported among patients coinfected with HIV who have restored immune function because of antiretroviral therapy (76 ). The synchronization and severity of paradoxical reactions associated with antiretroviral therapy are not well understood; therefore, experts do not know whether the occurrence of these reactions should affect the timing of initiating or changing antiretroviral therapy when such therapy is indicated for a patient with HIV infection. However, because an association between paradoxical reactions and initiation of antiretroviral therapy has been noted, clinicians should be aware of this possibility and discuss the risks with patients undergoing therapy for active TB.\n\n# Monthly Medical Evaluation and the Diagnosis and Management of Paradoxical Reactions A.II\nAll patients should receive a monthly clinical evaluation (see Box 2) to monitor their response to treatment, adherence to treatment, and medication side effects (Table 2A of Appendix). During the early days of therapy, the interval between these evaluations might be shorter (e.g., every 2 weeks).\n\n# A.II\nPatients suspected of having paradoxical reactions should be evaluated to rule out other causes for their clinical presentation (e.g., TB treatment failure) before attributing their signs and symptoms to a paradoxical reaction. C.III Some experts recommend that to avoid paradoxical reactions, clinicians should delay the initiation of or changes in antiretroviral therapy until the signs and symptoms of TB are well controlled (possibly 4-8 weeks from the initiation of TB therapy). No rating For patients with a paradoxical reaction in whom the symptoms are not severe or life-threatening, the management of these reactions might consist of symptomatic therapy and no change in antituberculosis or antiretroviral therapy. For patients with a paradoxical reaction associated with severe or life-threatening clinical manifestations (e.g., uncontrollable fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections , sepsis-like syndrome), the management might include hospitalization and possibly a time-limited use of corticosteroids (e.g., prednisone started daily at a dose of 60-80 mg and reduced after 1 or 2 weeks, with the resolution of symptoms as a guide; in most cases, corticosteroid therapy should last no more than 4-6 weeks).\n\n# TB Drug Interaction and Absorption E.II\nGiven the expected drug interactions that would result in markedly decreased serum levels of antiretroviral agents, and given the overlapping toxicities, the coadministration of rifampin with any of the protease inhibitors or with NNRTIs, as well as the coadministration of rifabutin with ritonavir, hard-gel saquinavir (Invirase ™ ), or delavirdine, is contraindicated.\n\n# A.II\nThe potent effect of rifampin as a CYP450 inducer, which lowers the serum concentration of protease inhibitors and NNRTIs, is expected to continue up to at least 2 weeks following the discontinuation of rifampin. Therefore, to diminish the likelihood of adverse effects on drug metabolism, clinicians should plan the start of therapy with protease inhibitors or NNRTIs at least 2 weeks after the date of the last dose of rifampin.\n\n# A.II\nRifabutin is a less potent CYP450 inducer than rifampin and thus can be used (with adjustments in dosages) concurrently with the NNRTIs nevirapine or efavirenz or with certain protease inhibitors (e.g., indinavir, nelfinavir, and possibly soft-gel saquinavir and amprenavir). No rating Indinavir serum concentrations are decreased by rifabutin-related induction of the hepatic cytochrome P450; therefore, when indinavir is used in combination with rifabutin, the dose of indinavir usually is increased from 800 mg every 8 hours to 1,200 mg every 8 hours. No rating Nelfinavir serum concentrations are also decreased when nelfinavir is used in combination with rifabutin (Table 1A of Appendix); however, the resultant metabolite of nelfinavir is known to be active against HIV. Nevertheless, some experts suggest increasing the dose of nelfinavir from 750 mg three times per day to 1,000 mg three times per day when used in combination with rifabutin. No rating Experts do not know whether dose-modifications are needed for soft-gel saquinavir (Fortovase ™ ), amprenavir, nevirapine, or efavirenz if these agents are used in combination with rifabutin. No rating Many other medications commonly used by patients with HIV infection have drug interactions with the rifamycins (rifampin or rifabutin) of sufficient magnitude to require interventions such as dose adjustments or use of alternative therapies. Some examples of these drugs are hormonal contraceptives, dapsone, ketoconazole, fluconazole, itraconazole, narcotics (including methadone), anticoagulants, corticosteroids, cardiac glycosides, hypoglycemics (sulfonylureas), diazepam, beta-blockers, anticonvulsants, and theophylline. No rating Malabsorption of antituberculosis drugs has been demonstrated in some patients with HIV infection, and in some cases, it has been associated with TB treatment failures and the selection of drug-resistant M. tuberculosis bacilli (141)(142)(143)(144)(145). Therapeutic drug monitoring has been advocated by some experts as an adjunct in the management of HIV-related TB (146 ). This approach might be useful when evaluating patients with TB treatment failure or relapse and in the treatment of multidrug-resistant (MDR) TB. However, the role of therapeutic drug monitoring in the routine management of TB among HIV-infected patients has not been established and is not presently recommended.\n\n# Treatment of TB in Special Situations\nThe following general treatment recommendations address special situations such as drug-resistant forms of HIV-related TB, TB among HIV-infected pregnant women, TB among HIV-infected children, and extrapulmonary HIV-related TB. Detailed recommendations for managing these patients are published elsewhere (2,64,(147)(148)(149)(150), and consultation with experts in these areas is highly recommended.\n\n# Treatment of Drug-Resistant TB A.II\nTB disease resistant to isoniazid only. The treatment regimen should generally consist of a rifamycin (rifampin or rifabutin), pyrazinamide, and ethambutol for the duration of treatment. Intermittent therapy administered twice weekly can be used following at least 2 weeks (14 doses) of daily induction therapy (see Duration of TB Treatment). The recommended duration of treatment is 6-9 months or 4 months after culture conversion. Isoniazid is generally stopped when resistance (>1% of bacilli resistant to 1.0 µg/mL of isoniazid) to this drug is discovered; however, when low-level resistance is discovered (>1% of bacilli resistant to 0.2 µg/mL of isoniazid, but no resistance to 1.0 µg/mL of isoniazid), some experts suggest continuing to use isoniazid as part of the treatment regimen. Because the development of acquired rifamycin resistance would result in MDR TB, clinicians should carefully supervise and manage TB treatment for these patients.\nisoniazid and rifampin. If drug-susceptibility results are not available, a four-drug regimen (e.g., isoniazid, rifamycin, pyrazinamide, and ethambutol) for 2 months, followed by intermittent administration of isoniazid and a rifamycin for 4 months, is recommended. Considerations for antiretroviral therapy for children and adolescents have been published elsewhere (154 ).\n\n# TB Treatment for HIV-Infected Patients with Extrapulmonary TB\nThe basic principles that support the treatment of pulmonary TB in HIVinfected patients also apply to extrapulmonary forms of the disease. Most extrapulmonary forms of TB (including TB meningitis, tuberculous lymphadenitis, pericardial TB, pleural TB, and disseminated or miliary TB) are more common among persons with advanced-stage HIV disease (155,156) than among patients with asymptomatic HIV infection. The drug regimens and treatment durations that are recommended for treating pulmonary TB in HIV-infected adults and children (Table 1A of Appendix) are also recommended for treating most patients with extrapulmonary disease. However, for certain forms of extrapulmonary disease, such as meningioma, bone, and joint TB, using a rifamycin-based regimen for at least 9 months is generally recommended.\n\n# Latent M. tuberculosis Infection Clinical and Public Health Principles\nWhen caring for persons with HIV infection, clinicians should make aggressive efforts to identify those who also are infected with M. tuberculosis. Because the reliability of the tuberculin skin test (TST) can diminish as the CD4+ T-cell count declines, TB screening with TST should be performed as soon as possible after HIV infection is diagnosed. Because the risk of infection and disease with M. tuberculosis is particularly high among HIV-infected contacts of persons with infectious pulmonary or laryngeal TB, these persons must be evaluated for TB as soon as possible after learning of exposure to a patient with infectious TB.\nHealth-care providers, administrators, and TB controllers must coordinate their work and establish TB screening initiatives in settings where a) the prevalence of infection with M. tuberculosis among persons with HIV-infection is expected to be high and b) referral for medical evaluation and TB preventive therapy can be accomplished. Such settings include prisons, jails, prenatal-care programs, drug treatment programs, syringe exchange programs, HIV specialty clinics, acute-care hospitals serving populations at high risk of TB, AIDS patient group residences, some community-health centers, psychiatric institutions, mental health residences, and homeless shelters. All HIV counseling and testing sites must have mechanisms in place to ensure that persons identified with HIV infection receive tuberculin skin testing. TB control programs in jurisdictions that have HIV reporting requirements should make efforts to ensure that all persons with HIV infection have TSTs.\nBecause of the complexity of problems associated with active TB disease in HIVinfected persons, and as part of the efforts to control and eliminate TB in the United States, all HIV-infected persons identified as latently infected with M. tuberculosis A.II\n\n# BOX 3. Components of the baseline medical evaluation for tuberculosis preventive treatment for patients infected with human immunodeficiency virus\nWhen conducting a medical evaluation to rule out active tuberculosis (TB) and administer preventive treatment for patients infected with human immunodeficiency virus (HIV), clinicians should include the following questions and assessments:\n\n# Medical History\n- Ask patients about their history of recent close contact with a person who has TB disease. If the infecting source-patient is known, his or her culture and drug-susceptibility results should be investigated and reviewed so that the preventive therapy regimen can be tailored appropriately (see Treatment of Latent M. Tuberculosis in Special Situations).\n- Assess patients for their risk of increased toxicity associated with the medications used for TB preventive therapy (e.g., history of excessive alcohol ingestion, liver disease, hepatitis, chronic use of other medications).\n- Assess patients for contraindications to TB preventive therapy (Table 3A of Appendix).\n- When persons have previously received TB preventive treatment, determine what drugs were used, duration of treatment, and any history of adverse reactions (Table 2A of Appendix) and adherence to preventive therapy.\n- Ask patients about their history of antiretroviral therapy and their history of therapies to prevent opportunistic infections. If a patient has ever received or is receiving any of these treatments, the care provider must determine the drugs used, duration of treatment, history of adverse reactions, potential for drug interactions with TB medications, and any reasons for discontinuation of treatment if treatment ended.\n\n# Chest X-Ray Examination\n- A chest x-ray is indicated for all persons being considered for preventive therapy, to rule out active pulmonary TB disease. Children younger than 5 years old should undergo both a posterior-anterior and a lateral chest x-ray. All other individuals should receive a posterior-anterior chest x-ray only; additional x-rays should be performed at the physician's discretion. Pregnant women who have a positive TST or who have negative TST results but are recent contacts of a person who has infectious TB disease should undergo a chest x-ray (with appropriate shielding) without delay, even during the first trimester of pregnancy.\n\n# Laboratory Tests\n- Obtain a complete blood cell count, and also obtain a platelet count if the patient will be treated with a rifamycin (rifampin or rifabutin).\n- Conduct chemistry panel tests, especially for liver enzyme levels (serum glutamic oxalacetic transaminase or aspartate aminotransferase and serum glutamic pyruvic transaminase or alanine aminotransferase ) and total bilirubin. In addition, check uric acid levels if the patient will be treated with pyrazinamide.\n\n# BOX 4. Components of the monthly medical evaluation for human immunodeficiency virus-infected patients undergoing preventive treatment for latent Mycobacterium tuberculosis infection\nFor patients infected with human immunodeficiency virus (HIV) who are undergoing preventive treatment for latent Mycobacterium tuberculosis infection, clinicians should include the following components in the monthly evaluation:\n- At every monthly evaluation, review signs and symptoms potentially related to active tuberculosis (TB) disease as well as signs and symptoms of drug reactions potentially related to antituberculosis drugs (Table 2A of Appendix).\n- At the start of preventive therapy and at each subsequent monthly visit, remind patients of the need to immediately discontinue preventive therapy and seek prompt medical attention if signs and symptoms of hepatotoxicity appear (e.g., anorexia, abdominal pain, nausea, vomiting, change in color of urine and feces, jaundice). - Patients with HIV infection often are treated with multiple drugs in addition to antituberculosis drugs. At each visit, all medications that a patient is taking should be reviewed and assessed for potential drug interactions with TB medications. Some examples of these drugs are hormonal contraceptives, ketoconazole, fluconazole, itraconazole, narcotics (including methadone), anticoagulants, corticosteroids, cardiac glycosides, hypoglycemics (sulfonylureas), diazepam, beta-blockers, anticonvulsants, and theophylline. Efforts to manage these potential problems related to drug interactions require the coordinated efforts of HIV and TB patients' care givers. The choices for preventive treatment for persons who are likely to be infected with a strain of M. tuberculosis resistant to both isoniazid and rifamycins are published elsewhere (161 ). In general, the recommended preventive therapy regimens for these persons include the use of a combination of at least two antituberculosis drugs that the infecting strain is believed to be susceptible to (e.g., ethambutol and pyrazinamide, levofloxacin and ethambutol). The clinician should review the drugsusceptibility pattern of the M. tuberculosis strain isolated from the infecting source-patient before choosing a preventive therapy regimen.\n\n# Treatment of Latent M. tuberculosis Infection in Special Situations\n\n# A.III\nFor HIV-infected women who are candidates for TB preventive therapy, the initiation or discontinuation of preventive therapy should not be delayed on the basis of pregnancy alone, even during the first trimester. A 9-month regimen of isoniazid administered daily or twice a week is the only recommended option (Table 3A of Appendix). No rating For HIV-infected children who are candidates for TB preventive therapy, a 12-month regimen of isoniazid administered daily is recommended by the American Academy of Pediatrics (162 ).\n\n# Follow-up of HIV-Infected Persons Who Have Completed Preventive Therapy\n\n# CONCLUSIONS\nImplementing TB prevention and control strategies for persons infected with HIV has always been important and is even more critical now that a larger selection of new, more potent antiretroviral drugs has enabled clinicians to implement therapies that improve the health and prolong the lives of HIV-infected persons. These antiretroviral therapeutic strategies often include the use of drugs such as the protease inhibitors or the nonnucleoside reverse transcriptase inhibitors (NNRTIs), which because of drug interactions cannot be used concurrently with certain other drugs (e.g., rifampin). Thus, to improve the diagnosis and management of TB and HIV coinfection, TB control programs need to be prepared for the following challenges:\n- Ensure that all patients with TB receive HIV counseling and testing either on site or elsewhere. Patients with latent M. tuberculosis infection who are at risk for HIV infection also should receive HIV counseling and testing.\n- Initiate prompt and effective antituberculosis treatment (ideally with directly observed therapy) for all patients diagnosed with HIV-related TB.\n- Promote optimal antiretroviral therapy for patients with M. tuberculosis and HIV infection.\n- Become knowledgeable about the indications, potential dosing adjustments, and monitoring requirements of a rifabutin-containing regimen (or an alternative regimen that does not contain rifamycin) for the treatment of TB in patients who are undergoing antiretroviral therapy with protease inhibitors or NNRTIs.\n- Identify potential risk factors for TB treatment failure or relapse as well as the potential for paradoxical treatment reactions, and learn how to recognize and manage these outcomes.\n- Follow procedures to ensure early recognition and implementation of effective treatment for drug-resistant TB.\n- Recognize that previous options that involved stopping protease inhibitor therapy to allow the use of rifampin for TB treatment are no longer recommended for two reasons: a) the most recent guidelines for the use of antiretroviral therapy advise against interrupting HIV therapy, and b) alternatives for TB therapy that do not contain rifampin are available.\n- Coordinate efforts and establish TB screening initiatives in settings where a) the prevalence of infection with M. tuberculosis among persons with HIV-infection is expected to be high and b) referral for medical evaluation and therapy for active or latent TB is possible.\n- Be aware of changes in options for TB preventive therapy. In addition to recommendations for using 9 months of isoniazid daily or twice a week, new shortcourse multidrug regimens (e.g., a 2-month course of a rifamycin such as rifabutin or rifampin with pyrazinamide) can be prescribed for HIV-infected patients with latent M. tuberculosis infection.\nWhen faced with treatment choices, TB controllers and clinicians can use these recommendations to make informed decisions based on the most current research results available, keeping in mind that as new antiretroviral and antituberculosis agents become available, these guidelines will likely change. The aim of these recommendations is to help reduce TB treatment failures, prevent cases of drug-resistant TB, diminish the adverse effects that TB has on HIV replication, and support efforts to not only control TB, but to eliminate it from the United States. No contraindication exists for the use of RFB with NRTIs.\nIf the patient also is taking indinavir, nelfinavir, or amprenavir, the daily dose of RFB is decreased from 300 mg to 150 mg. The twice-weekly dose of RFB (300 mg) remains unchanged if the patient is also taking these protease inhibitors.\nIf the patient also is taking efavirenz, the daily or twice weekly dose of RFB is increased from 300 mg to 450 mg.\nThree-times-a-week administration of RFB used in combination with antiretroviral therapy has not been studied. † The concurrent use of RFB is contraindicated with ritonavir, saquinavir (Invirase™), and delavirdine. Information regarding the use of rifabutin with saquinavir (Fortovase™), amprenavir, efavirenz, and nevirapine is limited. § Not applicable. If nelfinavir, indinavir, or amprenavir is administered with RFB, blood concentrations of these protease inhibitors decrease. Thus, when RFB is used concurrently with any of these three drugs, the daily dose of RFB is reduced from 300 mg to 150 mg (the twice-weekly dose of RFB is unchanged, however). ¶ NA=not applicable. If efavirenz is administered with RFB, blood concentrations of RFB decrease. Thus, when RFB is used concurrently with efavirenz, the dose of RFB for both daily and twice weekly administration should be increased from 300 mg to 450 mg."},"raw_text":{"kind":"string","value":"These guidelines update previous CDC recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) in the United States. The most notable changes in these guidelines reflect both the findings of clinical trials that evaluated new drug regimens for treating and preventing TB among HIV-infected persons and recent advances in the use of antiretroviral therapy. In September 1997, when CDC convened a meeting of expert consultants to discuss current information about HIV-related TB, special emphasis was given to issues related to coadministration of TB therapy and antiretroviral therapy and how to translate this information into management guidelines. Thus, these guidelines are based on the following scientific principles: restores immune function. Adding to CDC's current recommendations for administering isoniazid preventive therapy to HIV-infected persons with positive tuberculin skin tests and to HIV-infected persons who were exposed to patients with infectious TB, this report also describes in detail the use of new shortcourse (i.e., 2 months) multidrug regimens (e.g., a rifamycin, such as rifampin or rifabutin, combined with pyrazinamide) to prevent TB in persons with HIV infection. A continuing education component for U.S. physicians and nurses is included.# \n• Early diagnosis and effective treatment of TB among HIV-infected patients are critical for curing TB, minimizing the negative effects of TB on the course of HIV, and interrupting the transmission of Mycobacterium tuberculosis to other persons in the community.\n• All HIV-infected persons at risk for infection with M. tuberculosis must be carefully evaluated and, if indicated, administered therapy to prevent the progression of latent infection to active TB disease and avoid the complications associated with HIV-related TB.\n• All HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy, because most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies. However, the use of rifampin with protease inhibitors or nonnucleoside reverse transcriptase inhibitors is contraindicated.\nIdeally, the management of TB among HIV-infected patients taking antiretroviral drugs requires a) directly observed therapy, b) availability of experienced and coordinated TB/HIV care givers, and in most situations, c) use of a TB treatment regimen that includes rifabutin instead of rifampin. Because alternatives to the use of rifampin for antituberculosis treatment are now available, the previously recommended practice of stopping protease inhibitor therapy to allow the use of rifampin for TB treatment is no longer recommended for patients with HIV-related TB. The use of rifabutin-containing antituberculosis regimens should always include an assessment of the patient's response to treatment to decide the appropriate duration of therapy (i.e., 6 months or 9 months). Physicians and patients also should be aware that paradoxical reactions might occur during the course of TB treatment when antiretroviral therapy\n# INTRODUCTION\nThese guidelines update previous CDC recommendations for treating and preventing active tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) (1)(2)(3). The most notable changes in these guidelines reflect both the recent advances in the use of antiretroviral therapy and the findings of clinical trials that evaluated new drug regimens for the treatment and prevention of TB among HIV-infected persons. Antiretroviral therapy is discussed in the context of TB treatment only; more detailed information about antiretroviral therapy is published elsewhere (4 ).\nIn September 1997, CDC convened a meeting of expert consultants who reviewed and considered background information about HIV-related TB in the United States and the scientific principles of therapy for both diseases (Part I of this report). The consultants then used this review as the basis for updating the recommendations for HIV-infected patients with TB (Part II). During their review of the scientific principles of therapy, the expert consultants focused on epidemiologic and clinical interactions between Mycobacterium tuberculosis infection and HIV infection, considering the frequency of coexisting TB and HIV infection and rates of drug-resistant TB among patients infected with HIV in the United States; the copathogenicity of TB and HIV disease; the potential for a poorer outcome of TB therapy and paradoxical reactions to TB treatment among HIV-infected patients; drug interactions between rifampin used for TB therapy and agents commonly used in antiretroviral therapy; use of TB treatment regimens that do not contain rifampin; and results of clinical trials of therapies to prevent TB among HIV-infected persons. Thus, in addition to CDC's current recommendations, these new guidelines include information about the following topics:\n• directly observed therapy for all patients with HIV-related TB;\n• rifabutin-containing antituberculosis regimens (or a streptomycin-based alternative regimen that does not contain rifamycin) for treating TB among patients taking antiretroviral drugs that have interactions with rifampin;\n• monitoring responses to antituberculosis treatment to decide about the appropriate duration of TB therapy;\n• occurrence and management of paradoxical reactions during TB treatment, when immune function is restored because of antiretroviral therapy;\n• use of 9 months of isoniazid daily or twice weekly for the treatment of M. tuberculosis infection; 2 MMWR October 30, 1998\n• short-course multidrug therapy for latent M. tuberculosis infection; and\n• special considerations that apply to children and pregnant women with HIVrelated TB.\nHealth-care professionals need to be familiar with these new guidelines to ensure the use of the most effective management strategies for TB patients infected with HIV, while concurrently promoting optimal antiretroviral therapy for these patients. To help clinicians make informed treatment decisions based on the most current research results, the expert consultants have given each recommendation an evidence-based rating similar to the ratings used in previously issued guidelines (4,5 ). However, these recommendations are not intended to substitute for the judgment of an expert physician. When possible, the treatment of TB in HIV-infected persons should be directed by (or done in consultation with) a physician with extensive experience in the care of patients with TB and HIV disease. The implementation of these recommendations will help prevent cases of drug-resistant TB, reduce TB treatment failures, and diminish the adverse effects that TB has on HIV replication. Moreover, these guidelines will contribute to efforts to control TB and eliminate it from the United States by minimizing the likelihood of M. tuberculosis transmission, which will prevent the occurrence of new cases of TB.\nIn future years, health-care professionals can expect changes in the recommendations regarding the therapeutic options used to prevent and treat TB among patients infected with HIV. These changes will reflect the availability of new antiretroviral and antituberculosis agents, new information about existing agents, and subsequent changes in CDC's guidelines for the use of antiretroviral therapy for persons infected with HIV. Multiple copies of this report and all updates are available from the Office of Communications, National Center for HIV, STD, and TB Prevention, CDC, 1600 Clifton Road, Mail Stop E-06, Atlanta, GA 30333. The report also is posted on the CDC Division of TB Elimination Internet website at <http://www.cdc.gov/nchstp/tb> and the MMWR website at <http://www.cdc.gov/epo/mmwr/mmwr.html>. Readers should consult these sources regularly for updates in the guidelines.\n# PART I. BACKGROUND AND SCIENTIFIC RATIONALE\n\n# Frequency of Coexisting TB and HIV Infection and Disease in the United States\nIn the United States, epidemiologic evidence indicates that the HIV epidemic contributed substantially to the increased numbers of TB cases in the late 1980s and early 1990s (6,7 ). Overlap between the acquired immunodeficiency syndrome (AIDS) and TB epidemics continues to result in increases in TB morbidity. Analysis of national HIV-related TB surveillance data is limited by incomplete reporting of HIV status for persons with TB. As an alternative, state health department personnel have compared TB and AIDS registries to help estimate the proportion of persons reported with TB who are also infected with HIV. In the most recent comparison conducted by the 50 states and Puerto Rico, 14% of persons with TB in 1993-1994 (27% among those aged 25-44 years) also appeared in the AIDS registry (8 ). This proportion of TB patients with AIDS is believed to be a minimum estimate for the United States and might represent an increase in the proportion of TB patients identified as having TB and AIDS in 1990 (9%) (6 ). During 1993-1994, most persons with TB and AIDS (80%) were found in eight reporting areas: New York City, California, Florida, Georgia, Illinois, New Jersey, New York, and Texas (8 ).\nIn prospective epidemiologic studies, investigators have estimated that the annual rate of TB disease among untreated, tuberculin skin-test (TST)-positive, HIV-infected persons in the United States ranges from 1.7 to 7.9 TB cases per 100 person-years (Table 1) (9-11 ). The variability observed in these studies mirrors the differences in TB prevalence observed for different U.S. populations (i.e., the highest case rate was found in a study of a New York City population of intravenous drug users at a time when the incidence of TB was high and increasing [9 ]; and the lowest case rate was evident in a community-based cohort of persons enrolled in a study of the pulmonary complications of HIV infection at a time and in a population in which the incidence of TB was relatively low [11 ]). However, in all of these studies, the rate of TB disease among HIV-infected, TST-positive persons was approximately 4-26 times higher than the rate among comparable HIV-infected, TST-negative persons, and it was approximately 200-800 times higher than the rate of TB estimated for the U.S. population overall (0.01%) (12 ). Therefore, activities to control and eliminate TB in the United States must include aggressive efforts to identify HIV-infected persons with latent\n# TABLE 1. Annual rates* of tuberculosis among persons with human imunodeficiency virus infection, by tuberculin skin-test (TST) status -selected years and U.S. areas Location and source\n\n# Rate among persons with positive TSTs\n\n# Rate among persons with negative TSTs\nRate ratio New York City Selwyn et al., 1989 (9 ) 7.9 0. TB infection and to provide them with therapy to prevent progression to active TB disease.\n# Rates of Drug-Resistant TB Among HIV-Infected Persons in the United States\nResistance to antituberculosis drugs is an important consideration for some HIVinfected persons with TB. According to the results of a study of TB cases reported to CDC from 1993 through 1996, the risk of drug-resistant TB was higher among persons with known HIV infection compared with others (13 ). During this 4-year period, among U.S.-born persons aged 25-44 years with TB, HIV test results were reported as positive for 32% of persons, negative for 23%, and unknown for 45%. Using univariate analysis that excluded patients known to have had a previous episode of TB, investigators found that patients known to be HIV seropositive had a significantly higher rate of resistance to all first-line antituberculosis drugs, compared with HIV-seronegative patients and patients with unknown HIV serostatus (Table 2). Moreover, using a multivariate model that included age, history of previous TB, birth country, residence in New York City, and race/ethnicity, the investigators confirmed HIV-positive serostatus as a risk factor for resistance to at least isoniazid, for both isoniazid and rifampin resistance (multidrug-resistant [MDR] TB) and for rifampin monoresistance (TB resistant to rifampin only). In some areas of the United States with a low level of occurrence of MDR TB, however, differences in MDR TB related to HIV status have not been found (8 ). Reasons for the increased risk for TB drug resistance among HIV-seropositive persons might reflect a higher proportion of TB disease resulting from recently acquired M. tuberculosis infection (14,15 ) and thus an increased risk of disease caused by drug-resistant strains in areas with high community and institutional transmission of drug-resistant strains of M. tuberculosis (16 ). Several well-described outbreaks of † The patient's Mycobacterium tuberculosis isolate had resistance to at least the specified drug but may have had resistance to other drugs as well. § The differences in drug-resistance rates among patients with TB known to be HIV-seropositive, compared with those known to be HIV-seronegative or of unknown status, are statistically significant (Chi-square test statistic, p<0.05). ¶ These figures were calculated for patients with M. tuberculosis isolates tested for isoniazid and rifampin always and streptomycin sometimes. Monoresistant isolates were resistant to rifampin but susceptible to the other first-line drugs tested. Source: CDC, National Tuberculosis Surveillance System. nosocomially transmitted MDR TB, primarily affecting persons with AIDS, support this association (17)(18)(19)(20)(21).\nIn the past decade, reports have increased of TB caused by strains of M. tuberculosis resistant to rifampin only, and growing evidence has indicated that this rare event is associated with HIV coinfection (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). In retrospective studies, nonadherence with TB therapy has been associated with acquired rifampin monoresistance (22)(23)(24); and among a small number of patients, the use of rifabutin as prophylaxis for Mycobacterium avium complex was associated with the development of rifamycin resistance (31 ). However, the occurrence of TB relapse with acquired rifampin monoresistance also has been documented among patients with TB who initially had rifampin-susceptible isolates and who were treated with a rifampin-containing TB regimen by directly observed therapy (DOT) (30,32 ). The mechanisms involved in the development of acquired rifampin monoresistance are not clearly understood but could involve the persistence of actively multiplying mycobacteria in patients with severe cellular immunodeficiency, selective antituberculosis drug malabsorption, and inadequate tissue penetration of drugs.\nThus, of critical importance for HIV-infected persons is implementation of TB prevention and control strategies such as a) appropriate use of therapy for latent M. tuberculosis infection, b) early diagnosis and effective treatment of active TB (i.e., administering four-drug antituberculosis regimens by DOT to all coinfected patients), and c) prompt compliance with requirements for reporting TB cases and drug-susceptibility test results. Implementing these strategies for persons coinfected with HIV will not only help reduce new cases of TB in general; it also could decrease further transmission of drug-resistant strains and new cases of drug-resistant TB.\n# Copathogenicity of TB and HIV Disease\nHuman immunodeficiency virus type 1 (HIV-1) and M. tuberculosis are two intracellular pathogens that interact at the population, clinical, and cellular levels. Initial studies of HIV-1 and TB emphasized the impact of HIV-1 on the natural progression of TB, but mounting immunologic and virologic evidence now indicates that the host immune response to M. tuberculosis enhances HIV replication and might accelerate the natural progression of HIV infection (33 ). Therefore, the interaction between these two pathogens has important implications for the prevention and treatment of TB among HIV-infected persons. Studies of the immune response in persons with TB disease support the biologic plausibility of copathogenesis in dually infected persons. The initial interaction between the host immune system and M. tuberculosis occurs in the alveolar macrophages that present mycobacterial antigens to antigen-specific CD4+ T cells (34 ). These T cells release interferon-gamma, a cytokine that acts at the cellular level to activate macrophages and enhance their ability to contain mycobacterial infection. The activated macrophages also release proinflammatory cytokines, such as tumor necrosis factor and interleukin (IL)-1, cytokines that enhance viral replication in monocyte cell lines in vitro (35)(36)(37)(38). The mycobacteria and their products also enhance viral replication by inducing nuclear factor kappa-B, the cellular factor that binds to promoter regions of HIV (39,40 ).\nWhen TB disease develops in an HIV-infected person, the prognosis is often poor, though it depends on the person's degree of immunosuppression and response to appropriate antituberculosis therapy (41)(42)(43). The 1-year mortality rate for treated, HIV-related tuberculosis ranges from 20% to 35% and shows little variation between cohorts from industrialized and developing countries (44)(45)(46)(47)(48)(49). The observed mortality rate for HIV-infected persons with TB is approximately four times greater than the rate for TB patients not infected with HIV (44,46,49,50 ). Although the cause of death in the initial period of therapy can be TB (46 ), death after the induction phase of antituberculosis therapy usually is attributed to complications of HIV other than TB (45,51,52 ). Epidemiologic data suggest that active TB accelerates the natural progression of HIV infection. In a retrospective cohort study of HIV-infected women from Zaire, investigators estimated the relative risk of death to be 2.7 among women with active TB compared with those without TB (53 ). In a retrospective cohort study of HIV-infected subjects from the United States, active TB was associated with an increased risk for opportunistic infections and death (54 ). The risk of death, or hazard rate, for persons with HIV-related TB follows a bimodal distribution, peaking within the first 3 months of antituberculosis therapy and then again after 1 year (48 ); the reasons for this distribution are not clear but might relate to the impact of TB on HIV disease progression. The observation that active TB increases deaths associated with HIV infection has been corroborated in studies of three independent cohorts in Europe (55)(56)(57).\nEarly in the HIV epidemic, researchers postulated that the immune activation resulting from concurrent infection with parasitic or bacterial pathogens might alter the natural progression of HIV infection (58 ). Subsequent observations have demonstrated that immune activation from TB enhances both systemic and local HIV replication. In some patients with active TB, the plasma HIV RNA level rises substantially before TB is diagnosed (59 ). Moreover, TB treatment alone leads to reductions in the viral load in these dually infected patients. TB and HIV also interact in the lungs, the site of primary infection with M. tuberculosis. In a recently published study of HIVinfected patients with TB, researchers found that the viral load was higher in the bronchoalveolar lavage fluid from the affected versus the unaffected lung and was correlated with levels of tumor necrosis factor in bronchoalveolar fluid (60 ). Researchers used V3 loop viral sequences to construct a phylogenetic tree and observed that the HIV quasispecies from the affected lung differed from those in the plasma within the same patient. These data suggest that pulmonary TB might act as a potent stimulus for the cellular-level replication of HIV. In summary, recent research findings have improved clinicians' understanding of how HIV affects the natural progression of TB and how TB affects the clinical course of HIV disease, and these findings support the recommendation for prevention, early recognition, and effective treatment for both diseases.\n# TB Therapy Outcomes Among Patients with HIV-Related TB\nAmong patients treated for TB, early clinical response to therapy and the time in which M. tuberculosis sputum cultures convert from positive to negative appear to be similar for those with HIV infection and those without HIV infection (30,61,62 ). However, the data are less clear about whether rates of TB relapse (recurrence of TB following successful completion of treatment) differ among patients with or without HIV infection (63 ). Current CDC and American Thoracic Society guidelines recommend a 6-month treatment regimen for drug-susceptible TB disease for patients coinfected with HIV (2 ) but suggest prolonged treatment for patients who have a delayed clinical and bacteriologic response to antituberculosis therapy. Some experts have suggested that to ensure an optimal antituberculosis treatment outcome, all patients with HIV-related TB should be treated with a longer course of therapy (i.e., 9 months), regardless of evidence of early response to therapy (64,65 ).\nTo make a recommendation on duration of therapy for HIV-related TB, expert consultants at the September 1997 CDC meeting considered the results of prospective studies that ascertained the posttreatment relapse rate following 6-month TB therapy regimens among patients with HIV infection (Table 3) (29,30,49,66,67 ). Differences in the study designs, including those pertaining to eligibility for enrollment in the study and to the definition of TB relapse, limited the analysis of combined results from the five studies. Despite this limitation, the expert consultants were able to make the following observations: a) the studies had a posttreatment follow-up duration that ranged from 8 to 22 months (median duration: 18 months); b) in three studies (30,49,67 ), investigators found that 6-month TB regimens were associated with a clinically acceptable (≤5.4%) TB relapse rate; and c) in two studies (29,66 ), researchers found a high (≥9%) TB relapse rate associated with the use of 6-month TB regimens.\nIn the Zaire study (66 ), TB patients coinfected with HIV had almost twofold higher posttreatment relapse rates than patients not infected with HIV who received the same TB treatment regimen; however, the authors did not investigate whether the relapses were the result of a recurrence of disease with the same strain of M. tuberculosis or reinfection (new disease) with a different strain. In the other study (29 ), which enrolled HIV-seropositive patients from 21 different sites in the United States, in all three patients who relapsed, the strain of M. tuberculosis isolated during the relapse episode matched, by DNA fingerprint, the strain of M. tuberculosis that was isolated during the initial episode of TB; this finding ruled out the possibility of reinfection.\nThe expert consultants who reviewed the available data agreed that short-course (i.e., 6-month) regimens should be used for the treatment of HIV-related pansusceptible TB (i.e., susceptible to all first-line antituberculosis drugs) in the United States, where patients are usually treated with DOT and where response to antituberculosis daily induction regimen followed by a continuation regimen of 4-month intermittent isoniazid and rifampin.\nThe exceptions are that a) ethambutol was not used during the induction phase in Côte d'Ivoire, and b) half of patients in one of the U.S. studies (30 ) received levofloxacin in addition to the other four drugs during the induction phase. During the continuation phase, patients in Côte d'Ivoire received drugs daily, patients in Haiti received drugs three times a week, and patients in all other studies received drugs twice a week. † Also in this study, 51 comparable patients with HIV-related TB were randomly assigned to a treatment arm in which the duration of the continuation phase was prolonged from 4 months to 7 months. The cultureconfirmed posttreatment relapse rate (2%) in this study arm was not significantly different from the rate in the 6-month study arm (p=1.00); however, an isolate was not available for DNA fingerprinting.\ndrugs can be monitored. This approach limits the use of lengthier multidrug antituberculosis therapies to the minimum possible number of patients with TB and HIV disease. Some experts believe the risk of TB treatment failure is increased among patients with advanced HIV-related immunosuppression and therefore advocate greater caution (or longer duration of therapy) when treating such patients for TB. The available data do not permit CDC to make a definitive recommendation regarding this issue. However, the experts recommended that clinicians treating TB in patients with HIV infection should consider the factors that increase a person's risk for a poor clinical outcome (e.g., lack of adherence to TB therapy, delayed conversion of M. tuberculosis sputum cultures from positive to negative, and delayed clinical response) when deciding the total duration of TB therapy.\n# Paradoxical Reactions Associated with Initiation of Antiretroviral Therapy During the Course of TB Therapy\nThe temporary exacerbation of TB symptoms and lesions after initiation of antituberculosis therapy -known as a paradoxical reaction -has been described as a rare occurrence (68)(69)(70)(71)(72)(73)(74) attributed to causes such as recovery of the patient's delayed hypersensitivity response and an increase in exposure and reaction to mycobacterial antigens after bactericidal antituberculosis therapy is initiated (75 ). Recently, a similar phenomenon was reported among patients with HIV-related TB (76 ). These reactions appear to be related more often to the concurrent administration of antiretroviral and antituberculosis therapy and occur with greater frequency than do paradoxical reactions associated primarily with the administration of antituberculosis therapy. Patients with paradoxical reactions can have hectic fevers, lymphadenopathy (sometimes severe), worsening of chest radiographic manifestations of TB (e.g., miliary infiltrates, pleural effusions), and worsening of original tuberculous lesions (e.g., cutaneous and peritoneal). However, these reactions are not associated with changes in M. tuberculosis bacteriology (i.e., no change from negative to positive culture and smear), and patients generally feel well and have no signs of toxicity.\nIn a prospective study, paradoxical reactions were more common among 33 patients with HIV-related TB who received TB treatment and combination antiretroviral therapy (36%) than among 55 patients not infected with HIV who received antituberculosis drugs alone (2%) and among 28 HIV-infected patients (historical control patients during pre-zidovudine era) who received antituberculosis drugs alone (7%) (76 ). Furthermore, among patients treated for both diseases, the paradoxical reactions were more temporally related to the initiation of combination antiretroviral therapy (mean +/-standard deviation [SD]: 15 +/-11 days afterward) than to the initiation of antituberculosis treatment (mean SD: 109 +/-72 days afterward). Researchers investigated potential causes for these symptoms and lesions (i.e., TB treatment failure, antituberculosis drug resistance, nonadherence with TB therapy, drug fever, development of conditions not related to TB or HIV) but considered such causes unlikely because these evaluations produced negative results, and TB was cured in patients who remained on unmodified antituberculosis regimens. Among patients in this study who received combination antiretroviral therapy, which usually included a protease inhibitor, the paradoxical reactions corresponded with a concurrent drop in HIV viral loads after antiretroviral therapy began and, in all but one patient, occurred while peripheral blood CD4+ T-cell counts were <200 cells/µL (76 ). In the historical control group (i.e., patients who were treated for TB but not for HIV), two (7%) of the 28 patients had a paradoxical reaction after antituberculosis therapy was initiated. This finding indicates that treatment of TB alone might sometimes decrease HIV viral load substantially and improve immune function (40,59,68,76 ).\nAfter reviewing information about paradoxical reactions occurring during the course of TB therapy, expert consultants at the September 1997 CDC meeting concluded that exacerbation of TB signs and symptoms in patients with HIV-related TB can occur soon after combination antiretroviral therapy is initiated. Clinicians should always conduct a thorough investigation to eliminate other etiologies before making a diagnosis of paradoxical treatment reaction. For patients with paradoxical reactions, rarely are changes in antituberculosis or antiretroviral therapy needed. If the lymphadenopathy or other lesions are severe, one option is to continue with appropriate antituberculosis therapy and administer short-term steroids that suppress the enhanced immune response.\nIn the prospective study (76 ), despite having low CD4+ T-cell counts, six (86%) of seven TB patients who were initially tuberculin skin-test (TST)-negative had positive TST results after combination antiretroviral therapy was started. The reaction sizes of postantiretroviral TSTs ranged from 7 to 67 mm of induration. Clinicians must be aware of the potential public health and clinical implications of restored TST reactivity among persons who have not been diagnosed with active TB but who might be latently infected with M. tuberculosis. Persons previously known to have negative TST results might benefit from repeat tuberculin testing if they have evidence of restored immune function after antiretroviral therapy is initiated, because TB preventive therapy is recommended for TST-positive HIV-infected persons.\n# Considerations for TB Therapy for HIV-Infected Patients Treated with Antiretroviral Agents Drug Interactions Between Rifamycins Used for TB Therapy and Antiretroviral Drugs Used for HIV Therapy\nWidely used antiretroviral drugs available in the United States include protease inhibitors (saquinavir, indinavir, ritonavir, and nelfinavir) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, delavirdine, and efavirenz). Protease inhibitors and NNRTIs have substantive interactions with the rifamycins (rifampin, rifabutin, and rifapentine) used to treat mycobacterial infections (3,77 ). These drug interactions principally result from changes in the metabolism of the antiretroviral agents and the rifamycins secondary to induction or inhibition of the hepatic cytochrome CYP450 enzyme system (78,79 ). Rifamycin-related CYP450 induction decreases the blood levels of drugs metabolized by CYP450. For example, if protease inhibitors are administered with rifampin (a potent CYP450 inducer), blood concentrations of the protease inhibitors (all of which are metabolized by CYP450) decrease markedly, and most likely the antiretroviral activity of these agents declines as well. Conversely, if ritonavir (a potent CYP450 inhibitor) is administered with rifabutin, blood concentrations of rifabutin increase markedly, and most likely rifabutin toxicity increases as well.\nOf the available rifamycins, rifampin is the most potent CYP450 inducer; rifabutin has substantially less activity as an inducer; and rifapentine, a newer rifamycin, has intermediate activity as an inducer (80)(81)(82). The four currently approved protease inhibitors and amprenavir (141W94, an investigational agent in Phase III clinical trials) are all, in differing degrees, inhibitors of CYP450 (83,84 ). The rank order of the agents in terms of potency in inhibiting CYP450 is ritonavir (the most potent); amprenavir, indinavir, and nelfinavir (with approximately equal potencies); and saquinavir (the least potent). The magnitude of the effects of coadministering rifamycins and protease inhibitors has been evaluated in limited pharmacokinetic studies (Table 4) (85)(86)(87)(88)(89)(90)(91). The three approved NNRTIs have diverse effects on CYP450: nevirapine is an inducer, delavirdine is an inhibitor, and efavirenz is both an inducer and an inhibitor. The magnitude of the effects of coadministering rifamycins and NNRTIs has also been evaluated in pharmacokinetic studies or has been predicted on the basis of what is known about their potential for inducing or inhibiting CYP450 (Table 5) (92)(93)(94)(95)(96).\nIn contrast to the protease inhibitors and the NNRTIs, the other class of antiretroviral agents available, nucleoside reverse transcriptase inhibitors (NRTIs) (zidovudine, didanosine, zalcitabine, stavudine, and lamivudine) are not metabolized by CYP450. Rifampin (and to a lesser degree, rifabutin) increases the glucuronidation of zidovudine and thus slightly decreases the serum concentration of zidovudine (97)(98)(99)(100). The effect of this interaction probably is not clinically important, and the concurrent use of NRTIs and rifamycins is not contraindicated (77 ). Also, no contraindication exists for the use of NRTIs, NNRTIs, and protease inhibitors with isoniazid, pyrazinamide, ethambutol, or streptomycin. These first-line antituberculosis medications, in contrast to the rifamycins, are not CYP450 inducers.\n# Coadministration of Antituberculosis and Antiretroviral Therapies\nAccording to 1998 U.S. Department of Health and Human Services guidelines on the use of antiretroviral agents among HIV-infected adults and adolescents (4 ), to improve the length and quality of patients' lives, all persons with symptomatic HIV infection should be offered antiretroviral therapy. HIV-infected patients with TB fall in this category. When used appropriately, combinations of potent antiretroviral agents can effect prolonged suppression of HIV replication and reduce the inherent tendency of HIV to generate drug-resistant viral strains. However, as antiretroviral therapeutic regimens have become increasingly effective, they also have become increasingly complex in themselves as well as in the problems they cause for the treatment of other HIV-associated diseases.\nAt present, regimens that include two NRTIs combined with a potent protease inhibitor (or, as an alternative, combined with an NNRTI) are the preferred choice for combination antiretroviral therapy for the majority of patients. Each of the antiretroviral drug combination regimens must be used according to optimum schedules and doses (4 ) because the potential for resistant mutations of HIV decreases if serum concentrations of the multiple antiretroviral drugs are maintained steadily. Because rifampin markedly lowers the blood levels of these drugs and is likely to result in suboptimal antiretroviral therapy, the use of rifampin to treat active TB in a patient who is taking a protease inhibitor or an NNRTI is always contraindicated. Rifabutin is a less potent inducer of the CPY450 cytochrome enzymes than is rifampin and, when used in appropriately modified doses, might not be associated with a clinically significant reduction of protease inhibitors or nevirapine (Table 6). Thus, the substitution of rifabutin for rifampin in TB treatment regimens has been proposed as a practical * Effects are expressed as a percentage change in AUC of the concomitant treatment relative to that of the drug-alone treatment. No data are available regarding the magnitude of these bidirectional interactions when rifamycins are administered two or three times a week instead of daily. † Predicted effect based on knowledge of metabolic pathways for the two drugs.\n# TABLE 6. Feasibility of using different antiretroviral drugs and rifabutin\n\n# Antiretroviral agent\n\n# Can be used in combination with rifabutin? Comments\nSaquinavir (soft-gel formulation)\nProbably Use of the soft-gel formulation (Fortovase™) in higher-than-usual doses might allow adequate serum concentrations of this drug despite concurrent use of rifabutin.* However, the pharmacokinetic data for this combination are limited in comparison with other protease inhibitors. Because of the expected low bioavailability of the hard-gel formulation (Invirase™) the concurrent use of this agent with rifabutin is not recommended.\n# Ritonavir\nNo Ritonavir increases concentrations of rifabutin by 35-fold and results in increased rates of toxicity (arthralgia, uveitis, skin discoloration, and leukopenia). These adverse events have been noted in studies of high-dose rifabutin therapy, when rifabutin is administered with clarithromycin (another CYP450 inhibitor) -an indication that these events might result from high serum concentrations of rifabutin.\n# Indinavir\n\n# Yes\nData from drug interaction studies (unpublished report, Merck Research Laboratories, West Point, PA, 1998) suggest that the dose of indinavir should be increased from 800 mg every 8 hours to 1,200 mg every 8 hours if used in combination with rifabutin.*\n# Nelfinavir\nYes Some clinical experts suggest that the dose of nelfinavir should be increased from 750 mg three times a day to 1,000 mg three times a day if used in combination with rifabutin.*\n# Amprenavir\n\n# Probably\nThe drug interactions between amprenavir and rifabutin (and thus potential for rifabutin toxicity) are reported to be similar to those of ritonavir with rifabutin. However, potential advantages of using this combination are that a) rifabutin has a minimal effect on reducing the levels of amprenavir and b) even though it has not been studied, rifabutin toxicity is not expected if the daily dose of rifabutin is reduced when used in combination with amprenavir.\n# NRTIs †\nYes Not expected to have clinically significant interaction.\n# Nevirapine\nYes Not known whether nevirapine or rifabutin dose adjustments are necessary when these drugs are used together.*\n# Delavirdine\nNo Not recommended on the basis of marked decreases in concentrations of delavirdine when administered with rifamycins.\n# Efavirenz\nProbably Newly approved agent. Preliminary drug interaction studies suggest that when rifabutin is used concurrently with efavirenz, the dose of rifabutin for both daily and twice weekly administration should be increased from 300 mg to 450 mg.\n*Daily dose of rifabutin should be reduced from 300 mg to 150 mg if used in combination with amprenavir, nelfinavir, or indinavir. It is unknown whether the dose of rifabutin should be reduced if used in combination with saquinavir (Fortovase™) or nevirapine. † Nucleoside reverse transcriptase inhibitiors, including zidovudine, didanosine, zalcitabine, stavudine, and lamivudine. choice for patients who are also undergoing therapy with protease inhibitors (with the exception of ritonavir [86,87,[101][102][103] or hard-gel capsule saquinavir [Invirase ™ (85 )]) or with the NNRTIs nevirapine or efavirenz (but not delavirdine [93,94 ]). Currently, more clinical and pharmacokinetic data are available on the use of indinavir or nelfinavir with rifabutin than on the use of amprenavir or soft-gel saquinavir (Fortovase™) with rifabutin. Rifapentine is not recommended as a substitute for rifampin because its safety and effectiveness have not been established for the treatment of patients with HIV-related TB. As an alternative to the use of rifamycin for the treatment of TB, the use of streptomycin-based regimens that do not contain rifamycin can be considered for the treatment of TB in patients undergoing antiretroviral therapy with protease inhibitors or NNRTIs.\n# Use of Rifabutin-Based Regimens for the Treatment of HIV-Related TB\nAt present, TB drug regimens that include rifabutin instead of rifampin appear to offer the best alternative for the treatment of active TB among patients taking antiretroviral therapies that include protease inhibitors or NNRTIs. This recommendation is based on findings from studies of equivalent in vitro antituberculosis activity of rifabutin and rifampin (104,105 ) and the results of three clinical trials (106)(107)(108). These trials demonstrated that 6-month rifabutin-containing regimens (at a daily dose of either 150 mg or 300 mg) were as effective and as safe as similar control regimens containing rifampin for the treatment of TB (Table 7). The smallest (n=49) of these three trials was conducted in Uganda (108 ) and is the only one to include HIVcoinfected patients (who were not undergoing antiretroviral therapy at the time of the study). This study indicated that 81% of patients taking a TB treatment regimen containing daily rifabutin converted their sputum from M. tuberculosis positive to negative after 2 months of treatment, compared with a 48% sputum conversion rate among patients taking a TB regimen containing daily rifampin (p<0.05). However, when the researchers controlled for differences in baseline characteristics (a greater proportion of patients in the rifampin group had cavitary disease), they found no difference in the time to sputum conversion between the two study groups.\nStudies are under way to evaluate the use of rifabutin administered daily (at a dose of 150 mg) or twice a week (at a dose of 300 mg) for the treatment of TB in HIV-infected patients who take protease inhibitors. Physicians at a state tuberculosis hospital in Florida have treated or consulted on the treatment of approximately 30 HIV-infected patients who received a protease inhibitor while undergoing treatment for TB with rifabutin. Patients have been treated for TB primarily with administration of rifabutin (150 mg daily) as part of four-drug therapy for 2-4 weeks, followed by rifabutin (300 mg twice weekly) as part of four-drug therapy to complete 8 weeks of induction, and then a continuation phase consisting of twice-weekly isoniazid and rifabutin (300 mg) to complete 6 months of treatment. To date, patients treated with this regimen have not experienced clinically significant increases in rifabutin serum levels, have had a minimal incidence of adverse reactions from rifabutin (one patient developed a case of uveitis), and have had a good clinical response to TB and HIV therapies. Approximately 80% of the patients attained sputum conversion by the second month of treatment, most have attained and maintained suppression of HIV replication, and no TB relapses have occurred with up to 1 year of posttreatment follow-up (David Ashkin, M.D., and Masahiro Narita, M.D., A.G. Holley State Tuberculosis Hospital, Lantana, Florida, personal communication, 1998).\nIn previous reports, CDC and the American Thoracic Society jointly recommended the use of rifampin-containing short-course regimens for the initial treatment of HIVrelated TB (2 ). The inclusion of rifampin in regimens to treat TB was supported by data collected from approximately 90 controlled clinical trials conducted from 1968 to 1988 (109 ). Excluding rifampin from the TB treatment regimen was not recommended because regimens not containing rifampin a) had not been proven to have acceptable efficacy (i.e., have been associated with higher rates of TB treatment failure and death and with slower bacteriologic responses to therapy leading to potential increases in the likelihood of M. tuberculosis transmission) and b) require prolonging duration of therapy from 6 months to 12-15 months. Presently, available data suggest that rifabutin in short-course (i.e., 6 months) multidrug regimens to treat TB provides the same benefits as the use of rifampin. Three additional reasons support the use of rifabutin for treating HIV-related TB: a) observations suggest that rifabutin might be more reliably absorbed than rifampin in patients with advanced HIV disease (110,111 ); b) the use of rifabutin appears to have been better tolerated in patients with rifampininduced hepatotoxicity (David Ashkin, M.D., and Masahiro Narita, M.D., A.G. Holley State Tuberculosis Hospital, Lantana, Florida, personal communication, 1998); and c) the use of rifabutin might lessen the possibility of interactions with other medications commonly prescribed for patients with HIV infection (e.g., azole antifungal drugs, anticonvulsant agents, and methadone) (77 ).\n# Use of Alternative TB Treatment Regimens that Contain Minimal or No Rifamycin\nTB treatment regimens that contain no rifamycins have been proposed as an alternative for patients who take protease inhibitors or NNRTIs. Several clinical trials conducted in Hong Kong and Africa by the British Medical Research Council and published from 1974 through 1984 provide information about nonrifamycin and minimal-rifamycin regimens for the treatment of TB in patients who were not likely to be infected with HIV (Table 8) (112)(113)(114)(115). Most of these studies demonstrated high relapse rates when regimens not containing streptomycin were used and when the duration of therapy was less than 9 months. However, in a large (n=404) randomized controlled clinical trial in Hong Kong that evaluated the use of six TB treatment regimens consisting of streptomycin, isoniazid, and pyrazinamide either daily, three times a week, or two times a week for 6 or 9 months (112 ), almost all patients treated with any of the study regimens achieved rapid sputum conversions (86%-94% of patients converted within 3 months of therapy). In this study, the 30-month posttreatment follow-up relapse rates were high (18%-24%) among patients treated with 6-month regimens, but the relapse rates among patients treated with 9-month regimens (5%-6%) were similar to the relapse rates expected following the use of rifampin-based TB treatments. Thus, the expert consultants who developed these guidelines concluded that treatment of TB without rifamycin always requires longer-duration (at least 9 months) regimens that include streptomycin (or an injectable antituberculosis drug such as capreomycin, amikacin, or kanamycin) (63 ). However, these TB regimens have not been studied among patients with HIV infection. Streptomycin is highly bactericidal against M. tuberculosis, but it is rarely used in the United States to treat drug-susceptible TB because of problems associated with its administration by injection that can be intensified in patients with low body mass or wasting and because of potential ototoxicity and nephrotoxicity. The associated potential toxicities and increased duration of therapy and the patient's difficulty in adhering to an injectable-drug-based TB regimen can compromise the effectiveness of streptomycin-based TB regimens, and these limitations should be considered by physicians and patients.\n# Treatment of Latent M. tuberculosis Infection in Patients with HIV Infection Scientific Rationale\nPreventive therapy for TB is essential to controlling and eliminating TB in the United States (116,117 ). Treatment for HIV-infected persons who are latently infected with M. tuberculosis is an important part of this strategy and is also an important personal health intervention because of the serious complications associated with active TB in HIV-infected persons (118)(119)(120). Expert consultants attending the September 1997 CDC meeting and additional consultants attending a September 1998 meeting sponsored by the American Thoracic Society and CDC considered findings from multiple studies (121)(122)(123)(124)(125)(126)(127)(128)(129)(130) before developing recommendations about the optimal duration of isoniazid preventive therapy regimens; frequency of administration (intermittency) of preventive therapy; new short-course multidrug regimens; and preventive therapy for anergic HIV-infected adults with a high risk of M. tuberculosis infection.\nA key difference in most preventive therapy trials conducted before and after the beginning of the HIV epidemic is that the earlier trials focused on 12-month regimens of isoniazid, whereas five of seven trials (122)(123)(124)(125)(126) conducted in HIV-infected populations assessed 6-month regimens of isoniazid (Table 9). Four of these 6-month isoniazid regimens (122)(123)(124)(125) were chosen for study on the basis of the operational feasibility of providing therapy in countries with limited resources where preventive therapy programs were not available; the fifth study (126 ), a U.S. trial conducted among anergic patients, used a 6-month regimen because of the absence of previous data about optimal duration of therapy for TST-negative, HIV-infected patients. Despite these variations, the expert consultants concluded that the findings from these different preventive therapy studies should apply to most persons with latent M. tuberculosis infection, regardless of their HIV serostatus, because similar levels of protection have been observed when identical preventive therapy regimens have been administered to persons infected with HIV and those not infected.\n# Optimal Duration of Isoniazid Regimens for Treatment of Latent M. tuberculosis Infection\nThe American Thoracic Society and CDC have previously recommended a regimen of 12 months of isoniazid alone for treatment of latent M. tuberculosis infection in HIV-infected adults (2 ). The recommended duration of TB preventive therapy for persons not infected with HIV was a minimum of 6 months. When considering the optimal duration of isoniazid preventive therapy, the consultants reviewed findings from two studies conducted in populations not known to be infected with HIV (128,129 ). One of these studies, a controlled trial conducted in seven European countries, compared the efficacy of three durations (3, 6, and 12 months) of isoniazid preventive treatment for TST-positive persons with stable, fibrotic lesions on chest radiographs (128 ). In this study, compliant patients who received medication for 12 months had better protection against TB (93%) than those who received medication for 6 months (69%). The other study was conducted among the Inuits in the Bethel area of Alaska, where participants received 0-24 months of isoniazid preventive therapy (129 ). In an assessment of observed posttherapy case rates of TB relative to the amount of isoniazid ingested (expressed as a percentage of a 12-month regimen), researchers found that higher amounts of therapy corresponded with lower TB rates among participants who had received 0-9 months of isoniazid therapy; after 9 months of therapy, participants had no additional benefits in terms of decreased TB case rates.\nFour studies of HIV-infected persons have evaluated 6-month and 12-month regimens of daily isoniazid (121,123,125,127 ). Both of the studies that evaluated a 6-month regimen included a placebo comparison group and demonstrated reductions in the incidence of TB among persons in the treatment group -70% in Uganda (123 ) and 75% in Kenya (125 ). A study of the 12-month regimen (121 ), which was conducted in Haiti and also included a placebo comparison group, demonstrated an 83% reduction in the incidence of TB among persons in the treatment group. A multicenter trial conducted in the United States, Mexico, Brazil, and Haiti (127 ) demonstrated that the magnitude of protection obtained from a regimen of isoniazid administered daily for 12 months was similar to that obtained from a regimen of rifampin and pyrazinamide administered daily for 2 months. Isoniazid preventive therapy regimens of 6 and 12 months' duration have not been compared with each other in the same study conducted among HIV-infected persons. In summary, these data indicate that a) the optimal duration of isoniazid preventive therapy should be >6 months to provide the maximum degree of protection against TB; b) therapy for 9 months appears to be sufficient; c) therapy for >12 months does not appear to provide additional protection.\n# Frequency of Administering Isoniazid Preventive Therapy\nTwo clinical trials (122,124 ) have evaluated 6-month twice-weekly isoniazid regimens for the prevention of active TB in HIV-infected persons (Table 9). Participants enrolled in the twice-weekly 6-month isoniazid arm of a study conducted in Zambia had a 40% reduction in the rate of TB compared with persons who took a placebo for 6 months (124 ). The findings of a trial conducted in Haiti (122 ) suggest that the magnitude of protection obtained from isoniazid administered twice a week for 6 months is equivalent to that obtained from rifampin and pyrazinamide regimens administered twice a week for 2 months. Preventive therapy trials that include twice-weekly isoniazid regimens for >6 months or comparisons of the same drugs administered daily versus intermittently have not been conducted. However, in a Baltimore demonstration project in which isoniazid was administered twice a week (10-15 mg/kg, with a maximum dose of 900 mg) to a cohort of injecting-drug users under directly observed preventive therapy (DOPT), the findings support the efficacy of twice-weekly isoniazid preventive therapy (130 ). Twice-weekly regimens with DOPT were used in Baltimore because the project staff expected that supervised delivery of therapy would enhance adherence with and completion of the preventive therapy regimen. Thus, the available data suggest that the protection obtained from isoniazid preventive therapy regimens should be the same whether the drug is administered daily or twice a week.\n# Short-Course Multidrug Regimens for TB Preventive Therapy\nFour clinical trials (122)(123)(124)127 ) conducted among HIV-infected populations have evaluated courses of preventive therapy that are shorter than 6 months and that include rifampin in combination with isoniazid or pyrazinamide (Table 9). The largest and most recent of these trials was a multicenter, randomized TB prevention study conducted from 1992 through 1998 (127 ). Researchers found identical rates of TB (1.2 per 100 person-years) in two groups of TST-positive, HIV-infected persons: those who primarily self-administered isoniazid daily for 12 months and those who primarily self-administered rifampin and pyrazinamide daily for 2 months. Both study groups had similar adverse events and mortality rates; persons taking rifampin and pyrazinamide for 2 months were significantly more likely (80%) to complete therapy than were persons taking isoniazid for 12 months (68%) (p<0.001). Two other trials conducted in Haiti and Zambia (122,124 ) have also evaluated regimens of rifampin and pyrazinamide for the prevention of TB but have not included comparison arms of 12month isoniazid regimens. The study in Haiti ( 122) compared patients receiving rifampin and pyrazinamide administered twice a week for 2 months with patients receiving isoniazid twice a week for 6 months; in both arms of the study, one of the twice-weekly doses was administered by DOPT. Investigators observed no difference in TB risk or mortality among participants enrolled in the two treatment arms (122 ). The placebo-controlled trial in Zambia demonstrated comparable protection from 3 months of rifampin and pyrazinamide versus 6 months of isoniazid; both regimens were self-administered twice a week (124 ). In the multicenter trial (127 ) and in the Haiti and Zambia studies (122,124 ), regimens that included rifampin and pyrazinamide were well tolerated. In a study conducted in Uganda (123 ), investigators observed no statistically significant reduction in TB rates but a high rate of toxicity and drug intolerance among persons who took three drugs (isoniazid, rifampin, and pyrazinamide) daily for 3 months compared with persons who took a placebo (Table 9); 3 months of daily self-administered rifampin and isoniazid provided protection similar to that of 6 months of daily self-administered isoniazid. Thus, short-course multidrug regimens (i.e., two drugs for 2-3 months) have been shown to be effective for the prevention of active TB in HIV-infected persons. The use of three drugs for preventive therapy, however, can be associated with unacceptably high rates of toxicity, and the use of a 3-month regimen of rifampin and isoniazid is not being considered for use in the United States. Available data indicate that in the United States, a regimen of rifampin and pyrazinamide administered daily for 2 months is a reasonable treatment option for HIV-infected adults with latent M. tuberculosis infection. The available data do not permit CDC to make a definitive statement regarding the intermittent (i.e., twice a week) administration of a 2-month regimen of rifampin and pyrazinamide.\n# Preventive Therapy for Anergic HIV-Infected Adults with a High Risk of Latent M. tuberculosis Infection\nIsoniazid preventive therapy has not been found to be useful or cost-effective in preventing TB when administered to anergic, HIV-infected persons (123,126 ) (Table 9). The anergic subjects who received isoniazid in the Uganda trial had a statistically insignificant (17%) reduction in the rate of TB (2.5 cases per 100 person-years) compared with patients in the placebo group (3.1 cases per 100 person-years) (123 ). Similarly, anergic HIV-infected persons with a high risk for tuberculous infection who were enrolled in a U.S. multicenter trial and treated with isoniazid daily for 6 months had a rate of TB (0.4 cases per 100 person-years) that was 50% less than, but not statistically different from, the rate observed among patients treated with placebo (0.9 cases per 100 person-years) (126 ). In both of these studies, HIV-infected persons with anergy tolerated isoniazid well, as suggested by the low rates of adverse reactions and high rates of therapy completion. These study findings do not support the routine use of preventive therapy in anergic, HIV-infected persons. Preventive therapy for TST-negative, HIV-infected persons also has not been proven effective (121,124, 125 ) (Table 9); however, some experts recommend primary preventive therapy (to prevent M. tuberculosis infection) for TST-negative or anergic HIV-infected residents of institutions that pose an ongoing high risk for exposure to M. tuberculosis (e.g., prisons, jails, homeless shelters).\n# Implications of Results of TB Preventive Therapy Trials\nThe effects of TB preventive therapy on mortality and progression of HIV infection appear to be limited, with the exception that such therapy can protect against the development of TB disease and its associated consequences. Moreover, the duration of this protective effect has not been clearly established for HIV-infected persons. Despite these limitations and uncertainties, preventive therapy is recommended because its benefits in preventing TB disease are thought to be greater than the risks of serious treatment-related adverse events, and such therapy benefits society by helping to prevent the spread of infection to other persons in the community.\nThe implementation of TB preventive therapy programs should be facilitated by the use of newly recommended short-course multidrug regimens and twice-weekly isoniazid regimens, especially among patients for whom DOPT is feasible. Because of the drug interactions between rifampin and protease inhibitors or NNRTIs, the use of shorter regimens containing rifampin is contraindicated for patients taking these antiretroviral drugs. Although preventive therapy trials evaluating rifabutin use among TST-positive, HIV-infected persons have not been conducted, the expert consultants reviewed available data and agreed that the use of rifabutin instead of rifampin is valid on the basis of the same scientific principles that support the use of rifabutin for the treatment of active TB.\n# PART II. RECOMMENDATIONS\nThis section of the report provides clinicians with recommendations for diagnosing, treating, and preventing TB among persons coinfected with HIV while concurrently promoting optimal antiretroviral care for these patients. The recommendations reflect the current state of knowledge regarding the use of antiretroviral agents, but this field of science is rapidly evolving. As new antiretroviral agents and new data regarding existing agents alter therapeutic options and preferences for antiretroviral therapy, these changes might affect future recommendations for the treatment of TB infection and disease among patients coinfected with HIV and the treatment of HIV infection among persons with TB. Expert consultants updated these recommendations after a September 1997 CDC meeting, where they reviewed and considered available information about the scientific principles of therapy for TB and HIV.\nTo help clinicians make informed treatment decisions based on the most current research results, the expert consultants have given the recommendations evidencebased ratings (general recommendations have no rating). The ratings include a letter and a Roman numeral (Table 10), similar to the ratings used in previously issued guidelines (4,5 ). The letter indicates the strength of the recommendation, and the Roman numeral indicates the nature of the evidence supporting the recommendation. Thus, clinicians can use the ratings to differentiate between recommendations based on data from clinical trials versus those based on the opinions of experts familiar with the relevant clinical practice and scientific rationale for such practice (when clinical trial data are not available). However, these recommendations are not intended to substitute for the judgment of an expert physician. Management of HIV-related TB disease is complex, and clinical and public health consequences associated with treatment failure are serious. When possible, treatment of TB among HIV-infected persons should be directed by, or conducted in consultation with, a physician with extensive experience in the care of patients with these two diseases.\nThe objectives of implementing these recommendations are to reduce TB treatment failures, prevent drug-resistant TB, and diminish the adverse effects that TB has on HIV replication. Moreover, these guidelines contribute to efforts to control and eliminate TB from the United States by minimizing the likelihood of M. tuberculosis transmission, which will prevent the occurrence of new cases of TB. Multiple copies of this report and all updates are available from the Office of Communications, National \n# Active Tuberculosis Clinical and Public Health Principles\nPrompt initiation of effective antituberculosis treatment increases the probability that a patient with HIV infection who develops TB will be cured of this disease (45,131 ). TB treatment also quickly renders patients noninfectious (30 ), with the resulting reduction in the amount of M. tuberculosis transmitted to others, and it minimizes the patient's risk of death resulting from TB (41)(42)(43)132 ). Therefore, clinicians must immediately and thoroughly investigate the possibility of TB when a patient infected with HIV has symptoms consistent with TB. Persons suspected of having current TB disease should immediately be started on appropriate treatment, ideally with directly observed therapy (DOT) (133)(134)(135), and placed in TB isolation as necessary (136,137 ). Patients with TB and unknown HIV-infection status should be counseled and offered HIV testing. HIV-infected patients undergoing treatment for TB should be evaluated for antiretroviral therapy. Most patients with HIV-related TB are candidates for concurrent administration of antituberculosis and antiretroviral drug therapies (4 ).\nHealth-care providers, administrators, and TB controllers must strive to promote coordinated care for patients with TB and HIV and remove existing barriers to information-sharing between TB control programs and HIV/AIDS programs. TB control programs are responsible for setting TB treatment standards for physicians in the community, promoting the awareness and use of recommended TB infection-control practices, and enforcing state and local health department requirements concerning TB case notification and early reporting of drug-susceptibility test results. Because of the complexity of managing HIV-related TB disease and the serious public health consequences of mismanagement, care for persons with HIV-related TB should be provided by, or in consultation with, experts in the management of both TB and HIV disease.\n# Diagnosis of HIV-Related Tuberculosis\nThe typical signs and symptoms of pulmonary TB are cough with or without fever, night sweats, weight loss, and upper-lobe infiltrates with or without cavitation on chest x-rays. The diagnosis of TB for some HIV-infected patients might be difficult because TB in an immunocompromised host can be associated with atypical symptoms, a lack of typical symptoms, and a paucity of findings in chest x-rays (138-140 ). Among persons with AIDS, the diagnosis of TB also can be complicated by the presence of other pulmonary infections such as Pneumocystis carinii pneumonia and Mycobacterium avium complex disease and by the occurrence of TB in extrapulmonary sites. For patients with unusual clinical and radiographic findings, the starting point for diagnosing active TB often is a positive tuberculin skin test (TST). All patients with positive TSTs should be evaluated to rule out active TB (see Diagnosis of M. tuberculosis Infection Among HIV-Infected Persons). \n# Medical Evaluation of Patients Suspected of Having Active TB\n\n# Management of HIV-Infected Patients with Active TB Coadministration of TB Treatment and Antiretroviral Therapy\nThe following management strategies are for patients with HIV-related pulmonary TB a) who are not known to have or who do not have risk factors for multidrugresistant TB and b) for whom antiretroviral therapy is appropriate. When they first receive care for active TB disease, some patients might already be receiving antiretroviral therapy, whereas other patients might be newly diagnosed with HIV infection (Figure 1). For these newly diagnosed patients, in addition to the currently established recommendations for the immediate initiation of antituberculosis therapy, recently published guidelines (4 ) recommend the use of antiretroviral therapy. When treatments for HIV and TB disease are begun simultaneously, the optimal setting is one with experienced and coordinated care givers as well as accessible resources to provide a continuum of medical services (e.g., a reliable source of medications and social, psychosocial, and nutritional services). *Coadministration of rifabutin with ritonavir, saquinavir (Invirase™), or delavirdine is not recommended.\n# FIGURE 1. Recommended management strategies for patients with human immunodeficiency virus (HIV) infection and tuberculosis (TB) OBJECTIVE\nThe objective of this MMWR is to inform the reader of recommendations and guidelines for the diagnosis, treatment, and prevention of tuberculosis (TB) among patients with human immunodeficiency virus (HIV). These recommendations and guidelines are based on a meeting of expert consultants convened in September 1997 by CDC. These recommendations should guide clinical practice and policy development related to appropriate management of patients with or at risk for HIV-related TB. Upon completion of this educational activity, the reader should possess a clear working knowledge of the diagnosis, treatment, and prevention of TB among patients with HIV.\n# ACCREDITATION Continuing Medical Education (CME) Credit:\nThis activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) by CDC. CDC is accredited by the ACCME to provide continuing medical education for physicians. CDC awards 2.0 hours of category 1 credit toward the AMA Physician's Recognition Award for this activity.\n# Continuing Nursing Education (CNE) Credit:\nThis activity for 2.4 contact hours is provided by CDC, which is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC) Commission on Accreditation.\n# EXPIRATION -October 30, 1999\nThe response form must be completed and returned electronically, by fax, or by mail, postmarked no later than one year from the publication date of this report, for eligibility to receive continuing education credit. \n# INSTRUCTIONS\n\n# Recommendations and Reports\nTo receive continuing education credit, please answer all of the following questions:\n1. Which of the following statements are true? (Indicate all that are true.)\nA. Human immunodeficiency virus (HIV) infection accelerates the natural progression of tuberculosis (TB).\nB. Active TB accelerates the natural progression of HIV infection and disease.\nC. The mortality rate for HIV-infected persons with TB is four times greater than the rate for TB patients not infected with HIV.\nD. The toxicity associated with isoniazid TB preventive therapy significantly outweighs this therapy's benefits in preventing active TB in an HIV-infected person.\n2. Which of the following strategies are recommended for patients with TB taking protease inhibitors for HIV therapy? (Indicate all that are true.)\nA. Stop protease inhibitor therapy to allow the use of rifampin for TB treatment.\nB. Use an antituberculosis treatment regimen that includes rifabutin instead of rifampin.\nC. Ensure that experienced and coordinated TB/HIV care givers are available. D. Provide therapy for TB that is directly observed.\n# Which of the following strategies are recommended for HIV-infected patients with active TB\n? (Indicate all that are true.)\nA. Immediately and simultaneously begin treatment regimens that include a protease inhibitor for HIV therapy and drugs other than rifampin for antituberculosis therapy.\nB. Immediately and simultaneously begin treatment regimens that include a protease inhibitor for HIV therapy and rifampin for antituberculosis therapy.\nC. For patients who start antiretroviral therapy with a protease inhibitor, plan a 2-week period between the last dose of rifampin and the first dose of protease inhibitor.\nD. For patients who are not on antiretroviral therapy when TB is diagnosed, plan to start antiretroviral therapy at the end of the induction phase of TB therapy (8 weeks) or when TB therapy is completed.\n# When rifabutin is administered with indinavir, nelfinavir, or amprenavir, the recommended dosage of rifabutin is: (Choose the one correct answer.)\nA. 300 mg daily or 150 mg twice weekly.\nB. 300 mg daily or 300 mg twice weekly.\nC. 150 mg daily or 300 mg twice weekly.\nD. 150 mg daily or 150 mg twice weekly.\n# A paradoxical reaction during the course of TB and HIV treatment . . . (Indicate all that are true.)\nA. is a temporary exacerbation of symptoms and signs of TB in some patients who have restored immune function because of effective antiretroviral therapy.\nB. is always associated with a positive Mycobacterium tuberculosis culture.\nC. if suspected, calls for evaluating the patient to rule out other causes of the signs and symptoms (e.g., antituberculosis treatment failure).\nD. might require hospitalization and possibly time-limited use of corticosteroids (e.g., prednisone therapy) if the patient has severe or life-threatening clinical manifestations.\n6. When administered with rifamycins, which of the following drugs might require a dosage adjustment, the use of alternative therapies, or other changes because of drug interaction? (Indicate all that are true.) The following questions will assess your perceptions of the readability and applicability of the material.\nAnswer guide for questions 1-9 \n1\n# [ ]\nA [ ] B [ ] C [ ] D [ ] E [ ] F 2. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 3. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 4. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 5. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 6. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 7. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 8. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 9. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 10. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 11. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 12. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 13. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 14. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 15. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F 16. [ ] A [ ] B [ ] C [ ] D [ ] E [ ] F\nDetach or photocopy. Because of drug interactions, the use of rifampin to treat TB is not recommended for patients who a) will start treatment with an antiretroviral regimen that includes a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor (NNRTI) at the same time they begin treatment for TB (4 ) or b) have established HIV infection that is being maintained on such an antiretroviral regimen when TB is newly diagnosed and needs to be treated. Thus, two TB treatment options are currently recommended for these patients: a) a rifabutin-based regimen or b) an alternative nonrifamycin regimen that includes streptomycin (see Treatment Options for Patients with HIV Infection and Drug-Susceptible Pulmonary TB and Figure 1). Using a rifampin-based TB treatment regimen continues to be recommended for patients with HIV infection a) who have not started antiretroviral therapy, when both the patient and the clinician agree that waiting to start such therapy would be prudent or b) for whom antiretroviral management does not include a protease inhibitor or an NNRTI (4 ) (Figure 1).\n# BOX 1. Components of the medical evaluation for human immunodeficiency virus-infected patients suspected of having tuberculosis\nThe medical evaluation should include the following questions and assessments:\n# Medical History\n• Ask all patients about their history of tuberculosis (TB) treatment. If the patient has previously received treatment, care providers must determine the antituberculosis drugs used, duration of treatment, history of adverse reactions, reasons for discontinuation of treatment, history of adherence with treatment, and previous antituberculosis drugsusceptibility test results.\n• Question all patients about the following risk factors for drug-resistant TB: a) previous treatment for TB, especially if it was incomplete; b) previous residence in a country outside the United States where drug-resistant TB is common; c) close contact with a person who has drug-resistant TB or multidrug-resistant TB; and d) previous residence in an institution (i.e., hospital, prison, homeless shelter) with documented transmission of a drug-resistant strain of TB.\n• Ask all patients about their history of antiretroviral therapy and their history of therapies to prevent opportunistic infections. If the patient has previously or is currently receiving these treatments, care providers should determine the drugs used, duration of treatment, history of adverse reactions, and reasons for discontinuation of treatment if treatment ended.\n• Ask female patients whether they might be pregnant. Women of childbearing potential with menses more than 2 weeks late should receive a pregnancy test. (See TB Treatment for HIV-Infected Pregnant Women.)\n• When clinical specimens for culture and susceptibility testing cannot be obtained from patients (e.g., young children, patients with skeletal or meningeal TB), the culture and drug-susceptibility results of the Mycobacterium tuberculosis strain isolated from the infecting source-patient should be investigated and reviewed if available so that TB treatment for the current patient can be tailored appropriately. (See TB Treatment for HIV-Infected Children.)\n• If necessary, perform a Mantoux-method tuberculin skin test (TST) to help diagnose culture-negative TB.\nWhen determining the time to begin antiretroviral therapy for patients who are acutely ill with TB, clinicians and patients need to consider the existing clinical issues (e.g., drug interactions and toxicities, ability to adhere to two complex treatment regimens, and laboratory abnormalities). A staggered initiation of antituberculosis and antiretroviral treatments for patients not currently on antiretroviral therapy might promote greater adherence to the TB and HIV treatment regimens and reduce the associated drug toxicity of both regimens. This strategy might include starting antiretroviral therapy either at the end of the 2-month induction phase of TB therapy or after TB therapy is completed. When a decision is made to delay initiation of antiretroviral therapy, clinicians should monitor the patient's condition by measuring\n# BOX 1. Components of the medical evaluation for human immunodeficiency virus-infected patients suspected of having tuberculosis -Continued Chest X-Ray Examination\n• Perform a chest x-ray examination. HIV-related immunosuppression reduces the inflammatory reaction and cavitation of pulmonary lesions, and therefore HIV-infected patients with pulmonary TB can have atypical findings or normal chest x-rays. Children younger than age 5 years should undergo both a posterior-anterior and a lateral chest x-ray. All other persons should receive a posterior-anterior chest x-ray; additional chest x-ray examinations should be performed at the physician's discretion. Pregnant women who are being evaluated for active TB disease should undergo a chest x-ray (with the appropriate shielding) without delay, even during the first trimester of pregnancy. Patients suspected of having extrapulmonary TB should undergo a chest x-ray to rule out pulmonary TB.\n# Laboratory Tests\n• Collect smears for acid-fast bacilli, cultures, and drug susceptibilities from expectorated or induced sputum samples on 3 consecutive days, preferably in the mornings. Children who are unable to produce sputum spontaneously or who cannot use the sputum induction machine should be admitted to the hospital for early morning gastric aspirates on 3 consecutive, separate days.\n• Obtain a complete blood cell count, including platelets.\n• Conduct chemistry panel tests, especially for liver enzyme levels (serum glutamic oxalacetic transaminase or aspartate aminotransferase [SGOT/AST] and serum glutamic pyruvic transaminase or alanine aminotransferase [SGPT/ALT]); total bilirubin; uric acid; blood urea nitrogen; and creatinine.\n# Other Procedures\n• Perform a baseline visual acuity exam and test for red-green color perception for all patients who will be receiving ethambutol.\n• Perform baseline audiometry tests if an aminoglycoside (e.g, streptomycin, amikacin, kanamycin) or capreomycin will be administered.\n• Perform as necessary procedures such as bronchoscopies and bronchoalveolar lavage; biopsies and aspirates (e.g, of peripheral lymph nodes, visceral lymph nodes, liver, and bone marrow); mycobacterial culturing of nonrespiratory clinical specimens (e.g., blood, urine, pleural fluid); and radiologic evaluations other than chest x-rays (e.g., computerized tomographies, magnetic resonance imaging). plasma HIV RNA levels (viral load) and CD4+ T-cell counts and assessing the HIVassociated clinical condition at least every 3 months (4), because such information will assist in decisions regarding the timing for initiating such therapy. For some patients, switching from a rifampin-based TB regimen to either a rifabutin-based or a nonrifamycin-based TB regimen will be necessary if the decision is made to start antiretroviral therapy before completion of antituberculosis therapy. Clinicians and patients should be aware that the potent effect of rifampin as a CYP450 inducer (77,80), which lowers the serum concentration of protease inhibitors and NNRTIs, continues up to at least 2 weeks following the discontinuation of rifampin. Thus, they should consider planning for a 2-week period between the last dose of rifampin and the first dose of protease inhibitors or NNRTIs (see TB Drug Interaction and Absorption and Table 1A of Appendix).\n# Treatment Options for Patients with HIV Infection and Drug-Susceptible Pulmonary TB A.II\nDOT and other strategies that promote adherence to therapy should be used for all patients with HIV-related TB.\n# A.II\nFor patients who are receiving therapy with protease inhibitors or NNRTIs, the initial phase of a 6-month TB regimen consists of isoniazid, rifabutin, pyrazinamide, and ethambutol. These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment consists of isoniazid and rifabutin administered daily or twice a week for 4 months (see Six-month RFB-based therapy in Table 1A of Appendix).\n# B.II\nFor patients for whom the use of rifamycins is limited or contraindicated for any reason (e.g., intolerance to rifamycins, patient/clinician decision not to combine antiretroviral therapy with rifabutin), the initial phase of a 9-month TB regimen consists of isoniazid, streptomycin,* pyrazinamide, and ethambutol administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by twice-a-week dosing for 6 weeks, to complete the 2-month induction phase. The second phase of treatment consists of isoniazid, streptomycin,* and pyrazinamide administered 2-3 times a week for 7 months (see Nine-month SM-based therapy in Table 1A of Appendix). A.I For patients who are not candidates for antiretroviral therapy, or for those patients for whom a decision is made not to combine the initiation of antiretroviral therapy with TB therapy, the preferred option continues to be a 6-month regimen that consists of isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin). These drugs are administered a) daily for 8 weeks or b) daily for at least the first 2 weeks, followed by 2-3-times-perweek dosing for 6 weeks, to complete the 2-month induction phase. The *Every effort should be made to continue administering streptomycin for the total duration of treatment or for at least 4 months after culture conversion (approximately 6-7 months from the start of treatment). Some experts suggest that in situations in which streptomycin is not included in the regimen for all of the recommended 9 months, ethambutol should be added to the regimen to replace streptomycin, and the duration of treatment should be prolonged from 9 months to 12 months. Alternatives to streptomycin are the injectable drugs amikacin, kanamycin, and capreomycin.\nsecond phase of treatment consists of a) isoniazid and rifampin administered daily or 2-3 times a week for 4 months. Isoniazid, rifampin, pyrazinamide, and ethambutol (or streptomycin) also can be administered three times a week for 6 months (see Six-month RIF-based therapy in Table 1A of Appendix). D.II TB regimens consisting of isoniazid, ethambutol, and pyrazinamide (i.e., three-drug regimens that do not contain a rifamycin, an aminoglycoside [e.g., streptomycin, amikacin, kanamycin], or capreomycin) should generally not be used for the treatment of patients with HIV-related TB; if these regimens are used for the treatment of TB, the minimum duration of therapy should be 18 months (or 12 months after documented culture conversion). A.II Pyridoxine (vitamin B 6 ) (25-50 mg daily or 50-100 mg twice weekly) should be administered to all HIV-infected patients who are undergoing TB treatment with isoniazid, to reduce the occurrence of isoniazid-induced side effects in the central and peripheral nervous system. E.II Because CDC's most recent recommendations for the use of antiretroviral therapy strongly advise against interruptions of therapy,* and because alternative TB treatments that do not contain rifampin are available, previous antituberculosis therapy options that involved stopping protease inhibitor therapy to allow the use of rifampin (Option I and Option II [3 ]) are no longer recommended.\n# Medications and Doses for Treatment of TB\nNo rating When rifabutin is used concurrently with indinavir, nelfinavir, or amprenavir, the recommended daily dose of rifabutin should be decreased from 300 mg to 150 mg (Table 2A of Appendix). No rating The dose of rifabutin recommended for twice-weekly administration is 300 mg, and this dose recommendation does not change if rifabutin is used concurrently with indinavir, nelfinavir, or amprenavir (Table 2A of Appendix). No rating Preliminary drug interaction studies suggest that when rifabutin is used concurrently with efavirenz, the dose of rifabutin for both daily and twiceweekly administration should be increased from 300 mg to 450 mg. No rating Three-times-per-week administration of rifabutin used in combination with antiretroviral therapy has not been studied, and thus a recommendation for adjustment of dosages cannot currently be made. No rating Experts do not know whether the daily dose of rifabutin should be reduced when this drug is used concurrently with either soft-gel saquinavir (Fortovase ™ ) or nevirapine. No rating No modifications in the usually recommended doses of isoniazid, ethambutol, pyrazinamide, or streptomycin (Table 2A of Appendix) are necessary if these drugs are used concurrently with protease inhibitors, NNRTIs, or nucleoside reverse transcriptase inhibitors (NRTIs).\n*To minimize the emergence of drug-resistant HIV strains, if any antiretroviral medication must be temporarily discontinued for any reason, clinicians and patients should be aware of the theoretical advantage of stopping all antiretroviral agents simultaneously, rather than continuing the administration of one or two of these agents alone (4).\nNo rating The safety and effectiveness of rifapentine (Priftin ® ), a rifamycin newly approved by the U.S. Food and Drug Administration for the treatment of pulmonary tuberculosis, have not been established for patients infected with HIV. Administration of rifapentine to patients with HIV-related TB is not currently recommended.\n# Duration of TB Treatment\nA.II\nThe minimum duration of short-course rifabutin-containing TB treatment regimens is 6 months, to complete a) at least 180 doses (one dose per day for 6 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12 The final decision on the duration of therapy should consider the patient's response to treatment. For patients with delayed response to treatment (see Box 2), the duration of rifamycin-based regimens should be prolonged from 6 months to 9 months (or to 4 months after culture conversion is documented).\n# A.II\nThe minimum duration of nonrifamycin, streptomycin-based TB treatment regimens is 9 months, to complete a) at least 60 induction doses (one dose per day for 2 months) or b) 14 induction doses (one dose per day for 2 weeks) followed by 12-18 induction doses (two to three doses per week for 6 weeks) plus either 60 continuation doses (two doses per week for 30 weeks) or 90 continuation doses (three doses per week for 30 weeks).\n# A.II\nWhen making the final decision on the duration of therapy, clinicians should consider the patient's response to treatment. For patients with delayed response to treatment (see Box 2), the duration of streptomycinbased regimens should be prolonged from 9 months to 12 months (or to 6 months after culture conversion is documented).\n# A.III\nInterruptions in therapy because of drug toxicity or other reasons should be taken into consideration when calculating the end-of-therapy date for individual patients. Completion of therapy is based on total number of medication doses administered and not on duration of therapy alone. A.III Reinstitution of therapy for patients with interrupted TB therapy might require a continuation of the regimen originally prescribed (as long as needed to complete the recommended duration of the particular regimen) *Three-times-per-week rifabutin regimens, used in combination with antiretroviral therapy, have not been studied.\n# BOX 2. Components of the monthly medical evaluation for human immunodeficiency virus-infected patients undergoing treatment for active tuberculosis\nFor patients infected with human immunodeficiency virus (HIV) who are undergoing treatment for active tuberculosis (TB), clinicians should include the following components in the monthly evaluation:\n• Once a month, evaluate symptoms and signs of TB (response to treatment) by conducting a) a physical examination (the nature and extent of this evaluation will depend on the patient's symptoms and the site of disease) and b) for patients with pulmonary TB, an examination by smear and culture of an expectorated or induced sputum specimen until cultures are no longer positive for Mycobacterium tuberculosis.\n• Perform as necessary for individual patients laboratory tests such as: complete blood cell count, platelet count, and tests for serum glutamic oxalacetic transaminase or aspartate aminotransferase (SGOT/AST) and serum glutamic pyruvic transaminase or alanine aminotransferase (SGPT/ALT), alkaline phosphatase, total bilirubin, uric acid, blood urea nitrogen, and creatinine.\n• To assist in the decision about the duration of TB treatment, investigate the possibility of a delayed response to treatment (Table 1A of Appendix). Delayed response to treatment should be suspected (and in most cases treatment duration should be prolonged) if by the end of the 2-month induction phase of therapy, patients a) continue to be culture-positive for M. tuberculosis or b) do not experience resolution of signs or symptoms of TB or do experience progression of signs or symptoms of TB (e.g., persistent fever, progressive weight loss, or increase in size of lymph nodes, abscesses, or other tuberculous lesions, none of which can be accounted for by a disease other than TB). (See Duration of TB Treatment.)\n• Some factors potentially associated with TB treatment failure are a large mycobacterial load and extensive lung cavitation at baseline, nonadherence with the drug regimen (even among patients assumed to be on DOT), inappropriately low medication doses, and impaired absorption of drugs. Immediately institute corrective measures for those factors amenable to intervention.\n• Because patients with HIV-infection often are treated with multiple drugs in addition to antituberculosis drugs, at each visit, review all medications that the patient is taking and assess any change in medications for potential drug interactions with TB medications. Efforts to manage these potential problems related to drug interactions require the coordinated efforts of care givers for HIV and TB disease. (See TB Drug Interaction and Absorption.)\n• Because several antituberculosis drugs have hepatotoxicity as a potential side effect (Table 2A of Appendix), advise all persons taking TB medications about the symptoms consistent with hepatitis (e.g., anorexia, nausea, vomiting, abdominal pain, jaundice) and instruct them to discontinue all TB medications immediately and seek medical attention promptly if they exhibit such symptoms. These patients usually will need an examination by a physician, liver function tests, and a planned strategy for restarting TB treatment.\n• If ethambutol is administered, perform a monthly visual acuity exam and test for redgreen color perception.\n• If streptomycin is administered, perform audiometry and renal function tests as needed.\nor a complete renewal of the regimen. In either situation, when therapy is resumed after an interruption of ≥2 months, sputum samples (or other clinical samples as appropriate) should be taken for smear, culture, and drug-susceptibility testing.\n# Management of the Coadministration of TB and HIV Therapies, Including the Potential for Paradoxical Reactions\nWhen antituberculosis treatment has been started, all patients should be monitored for response to antituberculosis therapy, drug-related toxicity, and drug interactions. Detailed recommendations for managing antiretroviral therapy are published elsewhere (4 ), and consultation with experts in this area is highly recommended.\nThe frequency and type of most TB medication side effects are similar among TB patients with and without HIV infection (30,65,67 ). When caring for HIV-infected persons, clinicians must be aware of the following problems that can result from the administration of TB medications: a) patients might have a higher predisposition toward isoniazid-related peripheral neuropathy; b) evaluation of dermatologic reactions related to TB medications might be complicated because HIV-infected patients are subject to several dermatologic diseases related to HIV disease or to medications used for other treatment or prophylaxis reasons; and c) patients undergoing concurrent therapy with rifabutin and protease inhibitors or NNRTIs are at risk for rifabutin toxicity associated with increased serum concentrations of this drug. The reported adverse events associated with rifabutin toxicity include arthralgias, uveitis, and leukopenia (86,(101)(102)(103). Detailed recommendations for managing these adverse reactions are published elsewhere and should be consulted (2,64 ).\nParadoxical reactions -temporary exacerbation of symptoms, signs, or radiographic manifestations of TB (e.g., recurrence of fever, enlarged lymph nodes, appearance of cavitation in previously normal chest x-ray) among patients who have experienced a good clinical and bacteriologic response to antituberculosis therapyhave been reported among patients coinfected with HIV who have restored immune function because of antiretroviral therapy (76 ). The synchronization and severity of paradoxical reactions associated with antiretroviral therapy are not well understood; therefore, experts do not know whether the occurrence of these reactions should affect the timing of initiating or changing antiretroviral therapy when such therapy is indicated for a patient with HIV infection. However, because an association between paradoxical reactions and initiation of antiretroviral therapy has been noted, clinicians should be aware of this possibility and discuss the risks with patients undergoing therapy for active TB.\n# Monthly Medical Evaluation and the Diagnosis and Management of Paradoxical Reactions A.II\nAll patients should receive a monthly clinical evaluation (see Box 2) to monitor their response to treatment, adherence to treatment, and medication side effects (Table 2A of Appendix). During the early days of therapy, the interval between these evaluations might be shorter (e.g., every 2 weeks).\n# A.II\nPatients suspected of having paradoxical reactions should be evaluated to rule out other causes for their clinical presentation (e.g., TB treatment failure) before attributing their signs and symptoms to a paradoxical reaction. C.III Some experts recommend that to avoid paradoxical reactions, clinicians should delay the initiation of or changes in antiretroviral therapy until the signs and symptoms of TB are well controlled (possibly 4-8 weeks from the initiation of TB therapy). No rating For patients with a paradoxical reaction in whom the symptoms are not severe or life-threatening, the management of these reactions might consist of symptomatic therapy and no change in antituberculosis or antiretroviral therapy. For patients with a paradoxical reaction associated with severe or life-threatening clinical manifestations (e.g., uncontrollable fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections [pleuritis, pericarditis, peritonitis], sepsis-like syndrome), the management might include hospitalization and possibly a time-limited use of corticosteroids (e.g., prednisone started daily at a dose of 60-80 mg and reduced after 1 or 2 weeks, with the resolution of symptoms as a guide; in most cases, corticosteroid therapy should last no more than 4-6 weeks).\n# TB Drug Interaction and Absorption E.II\nGiven the expected drug interactions that would result in markedly decreased serum levels of antiretroviral agents, and given the overlapping toxicities, the coadministration of rifampin with any of the protease inhibitors or with NNRTIs, as well as the coadministration of rifabutin with ritonavir, hard-gel saquinavir (Invirase ™ ), or delavirdine, is contraindicated.\n# A.II\nThe potent effect of rifampin as a CYP450 inducer, which lowers the serum concentration of protease inhibitors and NNRTIs, is expected to continue up to at least 2 weeks following the discontinuation of rifampin. Therefore, to diminish the likelihood of adverse effects on drug metabolism, clinicians should plan the start of therapy with protease inhibitors or NNRTIs at least 2 weeks after the date of the last dose of rifampin.\n# A.II\nRifabutin is a less potent CYP450 inducer than rifampin and thus can be used (with adjustments in dosages) concurrently with the NNRTIs nevirapine or efavirenz or with certain protease inhibitors (e.g., indinavir, nelfinavir, and possibly soft-gel saquinavir [Fortovase ™ ] and amprenavir). No rating Indinavir serum concentrations are decreased by rifabutin-related induction of the hepatic cytochrome P450; therefore, when indinavir is used in combination with rifabutin, the dose of indinavir usually is increased from 800 mg every 8 hours to 1,200 mg every 8 hours. No rating Nelfinavir serum concentrations are also decreased when nelfinavir is used in combination with rifabutin (Table 1A of Appendix); however, the resultant metabolite of nelfinavir is known to be active against HIV. Nevertheless, some experts suggest increasing the dose of nelfinavir from 750 mg three times per day to 1,000 mg three times per day when used in combination with rifabutin. No rating Experts do not know whether dose-modifications are needed for soft-gel saquinavir (Fortovase ™ ), amprenavir, nevirapine, or efavirenz if these agents are used in combination with rifabutin. No rating Many other medications commonly used by patients with HIV infection have drug interactions with the rifamycins (rifampin or rifabutin) of sufficient magnitude to require interventions such as dose adjustments or use of alternative therapies. Some examples of these drugs are hormonal contraceptives, dapsone, ketoconazole, fluconazole, itraconazole, narcotics (including methadone), anticoagulants, corticosteroids, cardiac glycosides, hypoglycemics (sulfonylureas), diazepam, beta-blockers, anticonvulsants, and theophylline. No rating Malabsorption of antituberculosis drugs has been demonstrated in some patients with HIV infection, and in some cases, it has been associated with TB treatment failures and the selection of drug-resistant M. tuberculosis bacilli (141)(142)(143)(144)(145). Therapeutic drug monitoring has been advocated by some experts as an adjunct in the management of HIV-related TB (146 ). This approach might be useful when evaluating patients with TB treatment failure or relapse and in the treatment of multidrug-resistant (MDR) TB. However, the role of therapeutic drug monitoring in the routine management of TB among HIV-infected patients has not been established and is not presently recommended.\n# Treatment of TB in Special Situations\nThe following general treatment recommendations address special situations such as drug-resistant forms of HIV-related TB, TB among HIV-infected pregnant women, TB among HIV-infected children, and extrapulmonary HIV-related TB. Detailed recommendations for managing these patients are published elsewhere (2,64,(147)(148)(149)(150), and consultation with experts in these areas is highly recommended.\n# Treatment of Drug-Resistant TB A.II\nTB disease resistant to isoniazid only. The treatment regimen should generally consist of a rifamycin (rifampin or rifabutin), pyrazinamide, and ethambutol for the duration of treatment. Intermittent therapy administered twice weekly can be used following at least 2 weeks (14 doses) of daily induction therapy (see Duration of TB Treatment). The recommended duration of treatment is 6-9 months or 4 months after culture conversion. Isoniazid is generally stopped when resistance (>1% of bacilli resistant to 1.0 µg/mL of isoniazid) to this drug is discovered; however, when low-level resistance is discovered (>1% of bacilli resistant to 0.2 µg/mL of isoniazid, but no resistance to 1.0 µg/mL of isoniazid), some experts suggest continuing to use isoniazid as part of the treatment regimen. Because the development of acquired rifamycin resistance would result in MDR TB, clinicians should carefully supervise and manage TB treatment for these patients.\nisoniazid and rifampin. If drug-susceptibility results are not available, a four-drug regimen (e.g., isoniazid, rifamycin, pyrazinamide, and ethambutol) for 2 months, followed by intermittent administration of isoniazid and a rifamycin for 4 months, is recommended. Considerations for antiretroviral therapy for children and adolescents have been published elsewhere (154 ).\n# TB Treatment for HIV-Infected Patients with Extrapulmonary TB\nThe basic principles that support the treatment of pulmonary TB in HIVinfected patients also apply to extrapulmonary forms of the disease. Most extrapulmonary forms of TB (including TB meningitis, tuberculous lymphadenitis, pericardial TB, pleural TB, and disseminated or miliary TB) are more common among persons with advanced-stage HIV disease (155,156) than among patients with asymptomatic HIV infection. The drug regimens and treatment durations that are recommended for treating pulmonary TB in HIV-infected adults and children (Table 1A of Appendix) are also recommended for treating most patients with extrapulmonary disease. However, for certain forms of extrapulmonary disease, such as meningioma, bone, and joint TB, using a rifamycin-based regimen for at least 9 months is generally recommended.\n# Latent M. tuberculosis Infection Clinical and Public Health Principles\nWhen caring for persons with HIV infection, clinicians should make aggressive efforts to identify those who also are infected with M. tuberculosis. Because the reliability of the tuberculin skin test (TST) can diminish as the CD4+ T-cell count declines, TB screening with TST should be performed as soon as possible after HIV infection is diagnosed. Because the risk of infection and disease with M. tuberculosis is particularly high among HIV-infected contacts of persons with infectious pulmonary or laryngeal TB, these persons must be evaluated for TB as soon as possible after learning of exposure to a patient with infectious TB.\nHealth-care providers, administrators, and TB controllers must coordinate their work and establish TB screening initiatives in settings where a) the prevalence of infection with M. tuberculosis among persons with HIV-infection is expected to be high and b) referral for medical evaluation and TB preventive therapy can be accomplished. Such settings include prisons, jails, prenatal-care programs, drug treatment programs, syringe exchange programs, HIV specialty clinics, acute-care hospitals serving populations at high risk of TB, AIDS patient group residences, some community-health centers, psychiatric institutions, mental health residences, and homeless shelters. All HIV counseling and testing sites must have mechanisms in place to ensure that persons identified with HIV infection receive tuberculin skin testing. TB control programs in jurisdictions that have HIV reporting requirements should make efforts to ensure that all persons with HIV infection have TSTs.\nBecause of the complexity of problems associated with active TB disease in HIVinfected persons, and as part of the efforts to control and eliminate TB in the United States, all HIV-infected persons identified as latently infected with M. tuberculosis A.II\n# BOX 3. Components of the baseline medical evaluation for tuberculosis preventive treatment for patients infected with human immunodeficiency virus\nWhen conducting a medical evaluation to rule out active tuberculosis (TB) and administer preventive treatment for patients infected with human immunodeficiency virus (HIV), clinicians should include the following questions and assessments:\n# Medical History\n• Ask patients about their history of recent close contact with a person who has TB disease. If the infecting source-patient is known, his or her culture and drug-susceptibility results should be investigated and reviewed so that the preventive therapy regimen can be tailored appropriately (see Treatment of Latent M. Tuberculosis in Special Situations).\n• Assess patients for their risk of increased toxicity associated with the medications used for TB preventive therapy (e.g., history of excessive alcohol ingestion, liver disease, hepatitis, chronic use of other medications).\n• Assess patients for contraindications to TB preventive therapy (Table 3A of Appendix).\n• When persons have previously received TB preventive treatment, determine what drugs were used, duration of treatment, and any history of adverse reactions (Table 2A of Appendix) and adherence to preventive therapy.\n• Ask patients about their history of antiretroviral therapy and their history of therapies to prevent opportunistic infections. If a patient has ever received or is receiving any of these treatments, the care provider must determine the drugs used, duration of treatment, history of adverse reactions, potential for drug interactions with TB medications, and any reasons for discontinuation of treatment if treatment ended.\n# Chest X-Ray Examination\n• A chest x-ray is indicated for all persons being considered for preventive therapy, to rule out active pulmonary TB disease. Children younger than 5 years old should undergo both a posterior-anterior and a lateral chest x-ray. All other individuals should receive a posterior-anterior chest x-ray only; additional x-rays should be performed at the physician's discretion. Pregnant women who have a positive TST or who have negative TST results but are recent contacts of a person who has infectious TB disease should undergo a chest x-ray (with appropriate shielding) without delay, even during the first trimester of pregnancy.\n# Laboratory Tests\n• Obtain a complete blood cell count, and also obtain a platelet count if the patient will be treated with a rifamycin (rifampin or rifabutin).\n• Conduct chemistry panel tests, especially for liver enzyme levels (serum glutamic oxalacetic transaminase or aspartate aminotransferase [SGOT/AST] and serum glutamic pyruvic transaminase or alanine aminotransferase [SGPT/ALT]) and total bilirubin. In addition, check uric acid levels if the patient will be treated with pyrazinamide. \n# BOX 4. Components of the monthly medical evaluation for human immunodeficiency virus-infected patients undergoing preventive treatment for latent Mycobacterium tuberculosis infection\nFor patients infected with human immunodeficiency virus (HIV) who are undergoing preventive treatment for latent Mycobacterium tuberculosis infection, clinicians should include the following components in the monthly evaluation:\n• At every monthly evaluation, review signs and symptoms potentially related to active tuberculosis (TB) disease as well as signs and symptoms of drug reactions potentially related to antituberculosis drugs (Table 2A of Appendix).\n• At the start of preventive therapy and at each subsequent monthly visit, remind patients of the need to immediately discontinue preventive therapy and seek prompt medical attention if signs and symptoms of hepatotoxicity appear (e.g., anorexia, abdominal pain, nausea, vomiting, change in color of urine and feces, jaundice). • Patients with HIV infection often are treated with multiple drugs in addition to antituberculosis drugs. At each visit, all medications that a patient is taking should be reviewed and assessed for potential drug interactions with TB medications. Some examples of these drugs are hormonal contraceptives, ketoconazole, fluconazole, itraconazole, narcotics (including methadone), anticoagulants, corticosteroids, cardiac glycosides, hypoglycemics (sulfonylureas), diazepam, beta-blockers, anticonvulsants, and theophylline. Efforts to manage these potential problems related to drug interactions require the coordinated efforts of HIV and TB patients' care givers. The choices for preventive treatment for persons who are likely to be infected with a strain of M. tuberculosis resistant to both isoniazid and rifamycins are published elsewhere (161 ). In general, the recommended preventive therapy regimens for these persons include the use of a combination of at least two antituberculosis drugs that the infecting strain is believed to be susceptible to (e.g., ethambutol and pyrazinamide, levofloxacin and ethambutol). The clinician should review the drugsusceptibility pattern of the M. tuberculosis strain isolated from the infecting source-patient before choosing a preventive therapy regimen.\n# Treatment of Latent M. tuberculosis Infection in Special Situations\n\n# A.III\nFor HIV-infected women who are candidates for TB preventive therapy, the initiation or discontinuation of preventive therapy should not be delayed on the basis of pregnancy alone, even during the first trimester. A 9-month regimen of isoniazid administered daily or twice a week is the only recommended option (Table 3A of Appendix). No rating For HIV-infected children who are candidates for TB preventive therapy, a 12-month regimen of isoniazid administered daily is recommended by the American Academy of Pediatrics (162 ). \n# Follow-up of HIV-Infected Persons Who Have Completed Preventive Therapy\n\n# CONCLUSIONS\nImplementing TB prevention and control strategies for persons infected with HIV has always been important and is even more critical now that a larger selection of new, more potent antiretroviral drugs has enabled clinicians to implement therapies that improve the health and prolong the lives of HIV-infected persons. These antiretroviral therapeutic strategies often include the use of drugs such as the protease inhibitors or the nonnucleoside reverse transcriptase inhibitors (NNRTIs), which because of drug interactions cannot be used concurrently with certain other drugs (e.g., rifampin). Thus, to improve the diagnosis and management of TB and HIV coinfection, TB control programs need to be prepared for the following challenges:\n• Ensure that all patients with TB receive HIV counseling and testing either on site or elsewhere. Patients with latent M. tuberculosis infection who are at risk for HIV infection also should receive HIV counseling and testing.\n• Initiate prompt and effective antituberculosis treatment (ideally with directly observed therapy) for all patients diagnosed with HIV-related TB.\n• Promote optimal antiretroviral therapy for patients with M. tuberculosis and HIV infection.\n• Become knowledgeable about the indications, potential dosing adjustments, and monitoring requirements of a rifabutin-containing regimen (or an alternative regimen that does not contain rifamycin) for the treatment of TB in patients who are undergoing antiretroviral therapy with protease inhibitors or NNRTIs.\n• Identify potential risk factors for TB treatment failure or relapse as well as the potential for paradoxical treatment reactions, and learn how to recognize and manage these outcomes.\n• Follow procedures to ensure early recognition and implementation of effective treatment for drug-resistant TB.\n• Recognize that previous options that involved stopping protease inhibitor therapy to allow the use of rifampin for TB treatment are no longer recommended for two reasons: a) the most recent guidelines for the use of antiretroviral therapy advise against interrupting HIV therapy, and b) alternatives for TB therapy that do not contain rifampin are available.\n• Coordinate efforts and establish TB screening initiatives in settings where a) the prevalence of infection with M. tuberculosis among persons with HIV-infection is expected to be high and b) referral for medical evaluation and therapy for active or latent TB is possible.\n• Be aware of changes in options for TB preventive therapy. In addition to recommendations for using 9 months of isoniazid daily or twice a week, new shortcourse multidrug regimens (e.g., a 2-month course of a rifamycin such as rifabutin or rifampin with pyrazinamide) can be prescribed for HIV-infected patients with latent M. tuberculosis infection.\nWhen faced with treatment choices, TB controllers and clinicians can use these recommendations to make informed decisions based on the most current research results available, keeping in mind that as new antiretroviral and antituberculosis agents become available, these guidelines will likely change. The aim of these recommendations is to help reduce TB treatment failures, prevent cases of drug-resistant TB, diminish the adverse effects that TB has on HIV replication, and support efforts to not only control TB, but to eliminate it from the United States. No contraindication exists for the use of RFB with NRTIs.\nIf the patient also is taking indinavir, nelfinavir, or amprenavir, the daily dose of RFB is decreased from 300 mg to 150 mg. The twice-weekly dose of RFB (300 mg) remains unchanged if the patient is also taking these protease inhibitors.\nIf the patient also is taking efavirenz, the daily or twice weekly dose of RFB is increased from 300 mg to 450 mg.\nThree-times-a-week administration of RFB used in combination with antiretroviral therapy has not been studied. † The concurrent use of RFB is contraindicated with ritonavir, saquinavir (Invirase™), and delavirdine. Information regarding the use of rifabutin with saquinavir (Fortovase™), amprenavir, efavirenz, and nevirapine is limited. § Not applicable. If nelfinavir, indinavir, or amprenavir is administered with RFB, blood concentrations of these protease inhibitors decrease. Thus, when RFB is used concurrently with any of these three drugs, the daily dose of RFB is reduced from 300 mg to 150 mg (the twice-weekly dose of RFB is unchanged, however). ¶ NA=not applicable. If efavirenz is administered with RFB, blood concentrations of RFB decrease. Thus, when RFB is used concurrently with efavirenz, the dose of RFB for both daily and twice weekly administration should be increased from 300 mg to 450 mg.\n# Acknowledgments\nStaff with the Division of Tuberculosis Elimination (DTBE) at CDC's National Center for HIV, STD, and TB Prevention (NCHSTP) and the panel of expert consultants who prepared this report thank the following persons who attended a September 1998 meeting sponsored by the American Thoracic Society and CDC and provided advice about revising the recommendations on TB preventive therapy: George W. Comstock \n# A.II\nTB disease resistant to rifampin only. The 9-month treatment regimen should generally consist of an initial 2-month phase of isoniazid, streptomycin, pyrazinamide, and ethambutol (see Nine-month SM-based therapy in Table 1A of Appendix). The second phase of treatment should consist of isoniazid, streptomycin, and pyrazinamide administered for 7 months. Because the development of acquired isoniazid resistance would result in MDR TB, clinicians should carefully supervise and manage TB treatment for these patients.\n# A.III\nMultidrug-resistant TB (resistant to both isoniazid and rifampin). These patients should be managed by or in consultation with physicians experienced in the management of MDR TB. Findings from a retrospective study of patients with MDR TB strongly indicate that early aggressive treatment with appropriate regimens (based on the known or suspected drug-resistance pattern of the M. tuberculosis isolate) markedly decreases deaths associated with MDR TB (63,(151)(152)(153). Most drug regimens currently used to treat MDR TB include an aminoglycoside (e.g., streptomycin, kanamycin, amikacin) or capreomycin, and a fluoroquinolone. The recommended duration of treatment for MDR TB in HIV-seropositive patients is 24 months after culture conversion, and posttreatment followup visits to monitor for TB relapse should be conducted every 4 months for 24 months. Because of the serious personal and public health concerns associated with MDR TB, health departments should always use DOT for these patients and take whatever steps are needed to ensure their adherence to therapy.\n# TB Treatment for HIV-Infected Pregnant Women\nHIV-infected pregnant women who have a positive M. tuberculosis culture or who are suspected of having TB disease should be treated without delay. Choices of TB treatment regimens for HIV-infected pregnant women are those that include a rifamycin (Table 1A of Appendix). Routine use of pyrazinamide during pregnancy is recommended by international organizations but has not been recommended in the United States because of inadequate teratogenicity data (2 ). However, for HIV-infected pregnant women, the benefits of a TB treatment regimen that includes pyrazinamide outweigh potential pyrazinamide-related risks to the fetus. Aminoglycosides (e.g, streptomycin, kanamycin, amikacin) and capreomycin are contraindicated for all pregnant women because of potential adverse effects on the fetus. Considerations for antiretroviral therapy for pregnant HIV-infected women have been published elsewhere (4 ). \n# TB Treatment for HIV-Infected Children\n\n# Diagnosis of M. tuberculosis Infection Among HIV-Infected Persons\nThe Mantoux-method TST, with 5 TU of purified protein derivative, is used to diagnose M. tuberculosis infection. A TST reaction size of ≥5 mm of induration is considered positive (i.e., indicative of M. tuberculosis infection) in persons who are infected with HIV. Persons with a TST reaction size of <5 mm but with a history of exposure to TB also could be infected with M. tuberculosis; this possibility should be investigated (157 ). Whenever M. tuberculosis infection is suspected in a patient, an evaluation to rule out active TB and assess the need for preventive therapy should be conducted (see Box 3). This evaluation should include HIV counseling and testing for persons whose HIV status is unknown but who are at risk for HIV infection.\nTuberculin Skin Testing Among HIV-Infected Persons A.I As soon as possible after HIV infection is diagnosed, all persons should receive a TST unless previously tested and found to be TST-positive.\n# A.II\nAs soon as possible (ideally within 7 days) after learning of an exposure to a patient with infectious TB, all HIV-infected persons should be evaluated for TB and receive a TST, regardless of any previous TST results.\n# B.III\nTSTs should be conducted periodically for HIV-infected persons who are TST-negative on initial evaluation and who belong to populations with a substantial risk of exposure to M. tuberculosis (e.g., residents of prisons, jails, or homeless shelters). C.III Some experts recommend repeat TSTs for HIV-infected persons who are TST-negative on initial evaluation and whose immune function is restored because of effective antiretroviral therapy. C.I Because results of anergy testing in HIV-infected populations in the United States do not seem useful to clinicians making decisions about preventive therapy, anergy testing is no longer recommended as a routine component of TB screening among HIV-infected persons (157 ). However, some experts support the use of anergy testing to help guide individual decisions regarding preventive therapy, and some recommend that a TST be performed on patients previously classified as anergic if evidence indicates that these patients' immune systems have responded to therapy with antiretroviral drugs. 2A of Appendix). All patients on twice-a-week dosing regimens should receive DOPT; some experts also recommend DOPT for patients on 2-month preventive therapy regimens. The administration of TB preventive therapy regimens that contain rifampin is contraindicated for patients who take protease inhibitors or NNRTIs. For these patients, the substitution of rifabutin for rifampin in preventive therapy regimens is recommended; however, the substitution of rifapentine for rifampin is not currently recommended because rifapentine's safety and effectiveness have not been established for patients infected with HIV.\n# Candidates for TB Preventive Therapy Among HIV-Infected Persons\n\n# Recommended Preventive Therapy Regimens for Patients Receiving Protease Inhibitors or NNRTIs A.II\nFor HIV-infected adults, a 9-month regimen of isoniazid can be administered daily.\n# B.I\nFor HIV-infected adults, a 9-month regimen of isoniazid can be administered twice a week (DOPT should be used with intermittant dosing regimens).\n# B.III\nFor HIV-infected adults, a 2-month regimen of rifabutin and pyrazinamide can be administered daily. No rating The concurrent administration of rifabutin is contraindicated with ritonavir, hard-gel saquinavir (Invirase™), and delavirdine.\n# Recommended Preventive Therapy Regimens for Patients Not Receiving Protease Inhibitors or NNRTIs A.II\nFor HIV-infected adults, a 9-month regimen of isoniazid can be administered daily.\n# B.I\nFor HIV-infected adults, a 9-month regimen of isoniazid can be administered twice a week. A.I For HIV-infected adults, a 2-month regimen of rifampin and pyrazinamide can be administered daily.\n# Duration of TB Preventive Therapy A.II\nDaily isoniazid regimens should consist of at least 270 doses to be administered for 9 months or up to 12 months if interruptions in therapy occur.\n# Appendix\nRecommended Treatment Options for Persons with Human Immunodeficiency Virus-Related Tuberculosis Infection and Disease * For patients with intolerance to PZA, some experts recommend the use of rifamycin (RIF or RFB) alone for preventive treatment. Most experts agree that available data support the recommendation that this treatment can be administered for as short a duration as 4 months, although some experts would treat for 6 months. † The concurrent use of RFB is contraindicated with ritonavir, hard-gel saquinavir (Invirase™), and delavirdine. The information regarding the use of RFB with soft-gel saquinavir (Fortovase™), amprenavir, efavirenz, and nevirapine is limited. \n# FIRST-CLASS MAIL POSTAGE & FEES PAID\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":288,"cells":{"id":{"kind":"string","value":"4b5462aaadea53125e82acbd0baadd033b202f99"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"These recommendations update information concerning the vaccine and antiviral agents available for controlling influenza during the 1997-98 influenza season (superseding MMWR 1996;45:1-24). The principal changes include information about a) the influenza virus strains included in the trivalent vaccine for 1997-98, b) the vaccination of pregnant and breastfeeding women, and c) side effects and adverse reactions.# INTRODUCTION\nInfluenza A viruses are classified into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). Three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and N2) are recognized among influenza A viruses that have caused widespread human disease. Immunity to these antigens-especially to the hemagglutinin-reduces the likelihood of infection and lessens the severity of disease if infection occurs. Infection with a virus of one subtype confers little or no protection against viruses of other subtypes. Furthermore, over time, antigenic variation (antigenic drift) within a subtype may be so marked that infection or vaccination with one strain may not induce immunity to distantly related strains of the same subtype. Although influenza B viruses have shown more antigenic stability than influenza A viruses, antigenic variation does occur. For these reasons, major epidemics of respiratory disease caused by new variants of influenza continue to occur. The antigenic characteristics of circulating strains provide the basis for selecting the virus strains included in each year's vaccine.\nTypical influenza illness is characterized by abrupt onset of fever, myalgia, sore throat, and nonproductive cough. Unlike other common respiratory illnesses, influenza can cause severe malaise lasting several days. More severe illness can result if either primary influenza pneumonia or secondary bacterial pneumonia occurs. During influenza epidemics, high attack rates of acute illness result in both increased numbers of visits to physicians' offices, walk-in clinics, and emergency rooms and increased hospitalizations for management of lower respiratory tract complications.\nElderly persons and persons with underlying health problems are at increased risk for complications of influenza. If they become ill with influenza, such members of high-risk groups (see Groups at Increased Risk for Influenza-Related Complications) are more likely than the general population to require hospitalization. During major epidemics, hospitalization rates for persons at high risk may increase twofold to fivefold, depending on the age group. Previously healthy children and younger adults also may require hospitalization for influenza-related complications, but the relative increase in their hospitalization rates is less than for persons who belong to high-risk groups.\nAn increase in mortality further indicates the impact of influenza epidemics. Increased mortality results not only from influenza and pneumonia but also from cardiopulmonary and other chronic diseases that can be exacerbated by influenza. An estimated >20,000 influenza-associated deaths occurred during each of nine different U.S. epidemics from 1972-73 to 1991-92, and >40,000 influenza-associated deaths occurred during each of four of these epidemics. More than 90% of the deaths attributed to pneumonia and influenza occurred among persons aged ≥65 years.\nThe number of elderly persons in the U.S. population is increasing, as well as the number of persons aged <65 years at increased risk for influenza-related complications. Longer life expectancy for a) organ-transplant recipients, b) neonates in intensive-care units, and c) persons who have cystic fibrosis and acquired immunodeficiency syndrome (AIDS) results in a higher survival rate for younger persons at high risk for influenza.\nInfluenza vaccine campaigns are targeted to approximately 32 million persons aged ≥65 years and 27 million to 31 million persons aged <65 years who are at high risk for influenza-associated complications. National health objectives for the year 2000 include vaccination of at least 60% of persons at risk for severe influenza-related illness.\nInfluenza vaccination levels among persons aged ≥65 years increased substantially from 1985 (23%) to 1994 (55%), although vaccination levels among persons aged <65 years at high risk for influenza are estimated to be <30%. Possible reasons for the increase in influenza vaccination levels, especially among persons aged ≥65 years, include greater acceptance of preventive medical services by practitioners, increased delivery and administration of vaccine by health-care providers and sources other than physicians, and the initiation of Medicare reimbursement for influenza vaccination in 1993.\n\n# OPTIONS FOR THE CONTROL OF INFLUENZA\nIn the United States, two measures are available that can reduce the impact of influenza: immunoprophylaxis with inactivated (i.e., killed-virus) vaccine and chemoprophylaxis or therapy with an influenza-specific antiviral drug (amantadine or rimantadine). Vaccinating persons at high risk before the influenza season each year is the most effective measure for reducing the impact of influenza. Vaccination can be highly cost effective when it is a) directed at persons who are most likely to experience complications or who are at increased risk for exposure and b) administered to persons at high risk during hospitalizations or routine health-care visits before the influenza season, thus making special visits to physicians' offices or clinics unnecessary. When vaccine and epidemic strains of virus are well matched, achieving high vaccination rates among persons living in closed settings (e.g., nursing homes and other chronic-care facilities) can reduce the risk for outbreaks by inducing herd immunity.\n\n# INACTIVATED VACCINE FOR INFLUENZA A AND B\nEach year's influenza vaccine contains three virus strains (usually two type A and one type B) representing the influenza viruses that are likely to circulate in the United States in the upcoming winter. The vaccine is made from highly purified, egg-grown viruses that have been made noninfectious (inactivated). Influenza vaccine rarely causes systemic or febrile reactions. Whole-virus, subvirion, and purified-surfaceantigen preparations are available.\nMost vaccinated children and young adults develop high postvaccination hemagglutination-inhibition antibody titers. These antibody titers are protective against illness caused by strains similar to those in the vaccine or the related variants that may emerge during outbreak periods. Elderly persons and persons with certain chronic diseases may develop lower postvaccination antibody titers than healthy young adults and thus may remain susceptible to influenza-related upper respiratory tract infection. However, even if such persons develop influenza illness despite vaccination, the vaccine can be effective in preventing lower respiratory tract involvement or other secondary complications, thereby reducing the risk for hospitalization and death.\nThe effectiveness of influenza vaccine in preventing or attenuating illness varies, depending primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the virus strains included in the vaccine and those that circulate during the influenza season. When a good match exists between vaccine and circulating viruses, influenza vaccine has been shown to prevent illness in approximately 70%-90% of healthy persons aged <65 years. In these circumstances, studies also have indicated that the effectiveness of influenza vaccine in preventing hospitalization for pneumonia and influenza among elderly persons living in settings other than nursing homes or similar chronic-care facilities ranges from 30% to 70%.\nAmong elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and death. Studies of this population have indicated that the vaccine can be 50%-60% effective in preventing hospitalization and pneumonia and 80% effective in preventing death, even though efficacy in preventing influenza illness may often be in the range of 30%-40% among the frail elderly. Achieving a high rate of vaccination among nursing home residents can reduce the spread of infection in a facility, thus preventing disease through herd immunity.\n\n# RECOMMENDATIONS FOR THE USE OF INFLUENZA VACCINE\nInfluenza vaccine is strongly recommended for any person aged ≥6 months whobecause of age or underlying medical condition-is at increased risk for complications of influenza. Health-care workers and others (including household members) in close contact with persons in high-risk groups also should be vaccinated. In addition, influenza vaccine may be administered to any person who wishes to reduce the chance of becoming infected with influenza. The trivalent influenza vaccine prepared for the 1997-98 season will include A/Bayern/07/95-like (H1N1), A/Wuhan/359/95-like (H3N2), and B/Beijing/184/93-like hemagglutinin antigens. For the A/Bayern/07/95-like, A/Wuhan/ 359/95-like, and B/Beijing/184/93-like antigens, U.S. manufacturers will use the antigenically equivalent strains A/Johannesburg/82/96(H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/07/94 because of their growth properties. Guidelines for the use of vaccine among certain patient populations follow; dosage recommendations vary according to age group (Table 1).\nAlthough the current influenza vaccine can contain one or more of the antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines in the year following vaccination. Because the 1997-98 vaccine differs from the 1996-97 vaccine, supplies of 1996-97 vaccine should not be administered to provide protection for the 1997-98 influenza season.\nTwo doses administered at least 1 month apart may be required for satisfactory antibody responses among previously unvaccinated children aged <9 years; however, studies of vaccines similar to those being used currently have indicated little or no improvement in antibody response when a second dose is administered to adults during the same season.\nDuring recent decades, data on influenza vaccine immunogenicity and side effects have been obtained for intramuscularly administered vaccine. Because recent influenza vaccines have not been adequately evaluated when administered by other routes, the intramuscular route is recommended. Adults and older children should be vaccinated in the deltoid muscle and infants and young children in the anterolateral aspect of the thigh. - Children and teenagers (aged 6 months-18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing Reye syndrome after influenza\n- Women who will be in the second or third trimester of pregnancy during the influenza season Influenza-associated excess mortality among pregnant women has not been documented except during the pandemics of 1918-19 and 1957-58. However, because death-certificate data often do not indicate whether a woman was pregnant at the time of death, studies conducted during interpandemic periods may underestimate the impact of influenza in this population. Case reports and limited studies suggest that pregnancy may increase the risk for serious medical complications of influenza as a result of increases in heart rate, stroke volume and oxygen consumption, decreases in lung capacity, and changes in immunologic function. A recent study of the impact of influenza during 17 interpandemic influenza seasons documented that the relative risk of hospitalization for selected cardiorespiratory conditions among pregnant women increased from 1.4 during weeks 14-20 of gestation to 4.7 during weeks 37-42 compared with rates among women who were 1-6 months postpartum. Women in their third trimester of pregnancy were hospitalized at a rate comparable to that of nonpregnant women who have high-risk medical conditions for whom influenza vaccine has traditionally been recommended. Using data from this study, it was estimated that an average of 1 to 2 hospitalizations among pregnant women could be prevented for every 1,000 pregnant women immunized.\nOn the basis of these and other data that suggest that influenza infection may cause increased morbidity in women during the second and third trimesters of pregnancy, the Advisory Committee on Immunization Practices (ACIP) recommends that women who will be beyond the first trimester of pregnancy (14 weeks' gestation) during the influenza season be vaccinated. Pregnant women who have medical conditions that increase their risk for complications from influenza should be vaccinated before the influenza season-regardless of the stage of pregnancy. Studies of influenza immunization of more than 2,000 pregnant women have demonstrated no adverse fetal effects associated with influenza vaccine; however, more data are needed. Because influenza vaccine is not a live virus vaccine and major systemic reactions to it are rare, many experts consider influenza vaccination safe during any stage of pregnancy. However, because spontaneous abortion is common in the first trimester and unnecessary exposures have traditionally been avoided during this time, some experts prefer influenza vaccination during the second trimester to avoid coincidental association of the vaccine with early pregancy loss.\n\n# Groups that Can Transmit Influenza to Persons at High Risk\nPersons who are clinically or subclinically infected can transmit influenza virus to persons at high risk that they care for or live with. Some persons at high risk (e.g., the elderly, transplant recipients, and persons with AIDS) can have a low antibody response to influenza vaccine. Efforts to protect these members of high-risk groups against influenza might be improved by reducing the likelihood of influenza exposure from their caregivers. Therefore, the following groups should be vaccinated:\n- physicians, nurses, and other personnel in both hospital and outpatient-care settings;\n- employees of nursing homes and chronic-care facilities who have contact with patients or residents;\n- providers of home care to persons at high risk (e.g., visiting nurses and volunteer workers); and\n- household members (including children) of persons in high-risk groups.\n\n# VACCINATION OF OTHER GROUPS Persons Infected with Human Immunodeficiency Virus\nLimited information exists regarding the frequency and severity of influenza illness among human immunodeficiency virus (HIV)-infected persons, but reports suggest that symptoms might be prolonged and the risk for complications increased for some HIV-infected persons. Influenza vaccine has produced protective antibody titers against influenza in vaccinated HIV-infected persons who have minimal AIDSrelated symptoms and high CD4+ T-lymphocyte cell counts. In patients who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, however, influenza vaccine may not induce protective antibody titers; a second dose of vaccine does not improve the immune response for these persons.\nRecent studies have examined the effect of influenza vaccination on replication of HIV type 1 (HIV-1). Although some studies have demonstrated a transient (i.e., 2-to 4-week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration, other studies using similar laboratory techniques have not indicated any substantial increase in replication. Deterioration of CD4+ T-lymphocyte cell counts and progression of clinical HIV disease have not been demonstrated among HIV-infected persons who receive vaccine. Because influenza can result in serious illness and complications and because influenza vaccination may result in protective antibody titers, vaccination will benefit many HIV-infected patients.\n\n# Breastfeeding Mothers\nInfluenza vaccine does not affect the safety of breastfeeding for mothers or infants. Breastfeeding does not adversely affect immune response and is not a contraindication for vaccination.\n\n# Persons Traveling to Foreign Countries\nThe risk for exposure to influenza during travel to foreign countries varies, depending on season and destination. In the tropics, influenza can occur throughout the year; in the Southern Hemisphere, most activity occurs from April through September. Because of the short incubation period for influenza, exposure to the virus during travel can result in clinical illness that begins while traveling, which is an inconvenience or potential danger, especially for persons at increased risk for complications. Persons preparing to travel to the tropics at any time of year or to the Southern Hemisphere from April through September should review their influenza vaccination histories. If they were not vaccinated the previous fall or winter, they should consider influenza vaccination before travel. Persons in high-risk groups should be especially encouraged to receive the most current vaccine. Persons at high risk who received the previous season's vaccine before travel should be revaccinated in the fall or winter with the current vaccine.\n\n# General Population\nPhysicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza. Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics.\n\n# PERSONS WHO SHOULD NOT BE VACCINATED\nInactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Use of an antiviral agent (i.e., amantadine or rimantadine) is an option for prevention of influenza A in such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications of influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Specific information about vaccine components can be found in package inserts for each manufacturer.\nAdults with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever should not contraindicate the use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis.\n\n# SIDE EFFECTS AND ADVERSE REACTIONS\nBecause influenza vaccine contains only noninfectious viruses, it cannot cause influenza. Respiratory disease after vaccination represents coincidental illness unrelated to influenza vaccination. The most frequent side effect of vaccination is soreness at the vaccination site that lasts up to 2 days. These local reactions generally are mild and rarely interfere with the ability to conduct usual daily activities. In addition, two types of systemic reactions have occurred:\n- Fever, malaise, myalgia, and other systemic symptoms can occur following vaccination and most often affect persons who have had no exposure to the influenza virus antigens in the vaccine (e.g., young children). These reactions begin 6-12 hours after vaccination and can persist for 1 or 2 days. Recent placebo-controlled trials suggest that in elderly persons and healthy young adults, split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections.\n- Immediate-presumably allergic-reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. These reactions probably result from hypersensitivity to some vaccine component; most reactions likely are caused by residual egg protein. Although current influenza vaccines contain only a small quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have developed hives, have had swelling of the lips or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs-including those who have had occupational asthma or other allergic responses due to exposure to egg protein-might also be at increased risk for reactions from influenza vaccine, and similar consultation should be considered. The protocol for influenza vaccination developed by Murphy and Strunk may be considered for patients who have egg allergies and medical conditions that place them at increased risk for influenzaassociated complications.\nHypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, most patients do not develop reactions to thimerosal when administered as a component of vaccines-even when patch or intradermal tests for thimerosal indicate hypersensitivity. When reported, hypersensitivity to thimerosal usually has consisted of local, delayed-type hypersensitivity reactions.\nUnlike the 1976 swine influenza vaccine, subsequent vaccines prepared from other virus strains have not been clearly associated with an increased frequency of Guillain-Barré syndrome (GBS). However, obtaining a precise estimate of a small increase in risk is difficult for a rare condition such as GBS, which has an annual background incidence of only one to two cases per 100,000 adult population. During five of six seasons studied since 1976, the point estimates of the relative risks of GBS after influenza vaccination were slightly elevated; however, in none of these studies was the overall elevation in relative risk statistically significant. In the two most recently studied seasons, the combined number of GBS cases peaked 2 weeks after vaccination. Data from all of these studies suggest that if an increased relative risk does exist, it is lower for persons aged ≥65 years than for those 18-64 years of age. The slight increase in the point estimates of the relative risks and the increased number of cases in the second week after vaccination may be the result of vaccination but also could be due to other factors (e.g., confounding or diagnostic bias) rather than a true vaccinerelated risk.\nAmong persons who received the swine influenza vaccine in 1976, the rate of GBS that exceeded the background rate was slightly less than one case per 100,000 vaccinations. Even if GBS were a true side effect in subsequent years, the estimated risk for GBS was much lower than 1:100,000 and substantially less than that for severe influenza, which could be prevented by vaccination, especially for persons aged ≥65 years and those who have medical indications for influenza vaccination.\nWhereas the incidence of GBS in the general population is very low, persons with a history of GBS have a substantially greater likelihood of subsequently developing GBS than persons without such a history. Thus, the likelihood of coincidentally developing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination might be causally associated with this risk for recurrence is not known. Although avoiding a subsequent influenza vaccination in persons known to have developed GBS within 6 weeks of a previous influenza vaccination seems prudent, for most persons with a history of GBS who are at high risk for severe complications from influenza the established benefits of influenza vaccination justify yearly vaccination.\n\n# SIMULTANEOUS ADMINISTRATION OF OTHER VACCINES, INCLUDING CHILDHOOD VACCINES\nThe target groups for influenza and pneumococcal vaccination overlap considerably. For persons at high risk who have not previously been vaccinated with pneumococcal vaccine, health-care providers should strongly consider administering pneumococcal and influenza vaccines concurrently. Both vaccines can be administered at the same time at different sites without increasing side effects. However, influenza vaccine is administered each year, whereas pneumococcal vaccine is not. Children at high risk for influenza-related complications can receive influenza vaccine at the same time they receive other routine vaccinations, including pertussis vaccine (DTaP or DTP). Because influenza vaccine can cause fever when administered to young children, DTaP (which is less frequently associated with fever and other adverse events) is preferable.\n\n# TIMING OF INFLUENZA VACCINATION ACTIVITIES\nBeginning each September (when vaccine for the upcoming influenza season becomes available) persons at high risk who are seen by health-care providers for routine care or as a result of hospitalization should be offered influenza vaccine. Opportunities to vaccinate persons at high risk for complications of influenza should not be missed.\nThe optimal time for organized vaccination campaigns for persons in high-risk groups is usually the period from October through mid-November. In the United States, influenza activity generally peaks between late December and early March. High levels of influenza activity infrequently occur in the contiguous 48 states before December. Administering vaccine too far in advance of the influenza season should be avoided in facilities such as nursing homes, because antibody levels might begin to decline within a few months of vaccination. Vaccination programs can be undertaken as soon as current vaccine is available if regional influenza activity is expected to begin earlier than December.\nChildren aged <9 years who have not been vaccinated previously should receive two doses of vaccine at least 1 month apart to maximize the likelihood of a satisfactory antibody response to all three vaccine antigens. The second dose should be administered before December, if possible. Vaccine should be offered to both children and adults up to and even after influenza virus activity is documented in a community.\n\n# STRATEGIES FOR IMPLEMENTING INFLUENZA VACCINE RECOMMENDATIONS\nSuccessful vaccination programs have combined education for health-care workers, publicity and education targeted toward potential recipients, a plan for identifying persons at high risk (usually by medical-record review), and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine. Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following paragraphs.\n\n# Outpatient Clinics and Physicians' Offices\nStaff in physicians' offices, clinics, health-maintenance organizations, and employee health clinics should be instructed to identify and label the medical records of patients who should receive vaccine. Vaccine should be offered during visits beginning in September and throughout the influenza season. The offer of vaccine and its receipt or refusal should be documented in the medical record. Patients in high-risk groups who do not have regularly scheduled visits during the fall should be reminded by mail or telephone of the need for vaccine. If possible, arrangements should be made to provide vaccine with minimal waiting time and at the lowest possible cost.\n\n# Facilities Providing Episodic or Acute Care\nHealth-care providers in these settings (e.g., emergency rooms and walk-in clinics) should be familiar with influenza vaccine recommendations. They should offer vaccine to persons in high-risk groups or should provide written information on why, where, and how to obtain the vaccine. Written information should be available in language(s) appropriate for the population served by the facility.\n\n# Nursing Homes and Other Residential Long-Term-Care Facilities\nVaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians rather than by obtaining individual vaccination orders for each patient. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility, and all residents should be vaccinated at one time, immediately preceding the influenza season. Residents admitted during the winter months after completion of the vaccination program should be vaccinated when they are admitted.\n\n# Acute-Care Hospitals\nAll persons aged ≥65 years and younger persons (including children) with high-risk conditions who are hospitalized at any time from September through March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. Household members and others with whom they will have contact should receive written information about why and where to obtain influenza vaccine.\n\n# Outpatient Facilities Providing Continuing Care to Patients at High Risk\nAll patients should be offered vaccine before the beginning of the influenza season.\nPatients admitted to such programs (e.g., hemodialysis centers, hospital specialtycare clinics, and outpatient rehabilitation programs) during the winter months after the earlier vaccination program has been conducted should be vaccinated at the time of admission. Household members should receive written information regarding the need for vaccination and the places to obtain influenza vaccine.\n\n# Visiting Nurses and Others Providing Home Care to Persons at High Risk\nNursing-care plans should identify patients in high-risk groups, and vaccine should be provided in the home if necessary. Caregivers and other persons in the household (including children) should be referred for vaccination.\n\n# Facilities Providing Services to Persons Aged ≥65 Years\nIn these facilities (e.g., retirement communities and recreation centers), all unvaccinated residents/attendees should be offered vaccine on site before the influenza season. Education/publicity programs also should be provided; these programs should emphasize the need for influenza vaccine and provide specific information concerning how, where, and when to obtain it.\n\n# Clinics and Others Providing Health Care for Travelers\nIndications for influenza vaccination should be reviewed before travel. Vaccine should be offered, if appropriate (see Travelers to Foreign Countries).\n\n# Health-Care Workers\nAdministrators of all health-care facilities should arrange for influenza vaccine to be offered to all personnel before the influenza season. Personnel should be provided with appropriate educational materials and strongly encouraged to receive vaccine. Particular emphasis should be placed on vaccination of persons who care for members of high-risk groups (e.g., staff of intensive-care units , staff of medical/surgical units, and employees of nursing homes and chronic-care facilities). Using a mobile cart to take vaccine to hospital wards or other work sites and making vaccine available during night and weekend work shifts can enhance compliance, as can a follow-up campaign early in the course of a community outbreak.\n\n# ANTIVIRAL AGENTS FOR INFLUENZA A\nThe two antiviral agents with specific activity against influenza A viruses are amantadine hydrochloride and rimantadine hydrochloride. These chemically related drugs interfere with the replication cycle of type A (but not type B) influenza viruses. When administered prophylactically to healthy adults or children before and throughout the epidemic period, both drugs are approximately 70%-90% effective in preventing illness caused by naturally occurring strains of type A influenza viruses. Because antiviral agents taken prophylactically can prevent illness but not subclinical infection, some persons who take these drugs can still develop immune responses that will protect them when they are exposed to antigenically related viruses in later years.\nIn otherwise healthy adults, amantadine and rimantadine can reduce the severity and duration of signs and symptoms of influenza A illness when administered within 48 hours of illness onset. Studies evaluating the efficacy of treatment for children with either amantadine or rimantadine are limited. Amantadine was approved for treatment and prophylaxis of all influenza type A virus infections in 1976. Although few placebo-controlled studies were conducted to determine the efficacy of amantadine treatment among children before approval, amantadine is indicated for treatment and prophylaxis of adults and children aged ≥1 year. Rimantadine was approved in 1993 for treatment and prophylaxis in adults but was approved only for prophylaxis in children. Further studies might provide the data needed to support future approval of rimantadine treatment in this age group.\nAs with all drugs, amantadine and rimantadine can cause adverse reactions in some persons. Such adverse reactions rarely are severe; however, for some categories of patients, severe adverse reactions are more likely to occur. Amantadine has been associated with a higher incidence of adverse central nervous system (CNS) reactions than rimantadine (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment).\n\n# RECOMMENDATIONS FOR THE USE OF AMANTADINE AND RIMANTADINE\n\n# Use as Prophylaxis\nChemoprophylaxis is not a substitute for vaccination. Recommendations for chemoprophylaxis are provided primarily to help health-care providers make decisions regarding persons who are at greatest risk for severe illness and complications if infected with influenza A virus.\nWhen amantadine or rimantadine is administered as prophylaxis, factors such as cost, compliance, and potential side effects should be considered when determining the period of prophylaxis. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost effective, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community.\n\n# Persons at High Risk Vaccinated After Influenza A Activity Has Begun\nPersons at high risk still can be vaccinated after an outbreak of influenza A has begun in a community. However, the development of antibodies in adults after vaccination can take as long as 2 weeks, during which time chemoprophylaxis should be considered. Children who receive influenza vaccine for the first time can require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 2 weeks after the second dose of vaccine has been received). Amantadine and rimantadine do not interfere with the antibody response to the vaccine.\n\n# Persons Providing Care to Those at High Risk\nTo reduce the spread of virus to persons at high risk, chemoprophylaxis may be considered during community outbreaks for a) unvaccinated persons who have frequent contact with persons at high risk (e.g., household members, visiting nurses, and volunteer workers) and b) unvaccinated employees of hospitals, clinics, and chronic-care facilities. For those persons who cannot be vaccinated, chemoprophylaxis during the period of peak influenza activity may be considered. For those persons who receive vaccine at a time when influenza A is present in the community, chemoprophylaxis can be administered for 2 weeks after vaccination. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that might not be controlled by the vaccine.\n\n# Persons Who Have Immune Deficiency\nChemoprophylaxis might be indicated for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons who have HIV infection, especially those who have advanced HIV disease. No data are available concerning possible interactions with other drugs used in the management of patients who have HIV infection. Such patients should be monitored closely if amantadine or rimantadine chemoprophylaxis is administered.\n\n# Persons for Whom Influenza Vaccine Is Contraindicated\nChemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Influenza vaccine may be contraindicated in persons who have severe anaphylactic hypersensitivity to egg protein or other vaccine components.\n\n# Other Persons\nAmantadine or rimantadine also can be administered prophylactically to anyone who wishes to avoid influenza A illness. The health-care provider and patient should make this decision on an individual basis.\n\n# Use of Antivirals as Therapy\nAmantadine and rimantadine can reduce the severity and shorten the duration of influenza A illness among healthy adults when administered within 48 hours of illness onset. Whether antiviral therapy will prevent complications of influenza type A among persons at high risk is unknown. Insufficient data exist to determine the efficacy of rimantadine treatment in children. Thus, rimantadine is currently approved only for prophylaxis in children, but it is not approved for treatment in this age group. Amantadine-and rimantadine-resistant influenza A viruses can emerge when either of these drugs is administered for treatment; amantadine-resistant strains are cross-resistant to rimantadine and vice versa. Both the frequency with which resistant viruses emerge and the extent of their transmission are unknown, but data indicate that amantadine-and rimantadine-resistant viruses are no more virulent or transmissible than amantadine-and rimantadine-sensitive viruses.\nThe screening of naturally occurring epidemic strains of influenza type A has rarely detected amantadine-and rimantadine-resistant viruses. Resistant viruses have most frequently been isolated from persons taking one of these drugs as therapy for influenza A infection. Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy. Persons who have influenza-like illness should avoid contact with uninfected persons as much as possible, regardless of whether they are being treated with amantadine or rimantadine. Persons who have influenza type A infection and who are treated with either drug can shed amantadine-or rimantadinesensitive viruses early in the course of treatment, but can later shed drug-resistant viruses, especially after 5-7 days of therapy. Such persons can benefit from therapy even when resistant viruses emerge; however, they also can transmit infection to other persons with whom they come in contact. Because of possible induction of amantadine or rimantadine resistance, treatment of persons who have influenza-like illness should be discontinued as soon as clinically warranted, generally after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. Laboratory isolation of influenza viruses obtained from persons who are receiving amantadine or rimantadine should be reported to CDC through state health departments, and the isolates should be sent to CDC for antiviral sensitivity testing.\n\n# Outbreak Control in Institutions\nWhen confirmed or suspected outbreaks of influenza A occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. Contingency planning is needed to ensure rapid administration of amantadine or rimantadine to residents. This planning should include preapproved medication orders or plans to obtain physicians' orders on short notice. When amantadine or rimantadine is used for outbreak control, the drug should be administered to all residents of the institution-regardless of whether they received influenza vaccine the previous fall. The drug should be continued for at least 2 weeks or until approximately 1 week after the end of the outbreak. The dose for each resident should be determined after consulting the dosage recommendations and precautions (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment) and the manufacturer's package insert. To reduce the spread of virus and to minimize disruption of patient care, chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that is not controlled by the vaccine.\nChemoprophylaxis also may be considered for controlling influenza A outbreaks in other closed or semi-closed settings (e.g., dormitories or other settings where persons live in close proximity). To reduce the spread of infection and the chances of prophylaxis failure resulting from transmission of drug-resistant virus, measures should be taken to reduce contact as much as possible between persons on chemoprophylaxis and those taking drug for treatment.\n\n# CONSIDERATIONS FOR SELECTING AMANTADINE OR RIMANTADINE FOR CHEMOPROPHYLAXIS OR TREATMENT\n\n# Side Effects/Toxicity\nDespite the similarities between the two drugs, amantadine and rimantadine differ in their pharmacokinetic properties. More than 90% of amantadine is excreted unchanged, whereas approximately 75% of rimantadine is metabolized by the liver. However, both drugs and their metabolites are excreted by the kidneys.\nThe pharmacokinetic differences between amantadine and rimantadine might explain differences in side effects. Although both drugs can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine compared with those taking rimantadine. In a 6-week study of prophylaxis in healthy adults, approximately 6% of participants taking rimantadine at a dose of 200 mg/day experienced at least one CNS symptom, compared with approximately 14% of those taking the same dose of amantadine and 4% of those taking placebo. The incidence of gastrointestinal side effects (e.g., nausea and anorexia) is approximately 3% among persons taking either drug, compared with 1%-2% among persons receiving the pla-cebo. Side effects associated with both drugs are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects, and recommendations for reduced dosages for these groups of patients have been made. Because rimantadine has been marketed for a shorter period of time than amantadine, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently. Clinical trials of rimantadine have more commonly involved young, healthy persons.\nProviders should review the package insert before using amantadine or rimantadine for any patient. The patient's age, weight, and renal function; the presence of other medical conditions; the indications for use of amantadine or rimantadine (i.e., prophylaxis or therapy); and the potential for interaction with other medications must be considered, and the dosage and duration of treatment must be adjusted appropriately. Modifications in dosage might be required for persons who have impaired renal or hepatic function, the elderly, children, and persons with a history of seizures (Table 2). The following are guidelines for the use of amantadine and rimantadine in certain patient populations.\n\n# Persons Who Have Impaired Renal Function Amantadine\nAmantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion. Thus, renal clearance of amantadine is reduced substantially in persons with renal insufficiency. A reduction in dosage is recommended for patients with creatinine clearance ≤50 mL/min/1.73m 2 . Guidelines for amantadine dosage based on creatinine clearance are found in the packet insert. However, because recommended dosages based on creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully so that adverse reactions can be recognized promptly and either the dose can be further reduced or the drug can be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance.\n\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration. Further studies are needed to determine the multiple-dose pharmacokinetics and the most appropriate dosages for these patients.\nIn a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that in healthy controls of the same age. Hemodialysis did not contribute to drug clearance. In studies among persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher compared with control patients without renal disease who were the same weight, age, and sex.\nA reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance ≤10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including elderly persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary.\n\n# Persons Aged ≥65 Years Amantadine\nBecause renal function declines with increasing age, the daily dose for persons aged ≥65 years should not exceed 100 mg for prophylaxis or treatment. For some elderly persons, the dose should be further reduced. Studies suggest that because of their smaller average body size, elderly women are more likely than elderly men to experience side effects at a daily dose of 100 mg.\n\n# Rimantadine\nThe incidence and severity of CNS side effects among elderly persons appear to be substantially lower among those taking rimantadine at a dose of 200 mg/day compared with elderly persons taking the same dose of amantadine. However, when rimantadine has been administered at a dosage of 200 mg/day to chronically ill elderly persons, they have had a higher incidence of CNS and gastrointestinal symptoms than healthy, younger persons taking rimantadine at the same dosage. After longterm administration of rimantadine at a dosage of 200 mg/day, serum rimantadine concentrations among elderly nursing-home residents have been twofold to fourfold greater than those reported in younger adults.\nThe dosage of rimantadine should be reduced to 100 mg/day for treatment or prophylaxis of elderly nursing-home residents. Although further studies are needed to determine the optimal dose for other elderly persons, a reduction in dosage to 100 mg/day should be considered for all persons aged ≥65 years if they experience signs and symptoms that might represent side effects when taking a dosage of 200 mg/day.\n\n# Persons Who Have Liver Disease Amantadine\nNo increase in adverse reactions to amantadine has been observed among persons who have liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine, although a specific relationship between the drug and such changes has not been established.\n\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine only have been evaluated after single-dose administration. In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations were observed after a single dose. However, in persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease. A dose reduction to 100 mg/day is recommended for persons with severe hepatic dysfunction.\n\n# Persons Who Have Seizure Disorders Amantadine\nAn increased incidence of seizures has been reported in patients with a history of seizure disorders who have received amantadine. Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.\n\n# Rimantadine\nIn clinical trials, seizures (or seizure-like activity) have been observed in a few persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine. The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated, because such persons usually have been excluded from participating in clinical trials of rimantadine.\n\n# Children Amantadine\nThe use of amantadine in children aged <1 year has not been adequately evaluated. The FDA-approved dosage for children aged 1-9 years is 4.4-8.8 mg/kg/day, not to exceed 150 mg/day. Although further studies to determine the optimal dosage for children are needed, physicians should consider prescribing only 5 mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children aged ≥10 years is 200 mg/day; however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable.\n\n# Rimantadine\nThe use of rimantadine in children aged <1 year has not been adequately evaluated. In children aged 1-9 years, rimantadine should be administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day. The approved dosage for children aged ≥10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, also is recommended.\n\n# Drug Interactions Amantadine\nCareful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs may increase the incidence of adverse CNS reactions.\n\n# Rimantadine\nNo clinically significant interactions between rimantadine and other drugs have been identified. For more detailed information concerning potential drug interactions for either drug, the package insert should be consulted.\n\n# SOURCES OF INFORMATION ON INFLUENZA-CONTROL PROGRAMS\nThe Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to listserv@listserv.cdc.gov. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at / or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800.\nData in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (404) 332-4555.\nAll material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. 6U.S. Government Printing Office: 1996-733-175/47072 Region IV\nThe following CDC staff members prepared this report:"},"raw_text":{"kind":"string","value":"These recommendations update information concerning the vaccine and antiviral agents available for controlling influenza during the 1997-98 influenza season (superseding MMWR 1996;45[No. RR-5]:1-24). The principal changes include information about a) the influenza virus strains included in the trivalent vaccine for 1997-98, b) the vaccination of pregnant and breastfeeding women, and c) side effects and adverse reactions.# INTRODUCTION\nInfluenza A viruses are classified into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). Three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and N2) are recognized among influenza A viruses that have caused widespread human disease. Immunity to these antigens-especially to the hemagglutinin-reduces the likelihood of infection and lessens the severity of disease if infection occurs. Infection with a virus of one subtype confers little or no protection against viruses of other subtypes. Furthermore, over time, antigenic variation (antigenic drift) within a subtype may be so marked that infection or vaccination with one strain may not induce immunity to distantly related strains of the same subtype. Although influenza B viruses have shown more antigenic stability than influenza A viruses, antigenic variation does occur. For these reasons, major epidemics of respiratory disease caused by new variants of influenza continue to occur. The antigenic characteristics of circulating strains provide the basis for selecting the virus strains included in each year's vaccine.\nTypical influenza illness is characterized by abrupt onset of fever, myalgia, sore throat, and nonproductive cough. Unlike other common respiratory illnesses, influenza can cause severe malaise lasting several days. More severe illness can result if either primary influenza pneumonia or secondary bacterial pneumonia occurs. During influenza epidemics, high attack rates of acute illness result in both increased numbers of visits to physicians' offices, walk-in clinics, and emergency rooms and increased hospitalizations for management of lower respiratory tract complications.\nElderly persons and persons with underlying health problems are at increased risk for complications of influenza. If they become ill with influenza, such members of high-risk groups (see Groups at Increased Risk for Influenza-Related Complications) are more likely than the general population to require hospitalization. During major epidemics, hospitalization rates for persons at high risk may increase twofold to fivefold, depending on the age group. Previously healthy children and younger adults also may require hospitalization for influenza-related complications, but the relative increase in their hospitalization rates is less than for persons who belong to high-risk groups.\nAn increase in mortality further indicates the impact of influenza epidemics. Increased mortality results not only from influenza and pneumonia but also from cardiopulmonary and other chronic diseases that can be exacerbated by influenza. An estimated >20,000 influenza-associated deaths occurred during each of nine different U.S. epidemics from 1972-73 to 1991-92, and >40,000 influenza-associated deaths occurred during each of four of these epidemics. More than 90% of the deaths attributed to pneumonia and influenza occurred among persons aged ≥65 years.\nThe number of elderly persons in the U.S. population is increasing, as well as the number of persons aged <65 years at increased risk for influenza-related complications. Longer life expectancy for a) organ-transplant recipients, b) neonates in intensive-care units, and c) persons who have cystic fibrosis and acquired immunodeficiency syndrome (AIDS) results in a higher survival rate for younger persons at high risk for influenza.\nInfluenza vaccine campaigns are targeted to approximately 32 million persons aged ≥65 years and 27 million to 31 million persons aged <65 years who are at high risk for influenza-associated complications. National health objectives for the year 2000 include vaccination of at least 60% of persons at risk for severe influenza-related illness.\nInfluenza vaccination levels among persons aged ≥65 years increased substantially from 1985 (23%) to 1994 (55%), although vaccination levels among persons aged <65 years at high risk for influenza are estimated to be <30%. Possible reasons for the increase in influenza vaccination levels, especially among persons aged ≥65 years, include greater acceptance of preventive medical services by practitioners, increased delivery and administration of vaccine by health-care providers and sources other than physicians, and the initiation of Medicare reimbursement for influenza vaccination in 1993.\n# OPTIONS FOR THE CONTROL OF INFLUENZA\nIn the United States, two measures are available that can reduce the impact of influenza: immunoprophylaxis with inactivated (i.e., killed-virus) vaccine and chemoprophylaxis or therapy with an influenza-specific antiviral drug (amantadine or rimantadine). Vaccinating persons at high risk before the influenza season each year is the most effective measure for reducing the impact of influenza. Vaccination can be highly cost effective when it is a) directed at persons who are most likely to experience complications or who are at increased risk for exposure and b) administered to persons at high risk during hospitalizations or routine health-care visits before the influenza season, thus making special visits to physicians' offices or clinics unnecessary. When vaccine and epidemic strains of virus are well matched, achieving high vaccination rates among persons living in closed settings (e.g., nursing homes and other chronic-care facilities) can reduce the risk for outbreaks by inducing herd immunity.\n# INACTIVATED VACCINE FOR INFLUENZA A AND B\nEach year's influenza vaccine contains three virus strains (usually two type A and one type B) representing the influenza viruses that are likely to circulate in the United States in the upcoming winter. The vaccine is made from highly purified, egg-grown viruses that have been made noninfectious (inactivated). Influenza vaccine rarely causes systemic or febrile reactions. Whole-virus, subvirion, and purified-surfaceantigen preparations are available.\nMost vaccinated children and young adults develop high postvaccination hemagglutination-inhibition antibody titers. These antibody titers are protective against illness caused by strains similar to those in the vaccine or the related variants that may emerge during outbreak periods. Elderly persons and persons with certain chronic diseases may develop lower postvaccination antibody titers than healthy young adults and thus may remain susceptible to influenza-related upper respiratory tract infection. However, even if such persons develop influenza illness despite vaccination, the vaccine can be effective in preventing lower respiratory tract involvement or other secondary complications, thereby reducing the risk for hospitalization and death.\nThe effectiveness of influenza vaccine in preventing or attenuating illness varies, depending primarily on the age and immunocompetence of the vaccine recipient and the degree of similarity between the virus strains included in the vaccine and those that circulate during the influenza season. When a good match exists between vaccine and circulating viruses, influenza vaccine has been shown to prevent illness in approximately 70%-90% of healthy persons aged <65 years. In these circumstances, studies also have indicated that the effectiveness of influenza vaccine in preventing hospitalization for pneumonia and influenza among elderly persons living in settings other than nursing homes or similar chronic-care facilities ranges from 30% to 70%.\nAmong elderly persons residing in nursing homes, influenza vaccine is most effective in preventing severe illness, secondary complications, and death. Studies of this population have indicated that the vaccine can be 50%-60% effective in preventing hospitalization and pneumonia and 80% effective in preventing death, even though efficacy in preventing influenza illness may often be in the range of 30%-40% among the frail elderly. Achieving a high rate of vaccination among nursing home residents can reduce the spread of infection in a facility, thus preventing disease through herd immunity.\n# RECOMMENDATIONS FOR THE USE OF INFLUENZA VACCINE\nInfluenza vaccine is strongly recommended for any person aged ≥6 months whobecause of age or underlying medical condition-is at increased risk for complications of influenza. Health-care workers and others (including household members) in close contact with persons in high-risk groups also should be vaccinated. In addition, influenza vaccine may be administered to any person who wishes to reduce the chance of becoming infected with influenza. The trivalent influenza vaccine prepared for the 1997-98 season will include A/Bayern/07/95-like (H1N1), A/Wuhan/359/95-like (H3N2), and B/Beijing/184/93-like hemagglutinin antigens. For the A/Bayern/07/95-like, A/Wuhan/ 359/95-like, and B/Beijing/184/93-like antigens, U.S. manufacturers will use the antigenically equivalent strains A/Johannesburg/82/96(H1N1), A/Nanchang/933/95 (H3N2), and B/Harbin/07/94 because of their growth properties. Guidelines for the use of vaccine among certain patient populations follow; dosage recommendations vary according to age group (Table 1).\nAlthough the current influenza vaccine can contain one or more of the antigens administered in previous years, annual vaccination with the current vaccine is necessary because immunity declines in the year following vaccination. Because the 1997-98 vaccine differs from the 1996-97 vaccine, supplies of 1996-97 vaccine should not be administered to provide protection for the 1997-98 influenza season.\nTwo doses administered at least 1 month apart may be required for satisfactory antibody responses among previously unvaccinated children aged <9 years; however, studies of vaccines similar to those being used currently have indicated little or no improvement in antibody response when a second dose is administered to adults during the same season.\nDuring recent decades, data on influenza vaccine immunogenicity and side effects have been obtained for intramuscularly administered vaccine. Because recent influenza vaccines have not been adequately evaluated when administered by other routes, the intramuscular route is recommended. Adults and older children should be vaccinated in the deltoid muscle and infants and young children in the anterolateral aspect of the thigh. • Children and teenagers (aged 6 months-18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing Reye syndrome after influenza\n• Women who will be in the second or third trimester of pregnancy during the influenza season Influenza-associated excess mortality among pregnant women has not been documented except during the pandemics of 1918-19 and 1957-58. However, because death-certificate data often do not indicate whether a woman was pregnant at the time of death, studies conducted during interpandemic periods may underestimate the impact of influenza in this population. Case reports and limited studies suggest that pregnancy may increase the risk for serious medical complications of influenza as a result of increases in heart rate, stroke volume and oxygen consumption, decreases in lung capacity, and changes in immunologic function. A recent study of the impact of influenza during 17 interpandemic influenza seasons documented that the relative risk of hospitalization for selected cardiorespiratory conditions among pregnant women increased from 1.4 during weeks 14-20 of gestation to 4.7 during weeks 37-42 compared with rates among women who were 1-6 months postpartum. Women in their third trimester of pregnancy were hospitalized at a rate comparable to that of nonpregnant women who have high-risk medical conditions for whom influenza vaccine has traditionally been recommended. Using data from this study, it was estimated that an average of 1 to 2 hospitalizations among pregnant women could be prevented for every 1,000 pregnant women immunized.\nOn the basis of these and other data that suggest that influenza infection may cause increased morbidity in women during the second and third trimesters of pregnancy, the Advisory Committee on Immunization Practices (ACIP) recommends that women who will be beyond the first trimester of pregnancy (14 weeks' gestation) during the influenza season be vaccinated. Pregnant women who have medical conditions that increase their risk for complications from influenza should be vaccinated before the influenza season-regardless of the stage of pregnancy. Studies of influenza immunization of more than 2,000 pregnant women have demonstrated no adverse fetal effects associated with influenza vaccine; however, more data are needed. Because influenza vaccine is not a live virus vaccine and major systemic reactions to it are rare, many experts consider influenza vaccination safe during any stage of pregnancy. However, because spontaneous abortion is common in the first trimester and unnecessary exposures have traditionally been avoided during this time, some experts prefer influenza vaccination during the second trimester to avoid coincidental association of the vaccine with early pregancy loss.\n# Groups that Can Transmit Influenza to Persons at High Risk\nPersons who are clinically or subclinically infected can transmit influenza virus to persons at high risk that they care for or live with. Some persons at high risk (e.g., the elderly, transplant recipients, and persons with AIDS) can have a low antibody response to influenza vaccine. Efforts to protect these members of high-risk groups against influenza might be improved by reducing the likelihood of influenza exposure from their caregivers. Therefore, the following groups should be vaccinated:\n• physicians, nurses, and other personnel in both hospital and outpatient-care settings;\n• employees of nursing homes and chronic-care facilities who have contact with patients or residents;\n• providers of home care to persons at high risk (e.g., visiting nurses and volunteer workers); and\n• household members (including children) of persons in high-risk groups.\n# VACCINATION OF OTHER GROUPS Persons Infected with Human Immunodeficiency Virus\nLimited information exists regarding the frequency and severity of influenza illness among human immunodeficiency virus (HIV)-infected persons, but reports suggest that symptoms might be prolonged and the risk for complications increased for some HIV-infected persons. Influenza vaccine has produced protective antibody titers against influenza in vaccinated HIV-infected persons who have minimal AIDSrelated symptoms and high CD4+ T-lymphocyte cell counts. In patients who have advanced HIV disease and low CD4+ T-lymphocyte cell counts, however, influenza vaccine may not induce protective antibody titers; a second dose of vaccine does not improve the immune response for these persons.\nRecent studies have examined the effect of influenza vaccination on replication of HIV type 1 (HIV-1). Although some studies have demonstrated a transient (i.e., 2-to 4-week) increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration, other studies using similar laboratory techniques have not indicated any substantial increase in replication. Deterioration of CD4+ T-lymphocyte cell counts and progression of clinical HIV disease have not been demonstrated among HIV-infected persons who receive vaccine. Because influenza can result in serious illness and complications and because influenza vaccination may result in protective antibody titers, vaccination will benefit many HIV-infected patients.\n# Breastfeeding Mothers\nInfluenza vaccine does not affect the safety of breastfeeding for mothers or infants. Breastfeeding does not adversely affect immune response and is not a contraindication for vaccination.\n# Persons Traveling to Foreign Countries\nThe risk for exposure to influenza during travel to foreign countries varies, depending on season and destination. In the tropics, influenza can occur throughout the year; in the Southern Hemisphere, most activity occurs from April through September. Because of the short incubation period for influenza, exposure to the virus during travel can result in clinical illness that begins while traveling, which is an inconvenience or potential danger, especially for persons at increased risk for complications. Persons preparing to travel to the tropics at any time of year or to the Southern Hemisphere from April through September should review their influenza vaccination histories. If they were not vaccinated the previous fall or winter, they should consider influenza vaccination before travel. Persons in high-risk groups should be especially encouraged to receive the most current vaccine. Persons at high risk who received the previous season's vaccine before travel should be revaccinated in the fall or winter with the current vaccine.\n# General Population\nPhysicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza. Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics.\n# PERSONS WHO SHOULD NOT BE VACCINATED\nInactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Use of an antiviral agent (i.e., amantadine or rimantadine) is an option for prevention of influenza A in such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who are also at high risk for complications of influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Specific information about vaccine components can be found in package inserts for each manufacturer.\nAdults with acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever should not contraindicate the use of influenza vaccine, particularly among children with mild upper respiratory tract infection or allergic rhinitis.\n# SIDE EFFECTS AND ADVERSE REACTIONS\nBecause influenza vaccine contains only noninfectious viruses, it cannot cause influenza. Respiratory disease after vaccination represents coincidental illness unrelated to influenza vaccination. The most frequent side effect of vaccination is soreness at the vaccination site that lasts up to 2 days. These local reactions generally are mild and rarely interfere with the ability to conduct usual daily activities. In addition, two types of systemic reactions have occurred:\n• Fever, malaise, myalgia, and other systemic symptoms can occur following vaccination and most often affect persons who have had no exposure to the influenza virus antigens in the vaccine (e.g., young children). These reactions begin 6-12 hours after vaccination and can persist for 1 or 2 days. Recent placebo-controlled trials suggest that in elderly persons and healthy young adults, split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections.\n• Immediate-presumably allergic-reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. These reactions probably result from hypersensitivity to some vaccine component; most reactions likely are caused by residual egg protein. Although current influenza vaccines contain only a small quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have developed hives, have had swelling of the lips or tongue, or have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs-including those who have had occupational asthma or other allergic responses due to exposure to egg protein-might also be at increased risk for reactions from influenza vaccine, and similar consultation should be considered. The protocol for influenza vaccination developed by Murphy and Strunk may be considered for patients who have egg allergies and medical conditions that place them at increased risk for influenzaassociated complications.\nHypersensitivity reactions to any vaccine component can occur. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, most patients do not develop reactions to thimerosal when administered as a component of vaccines-even when patch or intradermal tests for thimerosal indicate hypersensitivity. When reported, hypersensitivity to thimerosal usually has consisted of local, delayed-type hypersensitivity reactions.\nUnlike the 1976 swine influenza vaccine, subsequent vaccines prepared from other virus strains have not been clearly associated with an increased frequency of Guillain-Barré syndrome (GBS). However, obtaining a precise estimate of a small increase in risk is difficult for a rare condition such as GBS, which has an annual background incidence of only one to two cases per 100,000 adult population. During five of six seasons studied since 1976, the point estimates of the relative risks of GBS after influenza vaccination were slightly elevated; however, in none of these studies was the overall elevation in relative risk statistically significant. In the two most recently studied seasons, the combined number of GBS cases peaked 2 weeks after vaccination. Data from all of these studies suggest that if an increased relative risk does exist, it is lower for persons aged ≥65 years than for those 18-64 years of age. The slight increase in the point estimates of the relative risks and the increased number of cases in the second week after vaccination may be the result of vaccination but also could be due to other factors (e.g., confounding or diagnostic bias) rather than a true vaccinerelated risk.\nAmong persons who received the swine influenza vaccine in 1976, the rate of GBS that exceeded the background rate was slightly less than one case per 100,000 vaccinations. Even if GBS were a true side effect in subsequent years, the estimated risk for GBS was much lower than 1:100,000 and substantially less than that for severe influenza, which could be prevented by vaccination, especially for persons aged ≥65 years and those who have medical indications for influenza vaccination.\nWhereas the incidence of GBS in the general population is very low, persons with a history of GBS have a substantially greater likelihood of subsequently developing GBS than persons without such a history. Thus, the likelihood of coincidentally developing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination might be causally associated with this risk for recurrence is not known. Although avoiding a subsequent influenza vaccination in persons known to have developed GBS within 6 weeks of a previous influenza vaccination seems prudent, for most persons with a history of GBS who are at high risk for severe complications from influenza the established benefits of influenza vaccination justify yearly vaccination.\n# SIMULTANEOUS ADMINISTRATION OF OTHER VACCINES, INCLUDING CHILDHOOD VACCINES\nThe target groups for influenza and pneumococcal vaccination overlap considerably. For persons at high risk who have not previously been vaccinated with pneumococcal vaccine, health-care providers should strongly consider administering pneumococcal and influenza vaccines concurrently. Both vaccines can be administered at the same time at different sites without increasing side effects. However, influenza vaccine is administered each year, whereas pneumococcal vaccine is not. Children at high risk for influenza-related complications can receive influenza vaccine at the same time they receive other routine vaccinations, including pertussis vaccine (DTaP or DTP). Because influenza vaccine can cause fever when administered to young children, DTaP (which is less frequently associated with fever and other adverse events) is preferable.\n# TIMING OF INFLUENZA VACCINATION ACTIVITIES\nBeginning each September (when vaccine for the upcoming influenza season becomes available) persons at high risk who are seen by health-care providers for routine care or as a result of hospitalization should be offered influenza vaccine. Opportunities to vaccinate persons at high risk for complications of influenza should not be missed.\nThe optimal time for organized vaccination campaigns for persons in high-risk groups is usually the period from October through mid-November. In the United States, influenza activity generally peaks between late December and early March. High levels of influenza activity infrequently occur in the contiguous 48 states before December. Administering vaccine too far in advance of the influenza season should be avoided in facilities such as nursing homes, because antibody levels might begin to decline within a few months of vaccination. Vaccination programs can be undertaken as soon as current vaccine is available if regional influenza activity is expected to begin earlier than December.\nChildren aged <9 years who have not been vaccinated previously should receive two doses of vaccine at least 1 month apart to maximize the likelihood of a satisfactory antibody response to all three vaccine antigens. The second dose should be administered before December, if possible. Vaccine should be offered to both children and adults up to and even after influenza virus activity is documented in a community.\n# STRATEGIES FOR IMPLEMENTING INFLUENZA VACCINE RECOMMENDATIONS\nSuccessful vaccination programs have combined education for health-care workers, publicity and education targeted toward potential recipients, a plan for identifying persons at high risk (usually by medical-record review), and efforts to remove administrative and financial barriers that prevent persons from receiving the vaccine. Persons for whom influenza vaccine is recommended can be identified and vaccinated in the settings described in the following paragraphs.\n# Outpatient Clinics and Physicians' Offices\nStaff in physicians' offices, clinics, health-maintenance organizations, and employee health clinics should be instructed to identify and label the medical records of patients who should receive vaccine. Vaccine should be offered during visits beginning in September and throughout the influenza season. The offer of vaccine and its receipt or refusal should be documented in the medical record. Patients in high-risk groups who do not have regularly scheduled visits during the fall should be reminded by mail or telephone of the need for vaccine. If possible, arrangements should be made to provide vaccine with minimal waiting time and at the lowest possible cost.\n# Facilities Providing Episodic or Acute Care\nHealth-care providers in these settings (e.g., emergency rooms and walk-in clinics) should be familiar with influenza vaccine recommendations. They should offer vaccine to persons in high-risk groups or should provide written information on why, where, and how to obtain the vaccine. Written information should be available in language(s) appropriate for the population served by the facility.\n# Nursing Homes and Other Residential Long-Term-Care Facilities\nVaccination should be routinely provided to all residents of chronic-care facilities with the concurrence of attending physicians rather than by obtaining individual vaccination orders for each patient. Consent for vaccination should be obtained from the resident or a family member at the time of admission to the facility, and all residents should be vaccinated at one time, immediately preceding the influenza season. Residents admitted during the winter months after completion of the vaccination program should be vaccinated when they are admitted.\n# Acute-Care Hospitals\nAll persons aged ≥65 years and younger persons (including children) with high-risk conditions who are hospitalized at any time from September through March should be offered and strongly encouraged to receive influenza vaccine before they are discharged. Household members and others with whom they will have contact should receive written information about why and where to obtain influenza vaccine.\n# Outpatient Facilities Providing Continuing Care to Patients at High Risk\nAll patients should be offered vaccine before the beginning of the influenza season.\nPatients admitted to such programs (e.g., hemodialysis centers, hospital specialtycare clinics, and outpatient rehabilitation programs) during the winter months after the earlier vaccination program has been conducted should be vaccinated at the time of admission. Household members should receive written information regarding the need for vaccination and the places to obtain influenza vaccine.\n# Visiting Nurses and Others Providing Home Care to Persons at High Risk\nNursing-care plans should identify patients in high-risk groups, and vaccine should be provided in the home if necessary. Caregivers and other persons in the household (including children) should be referred for vaccination.\n# Facilities Providing Services to Persons Aged ≥65 Years\nIn these facilities (e.g., retirement communities and recreation centers), all unvaccinated residents/attendees should be offered vaccine on site before the influenza season. Education/publicity programs also should be provided; these programs should emphasize the need for influenza vaccine and provide specific information concerning how, where, and when to obtain it.\n# Clinics and Others Providing Health Care for Travelers\nIndications for influenza vaccination should be reviewed before travel. Vaccine should be offered, if appropriate (see Travelers to Foreign Countries).\n# Health-Care Workers\nAdministrators of all health-care facilities should arrange for influenza vaccine to be offered to all personnel before the influenza season. Personnel should be provided with appropriate educational materials and strongly encouraged to receive vaccine. Particular emphasis should be placed on vaccination of persons who care for members of high-risk groups (e.g., staff of intensive-care units [including newborn intensive-care units], staff of medical/surgical units, and employees of nursing homes and chronic-care facilities). Using a mobile cart to take vaccine to hospital wards or other work sites and making vaccine available during night and weekend work shifts can enhance compliance, as can a follow-up campaign early in the course of a community outbreak.\n# ANTIVIRAL AGENTS FOR INFLUENZA A\nThe two antiviral agents with specific activity against influenza A viruses are amantadine hydrochloride and rimantadine hydrochloride. These chemically related drugs interfere with the replication cycle of type A (but not type B) influenza viruses. When administered prophylactically to healthy adults or children before and throughout the epidemic period, both drugs are approximately 70%-90% effective in preventing illness caused by naturally occurring strains of type A influenza viruses. Because antiviral agents taken prophylactically can prevent illness but not subclinical infection, some persons who take these drugs can still develop immune responses that will protect them when they are exposed to antigenically related viruses in later years.\nIn otherwise healthy adults, amantadine and rimantadine can reduce the severity and duration of signs and symptoms of influenza A illness when administered within 48 hours of illness onset. Studies evaluating the efficacy of treatment for children with either amantadine or rimantadine are limited. Amantadine was approved for treatment and prophylaxis of all influenza type A virus infections in 1976. Although few placebo-controlled studies were conducted to determine the efficacy of amantadine treatment among children before approval, amantadine is indicated for treatment and prophylaxis of adults and children aged ≥1 year. Rimantadine was approved in 1993 for treatment and prophylaxis in adults but was approved only for prophylaxis in children. Further studies might provide the data needed to support future approval of rimantadine treatment in this age group.\nAs with all drugs, amantadine and rimantadine can cause adverse reactions in some persons. Such adverse reactions rarely are severe; however, for some categories of patients, severe adverse reactions are more likely to occur. Amantadine has been associated with a higher incidence of adverse central nervous system (CNS) reactions than rimantadine (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment).\n# RECOMMENDATIONS FOR THE USE OF AMANTADINE AND RIMANTADINE\n\n# Use as Prophylaxis\nChemoprophylaxis is not a substitute for vaccination. Recommendations for chemoprophylaxis are provided primarily to help health-care providers make decisions regarding persons who are at greatest risk for severe illness and complications if infected with influenza A virus.\nWhen amantadine or rimantadine is administered as prophylaxis, factors such as cost, compliance, and potential side effects should be considered when determining the period of prophylaxis. To be maximally effective as prophylaxis, the drug must be taken each day for the duration of influenza activity in the community. However, to be most cost effective, amantadine or rimantadine prophylaxis should be taken only during the period of peak influenza activity in a community.\n# Persons at High Risk Vaccinated After Influenza A Activity Has Begun\nPersons at high risk still can be vaccinated after an outbreak of influenza A has begun in a community. However, the development of antibodies in adults after vaccination can take as long as 2 weeks, during which time chemoprophylaxis should be considered. Children who receive influenza vaccine for the first time can require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 2 weeks after the second dose of vaccine has been received). Amantadine and rimantadine do not interfere with the antibody response to the vaccine.\n# Persons Providing Care to Those at High Risk\nTo reduce the spread of virus to persons at high risk, chemoprophylaxis may be considered during community outbreaks for a) unvaccinated persons who have frequent contact with persons at high risk (e.g., household members, visiting nurses, and volunteer workers) and b) unvaccinated employees of hospitals, clinics, and chronic-care facilities. For those persons who cannot be vaccinated, chemoprophylaxis during the period of peak influenza activity may be considered. For those persons who receive vaccine at a time when influenza A is present in the community, chemoprophylaxis can be administered for 2 weeks after vaccination. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that might not be controlled by the vaccine.\n# Persons Who Have Immune Deficiency\nChemoprophylaxis might be indicated for persons at high risk who are expected to have an inadequate antibody response to influenza vaccine. This category includes persons who have HIV infection, especially those who have advanced HIV disease. No data are available concerning possible interactions with other drugs used in the management of patients who have HIV infection. Such patients should be monitored closely if amantadine or rimantadine chemoprophylaxis is administered.\n# Persons for Whom Influenza Vaccine Is Contraindicated\nChemoprophylaxis throughout the influenza season or during peak influenza activity might be appropriate for persons at high risk who should not be vaccinated. Influenza vaccine may be contraindicated in persons who have severe anaphylactic hypersensitivity to egg protein or other vaccine components.\n# Other Persons\nAmantadine or rimantadine also can be administered prophylactically to anyone who wishes to avoid influenza A illness. The health-care provider and patient should make this decision on an individual basis.\n# Use of Antivirals as Therapy\nAmantadine and rimantadine can reduce the severity and shorten the duration of influenza A illness among healthy adults when administered within 48 hours of illness onset. Whether antiviral therapy will prevent complications of influenza type A among persons at high risk is unknown. Insufficient data exist to determine the efficacy of rimantadine treatment in children. Thus, rimantadine is currently approved only for prophylaxis in children, but it is not approved for treatment in this age group. Amantadine-and rimantadine-resistant influenza A viruses can emerge when either of these drugs is administered for treatment; amantadine-resistant strains are cross-resistant to rimantadine and vice versa. Both the frequency with which resistant viruses emerge and the extent of their transmission are unknown, but data indicate that amantadine-and rimantadine-resistant viruses are no more virulent or transmissible than amantadine-and rimantadine-sensitive viruses.\nThe screening of naturally occurring epidemic strains of influenza type A has rarely detected amantadine-and rimantadine-resistant viruses. Resistant viruses have most frequently been isolated from persons taking one of these drugs as therapy for influenza A infection. Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy. Persons who have influenza-like illness should avoid contact with uninfected persons as much as possible, regardless of whether they are being treated with amantadine or rimantadine. Persons who have influenza type A infection and who are treated with either drug can shed amantadine-or rimantadinesensitive viruses early in the course of treatment, but can later shed drug-resistant viruses, especially after 5-7 days of therapy. Such persons can benefit from therapy even when resistant viruses emerge; however, they also can transmit infection to other persons with whom they come in contact. Because of possible induction of amantadine or rimantadine resistance, treatment of persons who have influenza-like illness should be discontinued as soon as clinically warranted, generally after 3-5 days of treatment or within 24-48 hours after the disappearance of signs and symptoms. Laboratory isolation of influenza viruses obtained from persons who are receiving amantadine or rimantadine should be reported to CDC through state health departments, and the isolates should be sent to CDC for antiviral sensitivity testing.\n# Outbreak Control in Institutions\nWhen confirmed or suspected outbreaks of influenza A occur in institutions that house persons at high risk, chemoprophylaxis should be started as early as possible to reduce the spread of the virus. Contingency planning is needed to ensure rapid administration of amantadine or rimantadine to residents. This planning should include preapproved medication orders or plans to obtain physicians' orders on short notice. When amantadine or rimantadine is used for outbreak control, the drug should be administered to all residents of the institution-regardless of whether they received influenza vaccine the previous fall. The drug should be continued for at least 2 weeks or until approximately 1 week after the end of the outbreak. The dose for each resident should be determined after consulting the dosage recommendations and precautions (see Considerations for Selecting Amantadine or Rimantadine for Chemoprophylaxis or Treatment) and the manufacturer's package insert. To reduce the spread of virus and to minimize disruption of patient care, chemoprophylaxis also can be offered to unvaccinated staff who provide care to persons at high risk. Prophylaxis should be considered for all employees, regardless of their vaccination status, if the outbreak is caused by a variant strain of influenza A that is not controlled by the vaccine.\nChemoprophylaxis also may be considered for controlling influenza A outbreaks in other closed or semi-closed settings (e.g., dormitories or other settings where persons live in close proximity). To reduce the spread of infection and the chances of prophylaxis failure resulting from transmission of drug-resistant virus, measures should be taken to reduce contact as much as possible between persons on chemoprophylaxis and those taking drug for treatment.\n# CONSIDERATIONS FOR SELECTING AMANTADINE OR RIMANTADINE FOR CHEMOPROPHYLAXIS OR TREATMENT\n\n# Side Effects/Toxicity\nDespite the similarities between the two drugs, amantadine and rimantadine differ in their pharmacokinetic properties. More than 90% of amantadine is excreted unchanged, whereas approximately 75% of rimantadine is metabolized by the liver. However, both drugs and their metabolites are excreted by the kidneys.\nThe pharmacokinetic differences between amantadine and rimantadine might explain differences in side effects. Although both drugs can cause CNS and gastrointestinal side effects when administered to young, healthy adults at equivalent dosages of 200 mg/day, the incidence of CNS side effects (e.g., nervousness, anxiety, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine compared with those taking rimantadine. In a 6-week study of prophylaxis in healthy adults, approximately 6% of participants taking rimantadine at a dose of 200 mg/day experienced at least one CNS symptom, compared with approximately 14% of those taking the same dose of amantadine and 4% of those taking placebo. The incidence of gastrointestinal side effects (e.g., nausea and anorexia) is approximately 3% among persons taking either drug, compared with 1%-2% among persons receiving the pla-cebo. Side effects associated with both drugs are usually mild and cease soon after discontinuing the drug. Side effects can diminish or disappear after the first week despite continued drug ingestion. However, serious side effects have been observed (e.g., marked behavioral changes, delirium, hallucinations, agitation, and seizures). These more severe side effects have been associated with high plasma drug concentrations and have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Clinical observations and studies have indicated that lowering the dosage of amantadine among these persons reduces the incidence and severity of such side effects, and recommendations for reduced dosages for these groups of patients have been made. Because rimantadine has been marketed for a shorter period of time than amantadine, its safety in certain patient populations (e.g., chronically ill and elderly persons) has been evaluated less frequently. Clinical trials of rimantadine have more commonly involved young, healthy persons.\nProviders should review the package insert before using amantadine or rimantadine for any patient. The patient's age, weight, and renal function; the presence of other medical conditions; the indications for use of amantadine or rimantadine (i.e., prophylaxis or therapy); and the potential for interaction with other medications must be considered, and the dosage and duration of treatment must be adjusted appropriately. Modifications in dosage might be required for persons who have impaired renal or hepatic function, the elderly, children, and persons with a history of seizures (Table 2). The following are guidelines for the use of amantadine and rimantadine in certain patient populations.\n# Persons Who Have Impaired Renal Function Amantadine\nAmantadine is excreted unchanged in the urine by glomerular filtration and tubular secretion. Thus, renal clearance of amantadine is reduced substantially in persons with renal insufficiency. A reduction in dosage is recommended for patients with creatinine clearance ≤50 mL/min/1.73m 2 . Guidelines for amantadine dosage based on creatinine clearance are found in the packet insert. However, because recommended dosages based on creatinine clearance might provide only an approximation of the optimal dose for a given patient, such persons should be observed carefully so that adverse reactions can be recognized promptly and either the dose can be further reduced or the drug can be discontinued, if necessary. Hemodialysis contributes minimally to drug clearance.\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine among patients with renal insufficiency have been evaluated only after single-dose administration. Further studies are needed to determine the multiple-dose pharmacokinetics and the most appropriate dosages for these patients.\nIn a single-dose study of patients with anuric renal failure, the apparent clearance of rimantadine was approximately 40% lower, and the elimination half-life was approximately 1.6-fold greater than that in healthy controls of the same age. Hemodialysis did not contribute to drug clearance. In studies among persons with less severe renal disease, drug clearance was also reduced, and plasma concentrations were higher compared with control patients without renal disease who were the same weight, age, and sex.\nA reduction in dosage to 100 mg/day is recommended for persons with creatinine clearance ≤10 mL/min. Because of the potential for accumulation of rimantadine and its metabolites, patients with any degree of renal insufficiency, including elderly persons, should be monitored for adverse effects, and either the dosage should be reduced or the drug should be discontinued, if necessary. \n# Persons Aged ≥65 Years Amantadine\nBecause renal function declines with increasing age, the daily dose for persons aged ≥65 years should not exceed 100 mg for prophylaxis or treatment. For some elderly persons, the dose should be further reduced. Studies suggest that because of their smaller average body size, elderly women are more likely than elderly men to experience side effects at a daily dose of 100 mg.\n# Rimantadine\nThe incidence and severity of CNS side effects among elderly persons appear to be substantially lower among those taking rimantadine at a dose of 200 mg/day compared with elderly persons taking the same dose of amantadine. However, when rimantadine has been administered at a dosage of 200 mg/day to chronically ill elderly persons, they have had a higher incidence of CNS and gastrointestinal symptoms than healthy, younger persons taking rimantadine at the same dosage. After longterm administration of rimantadine at a dosage of 200 mg/day, serum rimantadine concentrations among elderly nursing-home residents have been twofold to fourfold greater than those reported in younger adults.\nThe dosage of rimantadine should be reduced to 100 mg/day for treatment or prophylaxis of elderly nursing-home residents. Although further studies are needed to determine the optimal dose for other elderly persons, a reduction in dosage to 100 mg/day should be considered for all persons aged ≥65 years if they experience signs and symptoms that might represent side effects when taking a dosage of 200 mg/day.\n# Persons Who Have Liver Disease Amantadine\nNo increase in adverse reactions to amantadine has been observed among persons who have liver disease. Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine, although a specific relationship between the drug and such changes has not been established.\n# Rimantadine\nThe safety and pharmacokinetics of rimantadine only have been evaluated after single-dose administration. In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations were observed after a single dose. However, in persons with severe liver dysfunction, the apparent clearance of rimantadine was 50% lower than that reported for persons without liver disease. A dose reduction to 100 mg/day is recommended for persons with severe hepatic dysfunction.\n# Persons Who Have Seizure Disorders Amantadine\nAn increased incidence of seizures has been reported in patients with a history of seizure disorders who have received amantadine. Patients with seizure disorders should be observed closely for possible increased seizure activity when taking amantadine.\n# Rimantadine\nIn clinical trials, seizures (or seizure-like activity) have been observed in a few persons with a history of seizures who were not receiving anticonvulsant medication while taking rimantadine. The extent to which rimantadine might increase the incidence of seizures among persons with seizure disorders has not been adequately evaluated, because such persons usually have been excluded from participating in clinical trials of rimantadine.\n# Children Amantadine\nThe use of amantadine in children aged <1 year has not been adequately evaluated. The FDA-approved dosage for children aged 1-9 years is 4.4-8.8 mg/kg/day, not to exceed 150 mg/day. Although further studies to determine the optimal dosage for children are needed, physicians should consider prescribing only 5 mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved dosage for children aged ≥10 years is 200 mg/day; however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable.\n# Rimantadine\nThe use of rimantadine in children aged <1 year has not been adequately evaluated. In children aged 1-9 years, rimantadine should be administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day. The approved dosage for children aged ≥10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, also is recommended.\n# Drug Interactions Amantadine\nCareful observation is advised when amantadine is administered concurrently with drugs that affect the CNS, especially CNS stimulants. Concomitant administration of antihistamines or anticholinergic drugs may increase the incidence of adverse CNS reactions.\n# Rimantadine\nNo clinically significant interactions between rimantadine and other drugs have been identified. For more detailed information concerning potential drug interactions for either drug, the package insert should be consulted.\n# SOURCES OF INFORMATION ON INFLUENZA-CONTROL PROGRAMS\nThe Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Control and Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis for paper copy. To receive an electronic copy on Friday of each week, send an e-mail message to listserv@listserv.cdc.gov. The body content should read SUBscribe mmwr-toc. Electronic copy also is available from CDC's World-Wide Web server at http://www.cdc.gov/ or from CDC's file transfer protocol server at ftp.cdc.gov. To subscribe for paper copy, contact Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402; telephone (202) 512-1800.\nData in the weekly MMWR are provisional, based on weekly reports to CDC by state health departments. The reporting week concludes at close of business on Friday; compiled data on a national basis are officially released to the public on the following Friday. Address inquiries about the MMWR Series, including material to be considered for publication, to: Editor, MMWR Series, Mailstop C-08, CDC, 1600 Clifton Rd., N.E., Atlanta, GA 30333; telephone (404) 332-4555.\nAll material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. 6U.S. Government Printing Office: 1996-733-175/47072 Region IV\n# \nThe following CDC staff members prepared this report: "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":289,"cells":{"id":{"kind":"string","value":"028c6680c036c4e0df096ea0e214fb6b6176929d"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"This report updates the previously published summary o f recommendations for vaccinating health-care personnel (HCP) in the United States (CDC. Immunization o f health-care workers: recommendations o f the Advisory Committee on Immunization Practices and the Hospital Infection Control Practices Advisory Committee . M M W R 1997;46[No. RR-18J). This report was reviewed by and includes input from the Healthcare (formerly Hospital) Infection Control Practices Advisory Committee. These updated recommendations can assist hospital administrators, infection-controlpractitioners, employee health clinicians, and HCP in optimizing infection prevention and control programs. The recommendations for vaccinating HCP are presented by disease in two categories: 1) those diseases for which vaccination or documentation o f immunity is recommended because o f risks to HCP in their work settings for acquiring disease or transmitting to patients and 2) those for which vaccination might be indicated in certain circumstances. Background information for each vaccine-preventable disease and specific recommendations for use ofeach vaccine are presented. Certain infection-control measures that relate to vaccination also are included in this report. In addition, ACIP recommendations for the remaining vaccines that are recommended for certain or all adults are summarized, as are considerations for catch-up and travel vaccinations and for work restrictions. This report summarizes all current ACIP recommendations for vaccination o f HCP and does not contain any new recommendations or policies.# Immunization of Health-Care Personnel\n\n# Recom m endations of the A dvisory Committee on Im m unization Practices (ACIP)\nThis report updates the previously published summary o f recom m endations o f the A dvisory C om m ittee on Immunization Practices (ACIP) and the Healthcare (formerly Hospital) Infection Control Practices Advisory Committee (HICPAC) for vaccinating health-care personnel (HCP) in the United States (1). The report, which was reviewed by and includes input from HICPAC, summarizes all current ACIP recommendations for vaccination of H C P and does not contain any new recommendations or policies that have not been published previously. These recommendations can assist hospital administrators, infection-control practitioners, employee health clinicians, and H C P in optimizing infection prevention and control programs.\nH C P are defined as all paid and unpaid persons working in health-care settings who have the potential for exposure to patients and/or to infectious materials, including body substances, contaminated medical supplies and equipment, contaminated environmental surfaces, or contaminated air. H C P might include (but are not lim ited to) physicians, nurses, nursing assistants, therapists, technicians, emergency medical service personnel, dental personnel, pharmacists, laboratory personnel, autopsy personnel, students and trainees, contractual staff not employed by the health-care facility, and persons (e.g., clerical, dietary, housekeeping, laundry, security, maintenance, administrative, billing, and volunteers) not directly involved in patient care but potentially exposed to infectious agents that can be transmitted to and from HCP and patients (2).\nBecause of their contact with patients or infective material from patients, many HCP are at risk for exposure to (and possible transmission of) vaccine-preventable diseases. Employers and Introduction vaccination records for H C P so records can be retrieved easily as needed (3). Each record should reflect im m unity status for indicated vaccine-preventable diseases (i.e., documented disease, vaccination history, or serology results) as well as vaccinations adm inistered during em ploym ent and any documented episodes of adverse events after vaccination (4).\nFor each vaccine, the record should include date of vaccine administration (including for those vaccines that might have been received prior to employment), vaccine manufacturer and lot number, edition and distribution date of the languageappropriate Vaccine Information Statement (VIS) provided to the vaccinee at the time of vaccination, and the name, address, and title of the person administering the vaccine (4). Accurate vaccination records can help to rapidly identify susceptible H C P (i.e., those with no history of vaccination or lack of documentation of immunity) during an outbreak situation and can help reduce costs and disruptions to health care operations (5)(6)(7). H C P should be provided a copy of their vaccination records and encouraged to keep it with their personal health records so they can readily be made available to future employers. HICPAC has encouraged any facility or organization that provides direct patient care to formulate a comprehensive vaccination policy for all HCP (3). The American Hospital Association has endorsed the concept of vaccination programs for both hospital personnel and patients (8). To ensure that all H C P are up to date with respect to recommended vaccines, facilities should review H C P vaccination and immunity status at the time ofhire and on a regular basis (i.e., at least annually) with consideration of offering needed vaccines, if necessary, in conjunction with routine annual disease-prevention measures (e.g., influenza vaccination or tuberculin testing). These recommendations (Tables 2 and 3) should be considered during policy development. Several states and health-care facilities have established requirements relating to assessment of vaccination status and/or administration of one or more vaccines for H C P (9,10). Disease-specific outbreak control measures are described in this report and elsewhere (3,11,12). All HCP should adhere to all other recommended infectioncontrol guidelines, whether or not they are individually determined to have immunity to a vaccine-preventable disease.\n\n# Methods\nIn 2008, the ACIP Immunization of Health-Care Personnel Work Group (the W ork Group) was formed as a subgroup of the ACIP Adult Immunization W ork Group to update the previously published recommendations for im m unization of HCP. The W ork Group comprised professionals from academic medicine (pediatrics, family medicine, internal medicine, occupational and environmental medicine, and infectious disease); federal and state public health professionals; and liaisons from the Society for Healthcare Epidemiology of America and HICPAC. The W ork Group met monthly, developed an outline for the report, worked closely with subject matter experts at C D C (who developed, revised, and updated sections of the report), and provided subsequent critical review of the draft documents. The approach of the Work Group was to summarize previously published ACIP recommendations and not to m ake new recom m endations or policies; a comprehensive list of publications containing the various vaccine-specific recommendations is provided (Table 1). In February 2011, the updated report was presented to ACIP, which voted to approve it.\nThe recommendations for vaccination of HCP are presented below by disease in two categories: 1) those diseases for which routine vaccination or documentation of immunity is recommended for H C P because of risks to H C P in their work settings and, should H CP become infected, to the patients they serve and 2) those diseases for which vaccination of HCP might be indicated in certain circumstances. Vaccines recommended in the first category are hepatitis B, seasonal influenza, measles, mumps, and rubella, pertussis, and varicella vaccines. Vaccines in the second category are meningococcal, typhoid, and polio vaccines. Except for influenza, all of the diseases prevented by these vaccines are notifiable at the national level (13). Main changes from the 1997 ACIP recommendations have been summarized (Box).\n\n# Diseases for W hich Vaccination Is\nRecom m ended O n the basis of docum ented nosocomial transmission, H C P are considered to be at substantial risk for acquiring or transm itting hepatitis B, influenza, measles, mumps, rubella, pertussis, and varicella. Current recommendations for vaccination are provided below.\n\n# Hepatitis B\n\n# Background\n\n# Epidemiology and Risk Factors\nHepatitis B is an infection caused by the hepatitis B virus (HBV), which is transm itted through percutaneous (i.e., breaks in the skin) or mucosal (i.e., direct contact with mucous membranes) exposure to infectious blood or body fluids. The virus is highly infectious; for nonimmune persons, disease transmission from a needlestick exposure is up to 100 times more likely for exposure to hepatitis B e antigen (HBeAg)-positive blood than to HIV-positive blood (14). HBV infection is a well recognized occupational risk for U.S. HCP and globally. The risk for HBV is associated with degree of contact with blood in the work place and with the hepatitis B e-antigen status of the source persons (15). The virus is also environmentally stable, remaining infectious on environmental surfaces for at least 7 days (16).\nIn 2009 in the United States, 3,371 cases of acute HBV infection were reported nationally, and an estimated 38,000 new cases of HBV infection occurred after accounting for underreporting and underdiagnosis (17). O f 4,519 persons reported with acute HBV infection in 2007, approximately 40% were hospitalized and 1.5% died (18). HBV can lead to chronic infection, which can result in cirrhosis of the liver, liver failure, liver cancer, and death. An estimated 800,000- 1.4 million persons in the United States are living with chronic HBV infection; these persons serve as the main reservoir for continued HBV transmission (19).\nVaccines to prevent hepatitis B became available in the United States in 1981; a decade later, a national strategy to eliminate HBV infection was implemented, and the routine vaccination of children was recommended (20). During 1990During 2009, the rate of new HBV infections declined approximately 84%, from 8.5 to 1.1 cases per 100,000 population (17); the decline was greatest (98%) among persons aged <19 years, for whom recommendations for routine infant and adolescent vaccination have been applied. Although hepatitis B vaccine coverage is high in infants, children, and adolescents (91.8% in infants aged 19-35 months and 91.6% in adolescents aged 13-17 years) (21,22), coverage remains lower (41.8% in 2009) for certain adult populations, including those with behavioral risks for HBV infection (e.g., men who have sex with men and persons who use injection drugs) (23).\n\n# Hepatitis B in Health-Care Settings\nDuring 1982, when hepatitis B vaccine was first recommended for HCP, an estimated 10,000 infections occurred among persons employed in a medical or dental field. By 2004, the number of HBV infections among HCP had decreased to an estimated 304 infections, largely resulting from the im plem entation of routine preexposure vaccination and improved infection-control precautions (24)(25)(26).\nThe risk for acquiring HBV infection from occupational exposures is dependent on the frequency of percutaneous and mucosal exposures to blood or body fluids (e.g., semen, saliva, and wound exudates) containing HBV, particularly fluids containing HBeAg (a marker for high HBV replication and viral load) (27)(28)(29)(30)(31). The risk is higher during the professional BOX. Summary of main changes- from 1997 Advisory Comm ittee on Immunization Practices/Hospital (now Healthcare) Infection Control Practices Advisory Comm ittee recommendations for immunization of health-care personnel (HCP)\n\n# Hepatitis B\n- H C P and trainees in certain populations at high risk for chronic hepatitis B (e.g., those born in countries with high and intermediate endemicity) should be tested for HBsAg and anti-HBc/anti-HBs to determine infection status.\n\n# Influenza\n- Emphasis that all HCP, not just those with direct patient care duties, should receive an annual influenza vaccination - Comprehensive programs to increase vaccine coverage among H C P are needed; influenza vaccination rates among HCP within facilities should be measured and reported regularly. Measles, mumps, and rubella (MMR) - History of disease is no longer considered adequate presumptive evidence of measles or mumps immunity for HCP; laboratory confirmation of disease was added as acceptable presumptive evidence of immunity. History of disease has never been considered adequate evidence of immunity for rubella. - The footnotes have been changed regarding the recommendations for personnel born before 1957 in routine and outbreak contexts. Specifically, guidance is provided for 2 doses of M M R for measles and mumps protection and 1 dose of M M R for rubella protection. Pertussis - HCP, regardless of age, should receive a single dose of Tdap as soon as feasible if they have not previously received Tdap.\n- The minimal interval was removed, and Tdap can now be administered regardless of interval since the last tetanus or diphtheria-containing vaccine. - Hospitals and ambulatory-care facilities should provide Tdap for HCP and use approaches that maximize vaccination rates. Varicella Criteria for evidence of immunity to varicella were established. For H C P they include - written documentation with 2 doses of vaccine, - laboratory evidence of immunity or laboratory confirmation of disease, - diagnosis of history of varicella disease by health-care provider, or diagnosis of history of herpes zoster by health-care provider.\n\n# Meningococcal\n- H C P with anatomic or functional asplenia or persistent complement component deficiencies should now receive a 2-dose series of meningococcal conjugate vaccine. H C P with H IV infection who are vaccinated should also receive a 2 dose series. - Those HCP who remain in groups at high risk are recommended to be revaccinated every 5 years.\nAbbreviations: HBsAg = Hepatitis B surface antigen; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; Tdap = tetanus toxoid, reduced diptheria toxoid and acellular pertussis vaccine; HIV = human immunodeficiency virus. training period and can vary throughout a person's career (1). Depending on the tasks performed, health-care or public safety personnel m ight be at risk for HBV exposure; in addition, personnel providing care and assistance to persons in outpatient settings and those residing in long-term-care facilities (e.g., assisted living) might be at risk for acquiring or facilitating transmission of HBV infection when they perform procedures that expose them to blood (e.g., assisted bloodglucose monitoring and wound care) (32)(33)(34).\nA Federal Standard issued in D ecem ber 1991 under the O ccupational Safety and H ealth Act m andates that hepatitis B vaccine be made available at the employer's expense to all health-care personnel who are exposed occupationally to blood or other potentially infectious materials (35). The Federal Standard defines occupational exposure as reasonably anticipated skin, eye, m ucous m em brane, or parenteral contact with blood or other potentially infectious materials that might result from the performance of an employee's duties (35\n\n# Vaccine Effectiveness\nThe 3-dose vaccine series administered intramuscularly at 0, 1, and 6 months produces a protective antibody response in approximately 30% -55% of healthy adults aged 90% after the third dose (40)(41)(42). After age 40 years, <90% of persons vaccinated with 3 doses have a protective antibody response, and by age 60 years, protective levels of antibody develop in approximately 75% of vaccinated persons (43). Smoking, obesity, genetic factors, and immune suppression also are associated with dim inished im m une response to hepatitis B vaccination (43-46).\n\n# Duration of Immunity\nProtection against symptomatic and chronic HBV infection has been docum ented to persist for >22 years in vaccine responders (47). Im m unocom petent persons who achieve hepatitis B surface antibody (anti-HBs) concentrations of >10 mIU/mL after preexposure vaccination have protection against both acute disease and chronic infection. Anti-HBs levels decline over time. Regardless, responders continue to be protected, and the majority of responders will show an anamnestic response to vaccine challenge (47)(48)(49)(50)(51). Declines might be somewhat faster among persons vaccinated as infants rather than as older children, adolescents, or adults and among those administered recombinant vaccine instead of plasma vaccine (which has not been commercially available in the United States since the late 1980s). Although immunogenicity is lower among immunocompromised persons, those who achieve and maintain a protective antibody response before exposure to HBV have a high level of protection from infection (52).\nAmong persons who do not respond to a primary 3-dose vaccine series (i.e., those in whom anti-HBs concentrations of >10 mIU/mL were not achieved), 25% -50% respond to an additional vaccine dose, and 44% -100% respond to a 3-dose revaccination series using standard or high dosage vac cine (43,(53)(54)(55)(56)(57)(58). Persons who have measurable but low (i.e., 1-9 mIU/mL) levels of anti-HBs after the initial series have better response to revaccination than persons who have no anti-HBs (49,53,54). Persons who do not have protective levels of anti-HBs 1-2 months after revaccination either are infected with HBV or can be considered primary nonresponders; for the latter group, genetic factors might be associated with nonresponse to hepatitis B vaccination (54,58,59). ACIP does not recommend more than two vaccine series in nonresponders (52).\n\n# Vaccine Safety\nHepatitis B vaccines have been demonstrated to be safe when administered to infants, children, adolescents, and adults (52,60,61). Although rare cases of arthritis or alopecia have been associated temporally with hepatitis B vaccination, recent data do not support a causal relationship between hepatitis B vaccine and either arthritis or alopecia (61)(62)(63). During 1982During 2004, an estimated 70 million adolescents and adults and 50 million infants and children in the United States received >1 dose of hepatitis B vaccine (52). The most frequently reported side effects in persons receiving hepatitis B vaccine are pain at the injection site (3% -29% ) and temperature of >99.9 F (>37.7 C) (1% -6% ) (64-67). However, in placebo-controlled studies, these side effects were reported no more frequently among persons receiving hepatitis B vaccine than among persons receiving placebo (40,41,(64)(65)(66)(67). Revaccination is not associated with an increase in adverse events. Hepatitis B vaccination is contraindicated for persons with a history of hypersensitivity to yeast or any vaccine component (4,(64)(65)(66). Persons with a history of serious adverse events (e.g., anaphylaxis) after receipt of hepatitis B vaccine should not receive additional doses. As with other vaccines, vaccination of persons with moderate or severe acute illness, with or without fever, should be deferred until illness resolves (4). Vaccination is not contraindicated in persons with a history of multiple sclerosis, Guillain-Barre Syndrome, autoim m une disease (e.g., systemic lupus erythematosis and rheumatoid arthritis), or other chronic diseases. Pregnancy is not a contraindication to vaccination; limited data suggest that developing fetuses are not at risk for adverse events when hepatitis B vaccine is administered to pregnant women (4,68). Available vaccines contain noninfectious hepatitis B surface antigen (HBsAg) and do not pose any risk for infection to the fetus.\n\n# Postexposure\nThe need for postexposure prophylaxis should be evaluated immediately after H C P experience any percutaneous, ocular, m ucous-m em brane or nonintact skin exposure to blood or body fluid in the workplace. Decisions to administer postexposure prophylaxis should be based on the HBsAg status of the source and the vaccination history and vaccine-response status of the exposed H C P (Table 4) (72).\n\n# Unvaccinated and Incompletely Vaccinated HCP and Trainees\n- Unvaccinated or incompletely vaccinated persons who experience a workplace exposure from persons known to be HBsAg-positive should receive 1 dose of hepatitis B immune globulin HBIG (i.e., passive vaccination) as soon as possible after exposure (preferably within 24 hours).\nThe effectiveness of HBIG when administered >7 days after percutaneous or permucosal exposures is unknown (Table 4). - Hepatitis B vaccine should be administered in the deltoid muscle as soon as possible after exposure; HBIG should be administered at the same time at another injection site. The 3-dose hepatitis B vaccine series should be completed for previously unvaccinated and incompletely vaccinated persons who have needlestick or other percutaneous exposures, regardless of the HBsAg status of the source and w hether the status o f the source is known. To document protective levels of anti-HBs (>10mIU/mL), postvaccination testing of persons who received HBIG for postexposure prophylaxis should be performed after anti-HBs from HBIG is no longer detectable (4-6 months after administration).\n\n# Vaccinated HCP and Trainees\n- Vaccinated H C P with documented immunity (anti-HBs concentrations of >10 mIU/mL) require no postexposure prophylaxis, serologic testing, or additional vaccination. - Vaccinated H C P with docum ented nonresponse to a 3-dose vaccine series should receive 1 dose of HBIG and a second 3-dose vaccine series if the source is HBsAgpositive or known to be at high risk for carrying hepatitis.\nIf the source is known or determ ined to be HBsAgnegative, these previously nonresponding H C P should com p lete the rev accin atio n series and undergo postvaccination testing to ensure that their response status is docum ented ( Influenza causes an estim ated average of >200,000 hospitalizations and 3,000-49,000 deaths annually in the United States (74)(75)(76). The majority of influenza-related severe illnesses and deaths occur among persons with chronic medical conditions, infants and young children, seniors, and pregnant women (74)(75)(76)(77)(78). Reducing the risk for influenza among persons at higher risk for complications is a major focus of influenza prevention strategies (77).\n\n# Influenza Transmission in Health-Care Settings\nHCP are exposed to patients with influenza in the workplace and are thus at risk of occupationally acquired influenza and of transmitting influenza to patients and other HCP. In a cross sectional survey of hospital house staff (physicians in training), 37% reported influenza-like illness during September-April, and 9% reported more than one respiratory illness. Length of illness varied (range: 1-10 days; mean: 7 days), as did days of work missed (range: 0-10 days; mean: 0.7 days) (79). Infected HCP who continue to work while ill might transmit influenza to patients, many of whom are at increased risk for severe outcomes from influenza. H C P are therefore recommended for routine annual influenza vaccination (77).\nFew randomized trials of the effect that influenza vaccination has on illness in H CP have been conducted. In one randomized trial of 427 HCP, influenza vaccination of H C P failed to decrease episodes of respiratory infection or duration of illness but was associated with a 28% decrease in absenteeism (from 1.4 days to 1.0 day) attributable to respiratory infections (80). No laboratory confirmation of influenza was obtained in this study. In another randomized trial among HCP, vaccination was associated with a significantly lower rate of serological evidence of influenza infection, with a vaccine efficacy rate of 88% for influenza A and 89% for influenza B (p<0.05) (81); however, no significant differences were noted in days of febrile respiratory illness or absenteeism.\nInfluenza can cause outbreaks of severe respiratory illness among hospitalized persons and long-term-care residents (82)(83)(84)(85)(86)(87)(88)(89)(90). Influenza outbreaks in hospitals (86)(87)(88) and long-termcare facilities (91) have been associated with low vaccination rates among HCP. One nonrandomized study demonstrated an increase in H C W vaccination rates and decrease in nosocomially acquired, laboratory-confirmed influenza in a hospital after a mobile cart-based H C P vaccination program was introduced (86). Several randomized controlled studies of the impact of H C P vaccination on morbidity and mortality in long-term care facilities have been performed (92)(93)(94)(95). These studies have demonstrated substantial decreases in all cause mortality (92)(93)(94)(95) and influenza-like illness (92,94,95). However, studies which examine and demonstrate efficacy in preventing more specific outcomes (e.g., laboratory-confirmed influenza illness and mortality) are lacking. Recent systematic reviews suggest that vaccination of HCP in settings in which patients also were vaccinated provided significant reductions in deaths among elderly patients from all causes and deaths from pneumonia, but also note that additional randomized controlled trials are warranted (96,97), as are examination of more specific outcomes.\nPreventing influenza among HCP who might serve as sources of influenza virus transmission provides additional protection to patients at risk for influenza complications. Vaccination of H C P can specifically benefit patients who cannot receive vaccination (e.g., infants aged 85 years and immune-compromised persons), and persons for whom antiviral treatment is not available (e.g., persons with medical contraindications). Although annual vaccination has long been recommended for H C P and is a high priority for reducing morbidity associated with influenza in health-care settings (98)(99)(100), national survey data have demonstrated that the vaccination coverage level during the 2008-09 season was 52.9% (101).\n\n# Considerations Regarding Influenza Vaccination of HCP\nBarriers to H C P aceptance of influenza vaccination have included fear of vaccine side effects (particularly influenza like symptoms), insufficient time or inconvenience, perceived ineffectiveness of the vaccine, perceived low likelihood of contracting influenza, avoidance of medications, and fear of needles (79,(102)(103)(104)(105)(106)(107)(108)(109). Factors demonstrated to increase vaccine acceptance include a desire for self-protection, previous receipt of influenza vaccine, a desire to protect patients, and perceived effectiveness of vaccine (79,105,106,(109)(110)(111)(112). Strategies that have demonstrated improvement in H C P vaccination rates have included campaigns to emphasize the benefits of H C P vaccination for staff and patients, vaccination of senior medical staff or opinion leaders, removing administrative barriers (e.g., costs), providing vaccine in locations and at times easily accessible by HCP, and monitoring and reporting H C P influenza vaccination rates (99,(113)(114)(115)(116)(117)(118)(119)(120). Intranasally administered live attenuated influenza vaccine (LAIV) is an option for healthy, nonpregnant adults aged <50 years who dislike needles.\nThe practice of obtaining signed declinations from HCP offered influenza vaccination has been adopted by some institutions but has not yet been demonstrated to exceed coverage rates of >70% -80% (99,115,(121)(122)(123). Institutions that require declination statements from H C P who refuse influenza vaccination should educate and counsel these HCP about benefits of the vaccine.\nEach health-care facility should develop a comprehensive influenza vaccination strategy that includes targeted education about the disease, including disease risk among H C P and patients, and about the vaccine. In addition, the program should establish easily accessible vaccination sites and inform H C P about their locations and schedule. Facilities that employ H C P should provide influenza vaccine at no cost to personnel (124). The most effective combination of approaches for achieving high influenza vaccination coverage among H C P likely varies by institution. Hospitals and health-care organizations in the United States traditionally have employed an immunization strategy that includes one or more of the following components: education about influenza, easy access to vaccine, incentives to encourage immunization, organized campaigns, institution of declination policies, and legislative and regulatory efforts (e.g., vaccination requirements) (99,115,(121)(122)(123)(124)(125)(126).\nBeginning January 1, 2007, the Joint Comm ission on A ccreditation o f H ealth-C are O rganizations required accredited organizations to offer influenza vaccinations to staff, including volunteers and licensed independent practitioners and to report coverage levels among HCP (127). Standards are available for measuring vaccination coverage among HCP as a measure of program performance within a health care setting (128). Beginning January 2013, the Centers for Medicaid Services will require acute care hospitals to report HCP influenza vaccine as part of its hospital inpatient quality reporting program.*\n\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nEffectiveness of influenza vaccines varies from year to year and depends on the age and health status of the person getting the vaccine and the similarity or \"match\" between the viruses or virus in the vaccine and those in circulation. Vaccine strains are selected for inclusion in the influenza vaccine every year based on international surveillance and scientists' estimations about which types and strains of viruses will circulate in a given year. Annual vaccination is recommended because the predom inant circulating influenza viruses typically change from season to season and, because immunity declines over time postvaccination (77).\nIn placebo-controlled studies am ong adults, the most frequent side effect o f vaccination was soreness at the vaccination site (affecting 10% -64% of patients) that lasted <2 days (129,130). These injection-site reactions typically were mild and rarely interfered with the recipient's ability to conduct usual daily activities. The main contraindication to influenza vaccination is a history of anaphylactic hypersensitivity to egg or other components of the vaccine. A history of Guillain-Barre Syndrome within 6 weeks following a previous dose of influenza vaccine is considered to be a precaution for use of influenza vaccines (77\n\n# Vaccination\nAnnual influenza vaccination is recommended for all persons aged >6 m onths who have no medical contraindication; therefore, vaccination of all HCP who have no contraindications is recommended. The influenza vaccine is evaluated annually with one or more vaccine strains updated almost every year. In addition, antibody titers decline during the year after vaccination. T hus, annual vaccination w ith the current season's formulation is recommended. Annual vaccination is appropriate and safe to begin as early in the season as vaccine is available. HCP should be among the groups considered for prioritized receipt of influenza vaccines when vaccine supply is limited.\nTwo types of influenza vaccines are available. LAIV is administered intranasally and is licensed for use in healthy nonpregnant persons aged 2-49 years. The trivalent inactivated vaccine (TIV) is administered as an intramuscular injection and can be given to any person aged >6 months. Both vaccine types contain vaccine virus strains that are selected to stimulate a protective immune response against the wild-type viruses that are thought to be most likely in circulation during the upcoming season. Use of LAIV for H C P who care for patients housed in protective inpatient environments has been a theoretic concern, but transmission of LAIV in health-care settings has not been reported. LAIV can be used for HCP who work in any setting, except those who care for severely immunocompromised hospitalized persons who require care in a protective environment. H C P who themselves have a condition that confers high risk for influenza complications, who are pregnant, or who are aged >50 years should not receive LAIV and should be administered TIV instead. An inactivated trivalent vaccine containing 60 mcg of hemagglutinin antigen per influenza vaccine virus strain (Fluzone High-Dose ) is an alternative inactivated vaccine for persons aged >65 years. Persons aged >65 years may be administered any of the standard-dose TIV preparations or Fluzone High-Dose (77). The majority of T IV preparations are administered intramuscularly. An intradermally administered T IV was licensed in May 2011 and is an alternative to other TIV preparations for persons aged 18-64 years (131).\n\n# Use of Antiviral Drugs for Treating Exposed Persons and Controlling Outbreaks\nUse of antiviral drugs for chemoprophylaxis or treatment of influenza is an adjunct to (but not a substitute for) vaccination. Oseltamivir or zanamivir are recommended currently for chemoprophylaxis or treatment of influenza (132,133). TIV Recommendations can be administered to exposed, unvaccinated H C P at the same time as chemoprophylaxis, but LAIV should be avoided because the antiviral medication will prevent viral replication needed to stimulate a vaccine response (77). Antivirals are used often among patients during outbreaks in closed settings such as long-term-care facilities but also can be administered to unvaccinated H C P during outbreaks, when an exposure to a person with influenza occurs, or after exposure when vaccination is not thought to be protective against the strain to which a vaccinated H C P was exposed. Chemoprophylaxis consists of 1 dose (of either antiviral drug) daily for 10 days, and treatment consists of 1 dose twice daily for 5 days. In many instances of H C P exposure, watchful waiting and early initiation of treatment if symptoms appear is preferred rather than use of antiviral chemoprophylaxis immediately after exposure. The intensity and duration of the exposure and the underlying health status of the exposed worker are important factors in clinical judgm ents about w hether to provide chemoprophylaxis. If chemoprophylaxis is used, the provider should base choice of the agent on whether the circulating strain or strains of influenza have demonstrated resistance to particular antivirals.\n\n# Program Evaluation\n- Health-care adm inistrators should include influenza vaccination coverage among H C P as a measure of quality of care (124). - Influenza vaccination rates among HCP within facilities should be regularly measured and reported, and ward-, unit-, and specialty-specific coverage rates should be provided to staff and adm inistration (124). Such information might be useful to promote compliance with vaccination policies.\n\n# Measles\n\n# Background\n\n# Epidemiology and Risk Factors\nMeasles is a highly contagious rash illness that is transmitted by respiratory droplets and airborne spread. Severe complications, w hich m ight result in death, include pneum onia and encephalitis. Before the national measles vaccination program was im plem ented in 1963, almost every person acquired measles before adulthood; an estimated 3-4 million persons in the U nited States acquired measles each year (134). Approximately 500,000 persons were reported to have had measles annually, of whom 500 persons died, 48,000 were hospitalized, and another 1,000 had permanent brain damage from measles encephalitis (134).\nThrough a successful 2-dose measles vaccination program (i.e., a first dose at age 12-15 months and a second dose between ages 4 -6 years) (135) and better measles control throughout the region o f the Americas (136), endemic transmission of measles was interrupted in the United States, and measles was declared eliminated from the country in 2000 (137). However, measles remains widespread in the majority of countries outside the Western Hemisphere, with an estimated 20 m illion measles cases occurring worldwide (138) and approximately 164,000 related deaths (139). Thus, the United States continues to experience international importations that might lead to transmission among U.S. residents and limited outbreaks, especially in unvaccinated populations (140)(141)(142)(143).\nDuring 2001-2008, a total of 557 confirmed measles cases were reported in the United States from 37 states and the District of Columbia (annual median: 56; range: 37 in 2004 to 140 in 2008), representing an annual incidence ofless than one case per million population (144). O fthe 557 reported case-patients, 126 (23%) were hospitalized (annual median: 16; range: 5-29); of these, at least five case-patients were admitted to intensive care. Two deaths were reported, both in 2003 (144).\nO f the 557 reported case-patients during 2001-2008, a total of 223 (40%) were adults, including 156 (28%) aged 20-39 years and 67 (12%) aged >40 years. O f the 438 measles cases among U.S. residents, 285 (65%) cases were considered preventable (i.e., occurred among persons who were eligible for vaccination but were unvaccinated) (144). The remaining 153 (35%) cases were considered nonpreventable. Cases were defined as nonpreventable if they occurred among U.S. resident case-patients who had received >1 dose of measles-containing vaccine, if patients were vaccinated as recommended if traveling internationally, or if they were not vaccinated but had other evidence of im m unity (i.e., were born before 1957 and therefore presumed immune from natural disease in childhood, had laboratory evidence of immunity, or had documentation of physician-diagnosed disease) or for whom vaccination is not recommended. During 2001-2008, a total of 12.5% (one of eight) of measles cases reported to CD C among H C P occurred in persons born before 1957; the other seven cases occurred among H C P born after 1957.\nMeasles-mumps-rubella (MMR) vaccination policies have been enforced with variable success in United States health care facilities over the past decade. Even though medical settings were a primary site of measles transmission during the 1989-1991 measles resurgence (145,146), as of September 2011, only three states (New York, Oklahoma, and Rhode Island) had laws mandating that all hospital personnel have proof of measles immunity and did not allow for religious or philosophic exemptions (147).\nVaccine coverage in the United States is high; in 2010, a total of 91\n\n# Measles Transmission and the Costs of Mitigating Measles Exposures in Health-Care Settings\nHealth-care-associated cases of measles are of public health concern. Because of the severity of measles, infected persons are likely to seek medical care in primary health-care facilities, emergency departments, or hospitals (141,149,150). Medical settings played a prominent role in perpetuating outbreaks of measles transmission during the 1989-1991 measles resurgence (145,146) and were a primary site of measles transmission in a health-care-associated outbreak in 2008 (149). During 2001 2008, a total of 27 reported measles cases were transmitted in U.S. health-care facilities, accounting for 5% of all reported U.S. measles cases.\nBecause of the greater opportunity for exposure, HCP are at higher risk than the general population for becoming infected with measles. A study conducted in 1996 in medical facilities in a county in Washington state indicated that HCP were 19 times more likely to develop measles than other adults (151). During 2001During -2008, in the 23 health-care settings in which measles transmission was reported, eight cases occurred among HCP, six (75%) of whom were unvaccinated or had unknown vaccination status. One health-care provider was hospitalized in an intensive care unit for 6 days from severe measles complications (142). During a health-care-associated measles outbreak in Arizona in 2008 with 14 cases, six cases were acquired in hospitals, and one was acquired in an outpatient setting. One unvaccinated health-care worker developed measles and infected a hospital emergency room patient who required intensive care following hospital admission for measles (149).\nHigh costs also are involved in evaluating and containing exposures and outbreaks in health-care facilities, as well as a substantial disruption of regular hospital routines when control measures are instituted, especially if hospitals do not have readily available data on the measles immunity status of their staff and others included in the facility vaccination program. In 2005 in Indiana, one hospital spent more than $113,000 responding to a measles outbreak (142), and in 2008 in Arizona, two hospitals spent $799,136 responding to and containing cases in their facilities (149). The Arizona outbreak response required rapid review of measles documentation of 14,844 H C P at seven hospitals and emergency vaccination of approximately 4,500 H C P who lacked documentation of measles immunity. Serologic testing at two hospitals among 1,583 H C P without documented history of vaccination or without documented laboratory evidence of measles immunity revealed that 138 (9%) of these persons lacked measles IgG antibodies (149).\n\n# Vaccine Effectiveness, Duration of Immunity and Seroprevalence Studies, and Vaccine Safety\nVaccine Effectiveness M M R vaccine is highly effective in preventing measles with a 1-dose vaccine effectiveness of 95% when administered on or after age 12 months and a 2-dose vaccine effectiveness of 99% (135).\n\n# Duration of Immunity and Seroprevalence Studies\nTwo doses of live measles vaccine are considered to provide long-lasting immunity (135). Although antibody levels decline following vaccination, a study examining neutralizing antibody levels up to 10 years following the second dose of M M R vaccine in children indicates that antibodies remain above the level considered protective (152).\nStudies among H C P in the United States during the measles resurgence in the late 1980s through early 1990s demonstrated that 4% -10% of all H C P lacked measles IgG antibodies (153)(154)(155)(156). During the 2008 Arizona outbreak, of the 1,077 health-care providers born during or after 1957 without documented measles immunity, 121 (11%) were seronegative (149). In a study of measles seroprevalence among 469 newly hired H C P at a hospital in N orth Carolina who were born before 1957, and thus considered immune by age, who could not provide written evidence of immunity to measles, serologic testing indicated that six (1.3%) lacked measles IgG antibodies (157). Other serologic studies of hospital-based H C P indicate that 2%-9% of those born before 1957 lacked antibodies to measles (156,(158)(159)(160).\nA survey co n d u cted d u rin g 1999-2004 foun d a seroprevalence of measles antibodies of 95.9% among persons in the U.S. population aged 6-49 years (161). The survey indicated that the lowest prevalence, 92.4% , was among adults born during 1967-1976 (161). A 1999 study of U.S. residents aged >20 years determined that 93% had antibodies to measles virus (162).\n\n# Vaccine Safety\nMeasles vaccine is administered in combination with the mumps and rubella components as the M M R vaccine in the United States. Monovalent measles vaccine rarely has been used in the United States in the past 2 decades and is no longer available. After decades of use, evidence demonstrates that M M R vaccine has an excellent safety profile (134).\nT he m ajority of docum ented adverse events occur in children. In rare circumstances, M M R vaccination of adults has been associated w ith the following adverse events: anaphylaxis (approximately 1.0-3.5 occurrences per million doses administered) (134), thrombocytopenia from the measles component or rubella component (a rate of three to four cases for every 100,000 doses) ( 134), and acute arthritis from the rubella component (arthralgia develops among approximately 25% of rubella-susceptible postpubertal females after M M R vaccination, and approximately 10% have acute arthritis-like signs and symptoms) (135). W hen joint symptoms occur, they generally persist for 1 day-3 weeks and rarely recur (135). Chronic joint symptoms attributable to the rubella component of the M M R vaccine are reported very rarely, if they occur at all. Evidence does not support an association between M M R vaccination and any of the following: hearing loss, retinopathy, optic neuritis, Guillain-Barre Syndrome, type 1 diabetes, Crohn's disease, or autism (135,(163)(164)(165)(166)(167)(168)(169).\nA woman can excrete the rubella vaccine virus in breast milk and transmit the virus to her infant, but the infection remains asymptomatic (135) Presumptive evidence of immunity to measles for persons who work in health-care facilities includes any of the following:\n- written documentation of vaccination with 2 doses of live measles or M M R vaccine administered at least 28 days apart,'!' - laboratory evidence of immunity, § - laboratory confirmation of disease, or - birth before 1957.J\n\n# Prevaccination Testing\nPrevaccination antibody screening before M M R vaccination for an employee who does not have adequate presumptive evidence of im m unity is not necessary unless the medical facility considers it cost effective (134,(170)(171)(172) although no recent studies have been conducted. For H C P who have 2 documented doses of M M R vaccine or other acceptable evidence of immunity to measles, serologic testing for immunity is not recommended. In the event that a H C P who has 2 documented doses of M M R vaccine is tested serologically and determined to have negative or equivocal measles titer results, it is not recommended that the person receive an additional dose of M M R vaccine. Such persons should be considered to have presumptive evidence of measles immunity. Documented ageappropriate vaccination supersedes the results of subsequent serologic testing. Because rapid vaccination is necessary to halt disease transmission, during outbreaks of measles, serologic screening before vaccination is not recommended.\n\n# Use of Vaccine and Immune Globulin for Treating Exposed Persons and Controlling Outbreaks\nFollowing airborne infection-control precautions and implementing other infection-control measures are important to control the spread of measles but might fail to prevent all nosocomial transmission, because transmission to other susceptible persons might occur before illness is recognized. Persons infected with measles are infectious 4 days before rash onset through 4 days after rash onset. W hen a person who is suspected of having measles visits a health-care facility, airborne infection-control precautions should be followed stringently. The patient should be asked immediately to wear a medical mask and should be placed in an airborne-infection isolation room (i.e., a negative airpressure room) as soon as possible. If an airborne-infection isolation room is not available, the patient should be placed in a private room with the door closed and be asked to wear a mask. If possible, only staff with presumptive evidence of immunity should enter the room of a person with suspect or confirmed measles. Regardless of presumptive immunity status, all staff entering the room should use respiratory protection consistent with airborne infection-control precautions (i.e., use of an N95 respirator or a respirator with similar effectiveness in preventing airborne transmission) (3,150).\nBecause of the possibility, albeit low (~1%), of measles vaccine failure in H C P exposed to infected patients (173), all H C P should observe airborne precautions in caring for patients with measles. H C P in whom measles occurs should be excluded from work until >4 days following rash onset. Contacts w ith measles-compatible sym ptom s should be isolated, and appropriate infection-control measures (e.g., rapid vaccination of susceptible contacts) should be implemented to prevent further spread (174).\nIf measles exposures occur in a health-care facility, all contacts should be evaluated immediately for presumptive evidence of measles immunity. HCP without evidence of immunity should be offered the first dose of M M R vaccine and excluded from work from day 5-21 following exposure (135). HCP without evidence of immunity who are not vaccinated after exposure should be removed from all patient contact and excluded from the facility from day 5 after their first exposure through day 21 after the last exposure, even if they have received postexposure intramuscular immune globulin of 0.25 mL/kg (40 mg IgG/ kg) (135). Those with documentation of 1 vaccine dose may remain at work and should receive the second dose.\nC ase-patient contacts who do not have presum ptive evidence of measles immunity should be vaccinated, offered intramuscular immune globulin of 0.25 mL/kg (40 mg IgG/ kg), which is the standard dosage for nonimmunocompromised persons (135), or quarantined until 21 days after their exposure to the case-patient. Contacts with measles-compatible symptoms should be isolated, and appropriate infectioncontrol measures should be implemented to prevent further spread. If immune globulin is administered to an exposed person, observations should continue for signs and symptoms of measles for 28 days after exposure because immune globulin might prolong the incubation period.\nAvailable data suggest that live virus measles vaccine, if administered within 72 hours of measles exposure, will prevent, or modify disease (134). Even if it is too late to provide effective postexposure prophylaxis by administering MMR, the vaccine can provide protection against future exposure to all three infections. Identifying persons who lack evidence ofmeasles immunity during contact investigations provides a good opportunity to offer M M R vaccine to protect against measles as well as mumps and rubella, not only for HCP who are part of an organization' s vaccination program, but also for patients and visitors. If an exposed person is already incubating measles, M M R vaccination will not exacerbate symptoms. In these circumstances, persons should be advised that a measles-like illness occurring shortly after vaccination could be attributable either to natural infection or to the vaccine strain.\nIn such circumstances, specimens should be submitted for viral strain identification.\n\n# Mumps\n\n# Background\n\n# Epidemiology and Risk Factors\nMumps is an acute viral infection characterized by fever and inflammation of the salivary glands (usually parotitis) (175). The spectrum of illness ranges from subclinical infection (20% -40%) to nonspecific respiratory illness, sialadenitis including classic parotitis, deafness, orchitis, and meningoencephalitis; severity increases with age (175). In the prevaccine era, mumps was a common childhood illness, with approximately 186,000 mumps cases reported in the United States per year (176). After the introduction of the Jeryl Lynn strain mumps vaccine in 1967 and the implementation of the 1-dose mumps vaccine policy for children in 1977 (177), reports of mumps cases in the United States declined 99% (178). During 1986-1987, an increase in reported mumps cases occurred, primarily affecting unvaccinated adolescents and young adults. In the late 1980s, sporadic outbreaks continued to occur that affected both unvaccinated and 1-dose vaccinated adolescents and young adults (178). In 1989, a second dose of M M R vaccine was recommended nationwide for better measles control among school-aged children (179). Historically low rates of mumps followed with only several hundred reported cases per year in the United States during 2000-2005.\nIn 1998, a national goal to eliminate mumps was set for 2010 (180). However, in 2006, a total of 6,584 mumps cases were reported in the United States, the largest U.S. mumps outbreak in nearly 20 years (181-183). Whereas overall national mumps incidence was 2.2 per 100,000 population, eight states in the Midwest were the most affected, with 2.5-66.1 cases per 100.000 population (183). The highest incidence (31.1 cases per 100,000 population) was among persons aged 18-24 years (e.g., college-aged students), the majority of whom had received 2 doses of mumps-containing vaccine. O f the 4,017 case-patients for whom age and vaccination status were known, 1,786 (44%) were aged >25 years (incidence: 7.2 cases per 100.000 persons); of these 1,786 patients, 351 (20%) received at least 2 doses, 444 (25%) received 1 dose, 336 (19%) were unvaccinated, and 655 (37%) had unknown vaccination status.\nSince the 2006 resurgence, two additional large U.S. mumps outbreaks have occurred, both during 2009-2010, one among members o f a religious com m unity w ith cases occurring throughout the northeastern United States (184) and the other in Guam ( 185\n\n# Mumps Transmission and the Costs of Mitigating Mumps Exposures in Health-care Settings\nAlthough health-care-associated transmission of mumps is infrequent, it might be underreported because of the high percentage (~20%-40%) of infected persons who might be asymptomatic (186)(187)(188)(189). In a survey of 9,299 adults in different professions conducted in 1968, before vaccine was used routinely, the rate of mumps acquisition was highest among dentists and HCP, with rates of 18% among dentists and 15% among physicians (37% for pediatricians), compared with 9% among primary and secondary school teachers and 2% among university staff members (190).\nIn the postvaccine era, m um ps transm ission also has been documented in medical settings (191)(192)(193). During a Tennessee mumps outbreak during 1986-1987, a total of 17 (12%) of 146 hospitals and three (50%) of six long-term-care facilities reported one or more practices that could contribute to the spread of mumps, including not isolating patients with mumps, assigning susceptible staff to care for patients with mumps, and not immunizing susceptible employees. Health care-associated transmission resulted in six cases of mumps infections among health-care providers and nine cases of mumps infections among patients (191). In Utah in 1994, two health-care providers in a hospital developed mumps after they had contact with an infected patient (192). During the 2006 outbreak, one health-care facility in Chicago experienced ongoing mumps transmission lasting 4 weeks (193).\nDuring the 2006 multistate U.S. outbreak, 144 (8.5%) of 1,705 adult case-patients in Iowa for whom occupation was known were health-care providers (Iowa D epartm ent o f Public H ealth, unpublished data, 2006). W hether transmission occurred from patients, coworkers, or persons in the community is unknown. During the 2009-2010 outbreak in the northeastern region of the United States, seven (0.2%) of the 3,400 case-patients were health-care providers, six of whom likely were infected by patients because they had no other known exposure.\nExposures to mumps in health-care settings also can result in added economic costs because of furlough or reassignment of staff members from patient-care duties or closure of wards (194). In 2006, a Kansas hospital spent $98,682 containing a mumps outbreak (195). During a mumps outbreak in Chicago in 2006, one health-care facility spent $262,788 controlling the outbreak (193).\n\n# Vaccine Effectiveness, Duration of Immunity and Seroprevalence Studies, and Vaccine Safety\nVaccine Effectiveness M M R vaccine has a 1-dose vaccine effectiveness in preventing mumps of 80% -85% (range: 75% -91% ) (175,(196)(197)(198)(199) and a 2-dose vaccine effectiveness of 79% -95% (199)(200)(201)(202). In a study conducted on two Iowa college campuses during the 2006 mumps outbreak among a population that was primarily vaccinated with 2 doses, 2-dose vaccine effectiveness ranged from 79% to 88% (202).\n\n# Duration of Immunity and Seroprevalence Studies\nMumps antibody levels wane over time following the first or second dose of vaccination (203,204), but the correlates of im m unity to m um ps are poorly understood and the significance of these waning antibody levels is unclear. A study on a university campus in Nebraska in 2006 indicated lower levels of mumps neutralizing antibodies among students who had been vaccinated with a second M M R dose >15 years previously than among those who had been vaccinated 1-5 years previously, but the difference was not statistically significant (p>0.05) (205). In a 2006 study on a university campus in Kansas, students with mumps were more likely to have received a second dose of M M R vaccine >10 years previously than were their roommates without mumps (206). However, another 2006 study from an Iowa college campus identified no such association (202).\nDuring 1999-2004, national seroprevalence for mumps antibodies for persons aged 6 -4 9 years was 90% (95% confidence interval : 88.8-91.1) (207). In the Nebraska study, 414 (94%) of the 440 participants were seropositive for mumps antibodies (205). A study in Kansas in 2006 indicated that 13% of hospital employees lacked antibodies to the mumps virus (195). In a recent study on mumps seroprevalence among 381 newly hired health-care personnel at a hospital in North Carolina who were born before 1957 and thus considered immune by age and who could not provide written evidence of immunity to mumps, serologic testing indicated that 14 (3.7%) lacked IgG antibodies to mumps (157). For HCP who do not have adequate presumptive evidence of mum ps imm unity, prevaccination antibody screening before M M R vaccination is not necessary (135,175). For H C P who have 2 documented doses of M M R vaccine or other acceptable evidence of immunity to mumps, serologic testing for im m unity is not recommended. In the event that a health-care provider who has 2 docum ented doses of M M R vaccine is tested serologically and determined to have negative or equivocal mumps titer results, it is not recommended that the person receive an additional dose of M M R vaccine. Such persons should be considered immune to mumps. Documented age-appropriate vaccination supersedes the results of subsequent serologic testing. Likewise, during outbreaks of mumps, serologic screening before vaccination is not recommended because rapid vaccination is necessary to halt disease transmission.\n\n# Controlling Mumps Outbreaks in Health-Care Settings\nPlacing patients in droplet precautions and implementing other infection-control measures is important to control the spread of mumps but might fail to prevent all nosocomial transmission, because transmission to other susceptible persons might occur before illness is recognized (208). W hen a person suspected of having mumps visits a health-care facility, only H C P with adequate presum ptive evidence of im m unity should be exposed to the person, and in addition to standard precautions, droplet precautions should be followed. The index case-patient should be isolated, and respiratory precautions The first dose of mumps-containing vaccine should be administered on or after the first birthday; the second dose should be administered no earlier than 28 days after the first dose.\nMumps immunoglobulin (IgG) in the serum; equivocal results should be considered negative. § § The majority of persons born before 1957 are likely to have been infected naturally between birth and 1977, the year that mumps vaccination was recommended for routine use, and may be presumed immune, even if they have not had (gown and gloves) should be used for patient contact. Negative pressure rooms are not required. The patient should be isolated for 5 days after the onset of parotitis, during which time shedding of virus is likely to occur (209).\nIf mumps exposures occur in a health-care facility, all contacts should be evaluated for evidence of mumps immunity. HCP with no evidence of mumps immunity who are exposed to patients with mumps should be offered the first dose of M M R vaccine as soon as possible, but vaccine can be administered at any interval following exposure; they should be excluded from duty from day 12 after the first unprotected exposure through day 25 after the most recent exposure. H C P with documentation of 1 vaccine dose may remain at work and should receive the second dose. HCP with mumps should be excluded from work for 5 days from the onset of parotitis (209).\nAntibody response to the mumps com ponent of M M R vaccine generally is believed not to develop soon enough to provide effective prophylaxis after exposure to suspected mum ps (191,210), but data are insufficient to rule out a prophylactic effect. N onetheless, the vaccine is not recom m ended for prophylactic purposes after exposure. However, identifying persons who lack presumptive evidence of mumps immunity during contact investigations provides a good opportunity to offer M M R vaccine to protect against mumps as well as measles and rubella, not only for HCP who are part of an organization's vaccination program, but also for patients and visitors. If an exposed person already is incubating mumps, M M R vaccination will not exacerbate the symptoms. In these circumstances persons should be advised that a mumps-like illness occurring shortly after vaccination is likely to be attributable to natural infection. In such circumstances, specimens should be submitted for viral strain identification to differentiate between vaccine and wild type virus. Immune globulin is not routinely used for postexposure protection from mumps because no evidence exists that it is effective (135).\n\n# Rubella\n\n# Background\n\n# Epidemiology and Risk Factors\nRubella (German measles) is a viral disease characterized by rash, low-grade fever, lym phadenopathy, and malaise (211). A lthough rubella is considered a benign disease, transient arthralgia and arthritis are observed commonly in infected adults, particularly among postpubertal females. Chronic arthritis has been reported after rubella infection, but such reports are rare, and evidence of an association is weak (212). O ther complications that occur infrequently are thrombocytopenia and encephalitis (211). Infection is asymptomatic in 25%-50% of cases (213). Clinical diagnosis of rubella is unreliable and should not be considered in assessing immune status. Many rash illnesses might mimic rubella infection and many rubella infections are unrecognized. The only reliable evidence of previous rubella infection is the presence of serum rubella IgG antibody (211).\nO f primary concern are the effects that rubella can have when a pregnant woman becomes infected, especially during the first trimester, which can result in miscarriages, stillbirths, therapeutic abortions, and congenital rubella syndrome (CRS), a constellation of birth defects that often includes blindness, deafness, mental retardation, and congenital heart defects (211,213). Postnatal rubella is transmitted through direct or droplet contact from nasopharyngeal secretions. The incubation period ranges from 12 to 23 days (214,215). An ill person is most contagious when the rash first appears, but the period of maximal communicability extends from a few days before to 7 days after rash onset (213). Rubella is less contagious than measles.\nIn the prevaccine era, rubella was an endemic disease globally with larger epidemics that occurred; in the United States, rubella epidemics occurred approximately every 7 years (211). During the 1964-1965 global rubella epidemic, an estimated 12.5 million cases of rubella occurred in the United States, resulting in approximately 2,000 cases of encephalitis, 11,250 fetal deaths attributable to spontaneous or surgical abortions, 2,100 infants who were stillborn or died soon after birth, and 20,000 infants born with CRS. The economic impact of this epidemic in the United States alone was estimated at $1.5 billion in 1965 dollars ($10 billion in 2010 dollars) (216).\nAfter the rubella vaccine was licensed in the United States in 1969, reported rubella cases decreased from 57,686 in 1969 to 12,491 in 1976 (216), and CRS cases reported nationwide decreased from 68 in 1970 to 23 in 1976 (217). Declines in rubella age-specific incidence occurred in all age groups, including adolescents and adults, but the greatest declines were among children aged <15 years (216) As of September 2011, only three states (i.e., New York, Oklahoma, and Rhode Island) had laws mandating that all hospital personnel have proof of rubella immunity and did not allow for religious or philosophical exemptions (147). Additional states had requirements for specific types of facilities or for certain employees within those facilities, but they did not have universal laws mandating proof of rubella immunity for all hospital personnel (147).\n\n# Rubella Transmission and the Costs of Mitigating Rubella Exposures in Health-Care Settings\nNo documented transmission of rubella to HCP or other hospital staff or patients in U.S. health-care facilities has occurred since elimination was declared. However, in the decades before elimination, rubella transmission was documented in at least 10 U.S. medical settings (221)(222)(223)(224)(225)(226)(227)(228)(229)(230)(231) and led to outbreaks with serious consequences, including pregnancy terminations, disruption of hospital routine, absenteeism from work, expensive containment measures, negative publicity, and the threat of litigation (232). In these outbreaks, transmission occurred from HCP to susceptible coworkers and patients, as well as from patients to HCP and other patients. No data are available on whether HCP are at increased risk for acquiring rubella compared with other professions.\n\n# Vaccine Effectiveness, Duration of Immunity and Seroprevalence Studies, and Vaccine Safety\n\n# Vaccine Effectiveness\nVaccine effectiveness of the RA 27/3 rubella vaccine against clinical rubella is 95% (85%-99% CI) and >99% for clinical laboratory confirmed rubella (211,233). Antibody responses to rubella as part of M M R vaccine are equal (i.e., >99%) to those seen after the single-antigen RA 27/3 rubella vaccine (211,234).\n\n# Duration of Immunity and Seroprevalence Studies\nIn clinical trials, 97% -99% of susceptible persons who received a single dose of the RA 27/3 rubella vaccine when they were aged >12 months developed antibody (211,235,236). Two studies have demonstrated that vaccine-induced rubella antibodies might wane after 12-15 years (237,238); however, rubella surveillance data do not indicate that rubella and CRS are increasing among vaccinated persons.\nN ational seroprevalence for rubella antibodies among persons aged 6-49 years during 1999-2004 was 91% (239). During 1986-1990, serologic surveys in one hospital indicated that 5% of H C P (including persons born in 1957 or earlier) did not have detectable rubella antibody (240). Earlier studies indicated that up to 14%-19% of U.S. hospital personnel, including young women of childbearing age, lacked detectable rubella antibody (225,241,242). In a recent study on rubella seroprevalence among 477 newly hired HCP at a hospital in N orth Carolina who were born before 1957, and thus considered immune by age, who could not provide written evidence of immunity to rubella, serologic testing revealed that 14 (3.1%) lacked detectable levels of antibody to rubella (157).\nBecause of the potential for contact with pregnant women in any type of health-care facility, all HCP should have documented presumptive evidence of immunity to rubella. History of disease is not considered adequate evidence of immunity. As a result of the theoretic risk to the fetus, women should be counseled to avoid becoming pregnant for 28 days after receipt of a rubella-containing vaccine (243). However, receipt of rubella-containing vaccine during pregnancy should not be a reason to consider termination of pregnancy; data from 18 years of following to term 321 known rubella-susceptible women who were vaccinated within 3 months before or 3 m onths after conception indicated that none of the 324 infants born to these mothers had malformations compatible with congenital rubella syndrome, but five had evidence of subclinical rubella infection (244). The estimated risk for serious malformations to fetuses attributable to the mother receiving RA 27/3 vaccine is considered to range from zero to 1.6% (135,244).\nEvidence does not support a link between M M R vaccination and any of the following: hearing loss, retinopathy, optic neuritis, Guillain-Barre Syndrome, type 1 diabetes, Crohn's disease, or autism (135,(163)(164)(165)(166)(167)(168)(169).\nA woman can excrete the rubella vaccine virus in breast milk and transmit the virus to her infant, but the infection remains asymptomatic (135) Presumptive evidence of immunity to rubella for persons who work in health-care facilities includes any of the following:\n- written documentation of vaccination with 1 dose of live rubella or M M R vaccine, - laboratory evidence of im m unity,- laboratory confirmation of rubella infection or disease, or - birth before 1957* (except women of childbearing potential who could become pregnant, although pregnancy in this age group would be exceedingly ra re^).\n\n# Prevaccination Testing\nFor HCP who do not have adequate presumptive evidence of rubella im m unity, prevaccination antibody screening before M M R vaccination is not necessary unless the medical facility considers it cost effective (135). For HCP who have 1 documented dose of M M R vaccine or other acceptable evidence of immunity to rubella, serologic testing for immunity is not recommended. In the event that a health-care provider who has at least 1 documented dose of rubella-containing vaccine is tested serologically and determined to have negative or equivocal rubella titer results, receipt of an additional dose of M M R vaccine for prevention of rubella is not recommended. Such persons should be considered im m une to rubella. However, if the provider requires a second dose of measles or mumps vaccine, then a second dose of M M R should be adm inistered. D ocum ented age-appropriate vaccination supersedes the results of subsequent serologic testing. Likewise, during outbreaks of rubella, serologic screening before vaccination is not recommended because rapid vaccination is necessary to halt disease transmission.\n\n# Controlling Rubella Outbreaks\nTo prevent transmission of rubella in health-care settings, patients suspected to have rubella should be placed in private rooms. In addition to standard precautions, droplet precautions Because rubella can occur in some persons born before 1957 and because congenital rubella and congenital rubella syndrome can occur in the offspring of women infected with rubella virus during pregnancy, birth before 1957 is not acceptable evidence of rubella immunity for women who could become pregnant.\nshould be followed until 7 days after onset of symptoms. Room doors can remain open, and special ventilation is not required. Any exposed HCP who do not have adequate presumptive evidence of rubella immunity should be excluded from duty beginning 7 days after exposure to rubella and continuing through either 1) 23 days after the most recent exposure or 2) 7 days after rash appears if the provider develops rubella (213)(214)(215). Exposed H C P who do not have adequate presum ptive evidence of im m unity who are vaccinated postexposure should be excluded from duty for 23 days after the most recent exposure to rubella because no evidence exists that postexposure vaccination is effective in preventing rubella infection (244).\nN either rubella-containing vaccine (244) nor im m une globulin (IG) (211,244) is effective for postexposure prophylaxis of rubella. Although intramuscular administration of 20 mL of immune globulin within 72 hours of rubella exposure might reduce the risk for rubella, it will not eliminate the risk (135,245); infants with congenital rubella have been born to women who received IG shortly after exposure (213). In addition, administration of IG after exposure to rubella might modify or suppress symptoms and create an unwarranted sense of security with respect to transmission.\nIf exposure to rubella does not cause infection, postexposure vaccination with M M R vaccine should induce protection against subsequent infection of rubella, as well as measles and mumps. If the exposure results in infection, no evidence indicates that administration of M M R vaccine during the presymptomatic or prodromal stage of illness increases the risk for vaccine-associated adverse events (213).\n\n# Pertussis\n\n# Background\n\n# Epidemiology and Risk Factors\nPertussis is a highly contagious bacterial infection. Secondary attack rates among susceptible household contacts exceed 80% (246,247). Transmission occurs by direct contact with respiratory secretions or large aerosolized droplets from the respiratory tract of infected persons. The incubation period is generally 7-10 days but can be as long as 21 days. The period of communicability starts with the onset of the catarrhal stage and extends into the paroxysmal stage. Symptoms of early pertussis (catarrhal phase) are indistinguishable from other upper respiratory infections.\nVaccinated adolescents and adults, whose immunity from childhood vaccinations wanes 5-10 years after the most recent dose of vaccine (usually administered at age 4-6 years), are an important source of pertussis infection for susceptible infants. Infants too young to be vaccinated are at greatest risk for severe pertussis, including hospitalization and death. The disease can be transmitted from adults to close contacts, especially unvaccinated children.\nVaccination coverage am ong infants and children for diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine remains high. In 2010, coverage for children aged 19-35 months who have received >4 doses of DTaP/diphtheria and tetanus toxoids and pertussis vaccine (DTP)/diphtheria and tetanus toxoids vaccine (DT) was 84% (21). Among children entering kindergarten for the 2009-2010 school year, DTaP coverage was 93% (148). Vaccination coverage for tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine was 68.7% among adolescents in 2010 and <7% among adults in 2009 (22,248). Tdap vaccination coverage among H C P was 17.0% in 2009 (248).\n\n# Disease in Health-Care Settings and Impact on Health Care Personnel and Patients\nIn hospital settings, transmission of pertussis has occurred from hospital visitors to patients, from HCP to patients, and from patients to H C P (249-252). Although of limited size (range: 2-17 patients and 5-13 staff), documented outbreaks were costly and disruptive. In each outbreak, H C P were evaluated for cough illness and required diagnostic testing, prophylactic antibiotics, and exclusion from work.\nD uring outbreaks that occur in hospitals, the risk for contracting pertussis among patients or staff is often difficult to quantify because exposure is not well defined. Serologic studies conducted among hospital staff indicate that exposure to pertussis is much more frequent than suggested by attack rates of clinical disease (246,(249)(250)(251)(252)(253)(254). In one outbreak, seroprevalence of pertussis agglutinating antibodies among H C P correlated w ith the degree of patient contact and was highest among pediatric house staff (82%) and ward nurses (71%) and lowest among nurses with administrative responsibilities (35%) (251).\nA model to estimate the cost of vaccinating H CP and the net return from preventing nosocomial pertussis was constructed using probabilistic methods and a hypothetical cohort of 1,000 H C P with direct patient contact followed for 10 years (255). Baseline assumptions, determined from data in the literature, included incidence of pertussis in HCP, ratio of identified exposures per HCP case, symptomatic percentage of seroconfirmed pertussis infections in HCP, cost of infectioncontrol measures per exposed person, vaccine efficacy, vaccine coverage, employment turnover rate, adverse events, and cost of vaccine (255). In a 10-year period, the cost of infection control would be $388,000 w ithout Tdap vaccination of HCP compared with $69,000 with such a program (255). Introduction of a vaccination program would result in a net savings as high as $535,000 and a benefit-cost ratio of 2.38 (i.e., for every dollar spent on the vaccination program, the hospital would save $2.38 on control measures) (255).\n\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nA prelicensure im m unogenicity and safety study in adolescents and adults of a vaccine containing acellular pertussis estimated vaccine efficacy to be 92% (256). Recent postlicensure studies ofTdap demonstrate vaccine effectiveness at 78% and 66% (257,258). Duration of im m unity from vaccination has yet to be evaluated. D ata from pre-and postlicensure studies support the safety ofTdap in adolescents and adults (259)(260)(261)(262)(263).\nSince the 2005 Tdap recommendations for HCP, one study tried to determine if postexposure prophylaxis following pertussis exposure was necessary for Tdap-vaccinated H C P (264). During the study period, 116 exposures occurred among 94 HCP. Pertussis infection occurred in 2% of those who received postexposure prophylaxis compared with 10% of those who did not, suggesting a possible benefit of postexposure prophylaxis among Tdap-vaccinated HCP (264). Because Tdap coverage is suboptimal among HCP, and the duration of protection afforded by Tdap is unknown, vaccination status does not change the approach to evaluate the need for postexposure prophylaxis in exposed H CP Postexposure prophylaxis is necessary for HCP in contact with persons at risk for severe disease. Other HCP either should receive postexposure prophylaxis or be monitored for 21 days after pertussis exposure and treated at the onset of signs and symptoms of pertussis. Recommended postexposure prophylaxis antibiotics for HCP exposed to pertussis include azithromycin, clarithroymycin, or erythromycin. HCP are not at greater risk for diphtheria or tetanus than the general population.\n\n# Recommendations\n\n# Vaccination\nRegardless of age, H C P should receive a single dose ofTdap as soon as feasible if they have not previously received Tdap and regardless of the time since their most recent Td vaccination. Vaccinating HCP with Tdap will protect them against pertussis and is expected to reduce transmission to patients, other HCP, household members, and persons in the community. Tdap is not licensed for multiple administrations; therefore, after receipt of Tdap, H C P should receive Td for future booster vaccination against tetanus and diphtheria. Hospitals and ambulatory-care facilities should provide Tdap for H C P and use approaches that maximize vaccination rates (e.g., education about the benefits of vaccination, convenient access, and the provision of Tdap at no charge).\n\n# Prevaccination Testing\nPrevaccination serologic testing is not recommended.\n\n# Demonstrating Immunity\nIm m unity cannot be dem onstrated through serologic testing because serologic correlates of protection are not well established.\n\n# Controlling Pertussis Outbreaks in Health-Care Settings\nPrevention of pertussis transmission in health-care settings involves diagnosis and early treatment of clinical cases, droplet isolation of infectious patients who are hospitalized, exclusion from work of H C P who are infectious, and postexposure prophylaxis. Early diagnosis of pertussis, before secondary transmission occurs, is difficult because the disease is highly communicable during the catarrhal stage, when symptoms are still nonspecific. Pertussis should be considered in the differential diagnoses for any patient with an acute cough illness with severe or prolonged paroxysmal cough, particularly if characterized by posttussive vomiting, whoop, or apnea. Nasopharyngeal specimens should be taken, if possible, from the posterior nasopharynx with a calcium alginate or Dacron swab for cultures and/or polymerase chain reaction (PCR) assay.\nHealth-care facilities should maximize efforts to prevent transmission of Bordetella pertussis. Precautions to prevent respiratory droplet transmission or spread by close or direct contact should be employed in the care of patients admitted to hospital with suspected or confirmed pertussis (265). These precautions should remain in effect until patients are improved clinically and have completed at least 5 days of appropriate antimicrobial therapy. HCP in whom symptoms (i.e., unexplained rhinitis or acute cough) develop after known pertussis exposure might be at risk for transmitting pertussis and should be excluded from work until 5 days after the start of appropriate therapy (3).\nData on the need for postexposure prophylaxis in Tdapvaccinated H C P are inconclusive (264). Certain vaccinated H C P are still at risk for B. pertussis. Tdap might not preclude the need for postexposure prophylaxis. Postexposure antimicrobial prophylaxis is recommended for all HCP who have unprotected exposure to pertussis and are likely to expose a patient at risk for severe pertussis (e.g., hospitalized neonates and pregnant women). O ther H C P should either receive postexposure antimicrobial prophylaxis or be monitored daily for 21 days after pertussis exposure and treated at the onset of signs and symptoms of pertussis.\n\n# Varicella\n\n# Background\n\n# Epidemiology and Risk Factors\nVaricella is a highly infectious disease caused by primary infection with varicella-zoster virus (VZV). VZV is transmitted from person to person by direct contact, inhalation of aerosols from vesicular fluid of skin lesions of varicella or herpes zoster (HZ), a localized, generally painful vesicular rash commonly called shingles, or infected respiratory tract secretions that also might be aerosolized (266). The average incubation period is 14-16 days after exposure to rash (range: 10-21 days). Infected persons are contagious an estimated 1-2 days before rash onset until all lesions are crusted, typically 4 -7 days after rash onset (266). Varicella secondary attack rates can reach 90% among susceptible contacts. Typically, primary infection with VZV results in lifetime immunity. VZV remains dormant in sensory-nerve ganglia and can reactivate at a later time, causing H Z. Before the U.S. childhood varicella vaccination program began in 1995, approximately 90% ofvaricella disease occurred among children aged 85% in varicella incidence, hospitalizations, and deaths (267)(268)(269). The decline in disease incidence was greatest among children for whom vaccination was recommended; however, declines occurred in every age group including infants too young to be vaccinated and adults, indicating reduced communitywide transmission of VZV.\nC urrent incidence of varicella am ong adults is low (<0.1/1,000 population), and adult cases represent <10% of all reported varicella cases (270). National seroprevalence data from 1999-2004 demonstrated that, in the early vaccine era, adults continued to have high immunity to varicella (271). In this study, 98% of persons aged 20-49 years had VZV-specific IgG antibodies. However, with declining likelihood of exposure to VZV, children and adolescents who did not receive 2 doses of varicella vaccine could remain susceptible to VZV infection as they age into adulthood, when varicella can be more severe.\nThe clinical presentation of varicella has changed since the implementation of the varicella vaccination program, with more than half of varicella cases reported in 2008 occurring among persons who were vaccinated previously, the majority of them children. Varicella disease in vaccinated children (breakthrough varicella) usually has a modified or atypical presentation; the rash is typically mild, with 50 lesions were as infectious as unvaccinated children (272). Because the majority of adults are immune and few need vaccination, fewer breakthrough cases have been reported among adults than among children, and breakthrough varicella in adults has tended to be milder than varicella in unvaccinated adults (273,274).\nThe epidemiology of varicella in tropical and subtropical regions differs from that in the United States. In these regions, a higher proportion ofVZV infections are acquired later in life. Persons emigrating from these regions might be more likely to be susceptible to varicella compared to U.S.-born persons and, therefore, are at a higher risk for developing varicella if unvaccinated and exposed (275,276).\n\n# Disease in Health-Care Settings and Impact on Health Care Personnel and Patients\nA lthough relatively rare in the U nited States since introduction of varicella vaccine, nosocomial transmission of VZV is well recognized and can be life-threatening to certain patients (277)(278)(279)(280)(281)(282)(283)(284)(285)(286)(287)(288)(289). In addition to hospital settings, nosocomial VZV transmission has been reported in longterm-care facilities and a hospital-associated residential facility (290,291). Sources of nosocomial exposure that have resulted in transmission include patients, HCP, and visitors with either varicella or H Z. Both localized and disseminated H Z in immunocompetent as well as immunocompromised patients have been identified as sources of nosocomial transmission of VZV. Localized H Z has been demonstrated to be much less infectious than varicella; disseminated H Z is considered to be as infectious as varicella (266). Nosocomial transmission has been attributed to delays in the diagnosis or reporting of varicella or H Z and in failures to implement control measures promptly. In hospitals and other health-care settings, airborne transmission of VZV from patients with either varicella or H Z has resulted in varicella in HCP and patients who had no direct contact with the index case-patient (284)(285)(286)(287)(288)291). Although all susceptible patients in health-care settings are at risk for severe varicella disease with complications, certain patients without evidence of immunity are at increased risk: pregnant women, premature infants born to susceptible mothers, infants born at <28 weeks' gestation or who weigh <1,000 grams regardless of maternal immune status, and immunocompromised persons of all ages (including persons who are undergoing immunosuppressive therapy, have malignant disease, or are immunodeficient).\nVZV exposures among patients and HCP can be disruptive to patient care, time-consuming, and costly even when they do not result in VZV transmission (281,282,292). Studies ofVZV exposure in health-care settings have documented that a single provider with unrecognized varicella can result in the exposure of >30 patients and >30 employees (292). Identification of susceptible patients and staff, medical management of susceptible exposed patients at risk for complications of varicella, and furloughing of susceptible exposed HCP are time-consuming and costly (281,282). W ith the overall reduction in varicella disease attributable to the success of the vaccination program, the risk for exposure to VZV from varicella cases in health-care settings is likely declining. In addition, an increasing proportion of varicella cases occur in vaccinated persons who are less contagious. Diagnosis of varicella has become increasingly challenging as a growing proportion of cases occur in vaccinated persons in whom disease is mild, and HCP encounter patients with varicella less frequently. Although not currently routinely recommended for the diagnosis and management of varicella, laboratory testing of suspected varicella cases is likely to become increasingly useful in health-care settings, especially as the positive predictive value of clinical diagnosis declines.\n\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\n\n# Vaccine Effectiveness\nFormal studies to evaluate vaccine efficacy or effectiveness have not been performed among adults. Studies of varicella vaccine effectiveness performed among children indicated good performance of 1 dose for prevention of all varicella (80% -85%) and >95% effectiveness for prevention of moderate and severe disease (266,293). Studies have indicated that a second dose among children produces an improved humoral and cellular immune response that correlates with improved protection against disease (266,294).\nVaricella vaccine effectiveness is expected to be lower in adults than in children. Adolescents and adults require 2 doses to achieve seroconversion rates similar to those seen in children after 1 dose (266). A study of adults who received 2 doses of varicella vaccine 4 or 8 weeks apart and were exposed subsequently to varicella in the household estimated an 80% reduction in the expected number of cases (295).\n\n# Duration of Immunity\nSerologic correlates of protection against varicella using commercially available assays have not been established for adults (266). In clinical studies, detectable antibody levels have persisted for at least 5 years in 97% of adolescents and adults who were administered 2 doses of varicella vaccine 4-8 weeks apart, but boosts in antibody levels were observed following exposures to varicella, which could account for the long-term persistence of antibodies after vaccination in these studies (295). Studies have demonstrated that whereas 25%-31% of adult vaccine recipients who seroconverted lost detectable antibodies 1-11 years after vaccination (273,296), vaccine-induced VZV-specific T-cell proliferation (marker for cell-mediated immunity ) was maintained in 94% of adults 1 and 5 years postvaccination (297). Disease was mild in vaccinated persons who developed varicella after exposure to VZV, even among vaccinees who did not seroconvert or who lost detectable antibody (273,274). Severity of illness and attack rates among vaccinated adults did not increase over time. These studies suggest that VZV-specific CMI affords protection to vaccinated adults, even in the absence of detectable antibody response.\n\n# Vaccine Safety\nThe varicella vaccine has an excellent safety profile. In clinical trials, the most common adverse events among adolescents and adults were injection-site complaints (24.4% after the first dose and 32.5% after the second dose) (266,295). Varicella-like rash at the injection site occurred in 3% of vaccine recipients after the first dose and in 1% after the second. A nonlocalized rash occurred in 5.5% of vaccine recipients after the first dose and in 0.9% after the second, with a median number of lesions of five, at a peak of 7-21 and 0-23 days postvaccination, respectively (295). Data on serious adverse events among adults after varicella vaccination are limited, but the proportion of serious adverse events among all adverse events reported to the Vaccine Adverse Events Reporting System during 1995-2005 was low (5%) among both children and adults (298). Serious adverse events reported among children included pneumonia, hepatitis, H Z (some hospitalized), meningitis with H Z, ataxia, encephalitis, throm bocytopenic purpura. N ot all adverse events reported after varicella vaccination have been laboratory confirmed to be attributable to the vaccine strain VZV (266,298).\nRisk for transmission of vaccine virus was assessed in placebo recipients who were siblings of vaccinated children and among healthy siblings of vaccinated leukemic children (266). The findings suggest that transmission of varicella vaccine virus from healthy persons to susceptible contacts is very rare. The risk might be increased in vaccinees in whom a varicella-like rash develops after vaccination. However, this risk is also low. The benefits of vaccinating HC P without evidence of immunity outweigh this extremely low potential risk. Since implementation of the varicella vaccine program, transmission of vaccine virus has been documented from eight persons (all of whom had a rash after vaccination) resulting in nine secondary infections among household and long-term-care facility contacts (299). No transmission has been documented from vaccinated HCP.\n\n# Recommendations\n\n# Vaccination\nHealth-care institutions should ensure that all HCP have evidence of immunity to varicella. This information should be documented and readily available at the work location. HCP without evidence of immunity to varicella should receive 2 doses of varicella vaccine administered 4-8 weeks apart. If >8 weeks elapse after the first dose, the second dose may be administered without restarting the schedule. Recently vaccinated HCP do not require any restriction in their work activities; however, HCP who develop a vaccine-related rash after vaccination should avoid contact with persons without evidence of immunity to varicella who are at risk for severe disease and complications until all lesions resolve (i.e., are crusted over) or, if they develop lesions that do not crust (macules and papules only), until no new lesions appear within a 24-hour period.\nEvidence of immunity for HCP includes any of the following (266):\n- written documentation of vaccination with 2 doses of varicella vaccine, - laboratory evidence o f im m unity § § § or laboratory confirmation of disease, - diagnosis or verification of a history of varicella disease by a health-care provider,JJJ or - diagnosis or verification of a history of H Z by a health-care provider. In health-care settings, serologic screening before vaccination of personnel without evidence of immunity is likely to be cost effective. Key factors determining cost-effectiveness include sensitivity and specificity of serologic tests, the nosocomial transmission rate, seroprevalence of VZV antibody in the personnel population, and policies for managing vaccine recipients developing postvaccination rash or who are § § § Commercial assays can be used to assess disease-induced immunity, but they often lack sensitivity to detect vaccine-induced immunity (i.e., they might yield false-negative results). JJJ Verification of history or diagnosis of typical disease can be provided by any health-care provider (e.g., a school or occupational clinic nurse, nurse practitioner, physician assistant, or physician). For persons reporting a history of, or reporting with, atypical or mild cases, assessment by a physician or their designee is recommended, and one of the following should be sought: 1) an epidemiologic link to a typical varicella case or to a laboratoryconfirmed case or 2) evidence of laboratory confirmation if it was performed at the time of acute disease. W hen such documentation is lacking, persons should not be considered as having a valid history of disease because other diseases might mimic mild atypical varicella.\nexposed subsequently to VZV. Institutions may elect to test all unvaccinated HCP, regardless of disease history, because a small proportion of persons with a positive history of disease might be susceptible. For the purpose of screening HCP, a less sensitive and more specific commercial ELISA should be considered. The latex agglutination test can produce falsepositive results, and HCP who remained unvaccinated because of false test results subsequently contracted varicella (289).\nRoutine testing for varicella im m unity after 2 doses of vaccine is not recommended. Available commercial assays are not sensitive enough to detect antibody after vaccination in all instances. Sensitive tests that are not generally available have indicated that 92% -99% of adults develop antibodies after the second dose (266). Seroconversion does not always result in full protection against disease and, given the role of CMI for providing long-term protection, absence of antibodies does not necessarily mean susceptibility. Documented receipt of 2 doses of varicella vaccine supersedes results of subsequent serologic testing.\nHealth-care institutions should establish protocols and recommendations for screening and vaccinating HCP and for management of H CP after exposures in the work place. Institutions also should consider precautions for H C P in whom rash occurs after vaccination, although they should also consider the possibility of wild-type disease in HCP with recent exposure to varicella or HZ.\nA vaccine to prevent H Z is available and recommended for all persons aged >60 years without contraindications to vaccination. H Z vaccine is not indicated for HCP for the prevention of nosocomial transmission, but HCP aged >60 years may receive the vaccine on the basis of the general recom m endation for H Z vaccination, to reduce their individual risk for HZ.\n\n# Varicella Control Strategies\nAppropriate measures should be implemented to manage cases and control outbreaks (300).\n\n# Patient Care\nOnly HCP with evidence of immunity to varicella should care for patients who have confirmed or suspected varicella or HZ. Airborne precautions (i.e., negative air-flow rooms) and contact precautions should be employed for all patients with varicella or disseminated H Z and for immunocompromised patients with localized H Z until disseminated infection is ruled out. These precautions should be kept in place until lesions are dry and crusted. If negative air-flow rooms are not available, patients should be isolated in closed rooms and should not have contact with persons without evidence of immunity to varicella. For immunocompetent persons with localized HZ, standard precautions and complete covering of the lesions are recommended.\n\n# Postexposure Management of HCP and Patients\nExposure to V ZV is defined as close contact w ith an infectious person, such as close indoor contact (e.g., in the same room) or face-to-face contact. Experts differ regarding the duration of contact; some suggest 5 minutes, and others up to 1 hour; all agree that it does not include transitory contact (301).\nAll exposed, susceptible patients and H C P should be identified using the criteria for evidence of immunity. An additional criterion of evidence of immunity only for patients who are not immunocompromised or pregnant is birth in the United States before 1980. Postexposure prophylaxis with vaccination or varicella-zoster immunoglobulin, depending on immune status, of exposed HCP and patients without evidence of immunity is recommended (266).\nHCP who have received 2 doses of vaccine and who are exposed to VZV (varicella, disseminated H Z, and uncovered lesions of a localized HZ) should be monitored daily during days 8-21 after exposure for fever, skin lesions, and systemic symptoms suggestive of varicella. H C P can be monitored directly by occupational health program or infection-control practitioners or instructed to report fever, headache, or other constitutional symptoms and any atypical skin lesions immediately. HCP should be excluded from a work facility immediately if symptoms occur. H C P who have received 1 dose of vaccine and who are exposed to VZV (varicella, disseminated H Z, and uncovered lesions of a localized HZ) (in the community or health-care setting/workplace) should receive the second dose within 3-5 days after exposure to rash (provided 4 weeks have elapsed after the first dose). After vaccination, management is similar to that of 2-dose vaccine recipients. Those who did not receive a second dose or who received the second dose >5 days after exposure should be excluded from work for 8-21 days after exposure.\nUnvaccinated HCP who have no other evidence of immunity who are exposed to VZV (varicella, disseminated H Z, and uncovered lesions of a localized HZ) are potentially infective from days 8-21 after exposure and should be furloughed during this period. They should receive postexposure vaccination as soon as possible. Vaccination within 3-5 days of exposure to rash might modify the disease if infection occurred. Vaccination >5 days postexposure is still indicated because it induces protection against subsequent exposures (if the current exposure did not cause infection). For HCP at risk for severe disease for whom varicella vaccination is contraindicated (e.g., pregnant or immunocomprosed HCP), varicella-zoster immune globulin after exposure is recommended. The varicella-zoster immune globulin product currently used in the United States, VariZIG (Cangene Corporation, Winnipeg, Canada), is available under an Investigational New Drug Application Expanded Access protocol; a sample release form is available at . gov/downloads/BiologicsBloodVaccines/SafetyAvailability/ UCM 176031.pdf. Varicella-zoster immune globulin might prolong the incubation period by a week, thus extending the time during which personnel should not work from 21 to 28 days. In case of an outbreak, H C P without evidence of immunity who have contraindications to vaccination should be excluded from the outbreak setting through 21 days after rash onset of the last identified case-patient because of the risk for severe disease in these groups. If the VZV exposure was to localized H Z with covered lesions, no work restrictions are needed if the exposed HCP had previously received at least 1 dose of vaccine or received the first dose within 3-5 days postexposure. A second dose should be administered at the appropriate interval. H C P should be monitored daily during days 8-21 after exposure for fever, skin lesions, and systemic symptoms suggestive of varicella and excluded from a work facility if symptoms occur. If at least 1 dose was not received, restriction from patient contact is recommended.\n\n# Diseases for W hich Vaccination Might\nBe Indicated in Certain Circum stances Health-care facilities and other organizations should consider including in their vaccination programs vaccines to prevent meningococcal disease, typhoid fever, and polio for H CP who have certain health conditions or who work in laboratories or regions outside the United States where the risk for workrelated exposure exists.\n\n# Meningococcal Disease\n\n# Background\n\n# Epidemiology and Risk Factors\nMeningococcal disease is rare among adults in the United States and incidence has decreased to historic lows; during 1998-2007 the average annual incidence of meningococcal disease was 0.28 (range: 0.26-0.31) cases per 100,000 population among persons aged 25-64 years (302).\nRoutine vaccination with meningococcal conjugate vaccine is recommended by ACIP for adolescents aged 11-18 years, with the primary dose at age 11-12 years and the booster dose at age 16 years. In 2010, coverage with meningococcal conjugate vaccine among persons aged 13-17 years was 62.7% (22). Nosocomial transmission of Neisseria meningitidis is rare, but H C P have become infected after direct contact with respiratory secretions of infected persons (e.g., managing of an airway during resuscitation) and in a laboratory setting. HCP can decrease the risk for infection by adhering to precautions to prevent exposure to respiratory droplets (303,304) and by taking antimicrobial chemoprophylaxis if exposed directly to respiratory secretions.\n\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nTwo quadrivalent (A, C, W-135, Y) conjugate meningococcal vaccines (MCV4) are licensed for persons aged through 55 years (305,306). Both protect against two of the three serogroups that cause the majority of meningococcal disease in the United States and against 75% of disease among adults. Available data indicate that the majority of persons do not have enough circulating functional antibody to be protected >5 years after a single dose of MCV4. Both vaccines had similar safety profiles in clinical trials. Quadrivalent (A, C, W -135, Y) meningococcal polysaccharide vaccine (MPSV4) is available for use in persons aged >55 years. No vaccine for serogroup B meningococcal disease is licensed in the United States.\n\n# Recommendations\n\n# Vaccination\n\n# M CV4 is not recommended routinely for all HCP\n\n# HCP Recommended to Receive Vaccine to Prevent Meningococcal Disease\nA 2-dose vaccine series is recommended for H C P with know n asplenia or persistent com plem ent com ponent deficiencies, because these conditions increase the risk for meningococcal disease. HCP traveling to countries in which meningococcal disease is hyperendemic or epidemic also are at increased risk for infection and should receive vaccine. Those with known asplenia or persistent complement component deficiencies should receive a 2-dose vaccine series. All other HCP traveling to work to high-risk areas should receive a single dose of M CV4 before travel if they have never received it or if they received it >5 years previously. Clinical microbiologists and research microbiologists who might be exposed routinely to isolates of N. meningitides should receive a single dose of M CV4 and receive a booster dose every 5 years if they remain at increased risk. Health-care personnel aged >55 years who have any of the above risk factors for meningococcal disease should be vaccinated with MPSV4 (305).\n\n# HCP Who May Elect to Receive Vaccine to Prevent Meningococcal Disease\nH CP with known HIV infection are likely at increased risk for meningococcal disease and may elect vaccination. If these HCP are vaccinated, they should receive a 2-dose vaccine series (307).\n\n# Booster Doses\nH CP who receive the 2-dose M CV4 vaccine series and/or remain in a group at increased risk should receive a booster dose every 5 years (306).\n\n# Postexposure Management of Exposed HCP\nPostexposure prophylaxis is advised for all persons who have had intensive, unprotected contact (i.e., without wearing a mask) with infected patients (e.g., via m outh-to-m outh resuscitation, endotracheal intubation, or endotracheal tube management), including HCP who have been vaccinated with either the conjugate or polysaccharide vaccine (3).\nA ntim icrobial prophylaxis can eradicate carriage o f N. meningitidis and prevent infections in persons who have unprotected exposure to patients w ith m eningococcal infections (305). Rifampin, ciprofloxacin, and ceftriaxone are effective in eradicating nasopharyngeal carriage of N. meningitidis. In areas of the United States where ciprofloxacinresistant strains of N. meningitidis have been detected (as of August 30, 2011, only parts of Minnesota and North Dakota), ciprofloxacin should not be used for chemoprophylaxis (308). Azithromycin can be used as an alternative. Ceftriaxone can be used during pregnancy. Postexposure prophylaxis should be administered within 24 hours of exposure when feasible; postexposure prophylaxis administered >14 days after exposure is of limited or no value (305). H C P not otherwise indicated for vaccination may be recommended to be vaccinated with meningococcal vaccine in the setting of a com m unity or institutional outbreak of meningococcal disease caused by a serogroup contained in the vaccine.\n\n# Typhoid Fever\n\n# Background\n\n# Epidemiology and Risk Factors\nThe incidence of typhoid fever declined steadily in the United States during 1900-1960 and has since remained low. During 1999-2006, on average, 237 cases were reported annually to the National Typhoid and Paratyphoid Fever Surveillance System (309). The median age of patients was 22 years and 54% were male; 79% reported foreign travel during the 30 days before onset of symptoms. Among international travelers, the risk for Salmonella Typhi infection appears to be highest for those who visit friends and relatives in countries in which typhoid fever is endemic and for those who visit (even for a short time) the most highly endemic areas (e.g., the Indian subcontinent) (310).\nIncreasing resistance to flu o ro q u in o lo n es such as ciprofloxacin, which are used to treat multidrug-resistant. S. Typhi, has been seen particularly among travelers to south and southeast Asia (311). Isolates with decreased susceptibility to ciprofloxacin (DCS) do not qualify as resistant according to current Clinical and Laboratory Standards Institute criteria but are associated with poorer clinical outcomes (311,312). Resistance to nalidixic acid, a quinolone, is a marker for DCS and increased from 19% in 1999 to 59% in 2008 (313). Nine isolates resistant to ciprofloxacin also were seen during this time period (313).\nAlthough overall S. Typhi infections have declined in the United States, increased incidence and antimicrobial resistance including resistance to fluoroquinolones have been seen for paratyphoid fever caused by Paratyphi A (314). No vaccines that protect against Paratyphi A infection are available.\n\n# Transmission and Exposure in Health-Care Settings\nDuring 1985-1994, seven cases oflaboratory-acquired typhoid fever were reported among persons working in microbiology laboratories, only one of whom had been vaccinated (315). Additionally, S. Typhi might be transmitted nosocomially via the hands of infected persons (315).\n\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nTwo typhoid vaccines are distributed in the United States: oral live-attenuated Ty21a vaccine (one enteric-coated capsule taken on alternate days for a total of four capsules) and the capsular polysaccharide parenteral vaccine (1 0.5 mL intramuscular dose). Both vaccines protect 50% -80% of recipients. To maintain immunity, booster doses of the oral vaccine are required every 5 years, and booster doses of the injected vaccine are required every 2 years. Complication rates are low for both types of S. Typhi vaccines. During 1994-1999, serious adverse events requiring hospitalization occurred in an estimated 0.47 to 1.3 per 100,000 doses, and no deaths occurred (310). However, live-attenuated Ty21a vaccine should not be used among immunocompromised persons, including those infected with HIV (316). Theoretic concerns have been raised about the immunogenicity of live, attenuated Ty21a vaccine in persons concurrently receiving antimicrobials (including antimalarial chemoprophylaxis), viral vaccines, or immune globulin (317). A third type of vaccine, a parenteral heat-inactivated vaccine associated with higher reactogenicity, was discontinued in 2000 (310,318).\n\n# Vaccination\nM icrobiologists and others who work frequently with S. Typhi should be vaccinated with either of the two licensed and available vaccines. Booster vaccinations should be administered on schedule according to the manufacturers' recommendations.\n\n# Controlling the Spread of Typhoid Fever\nPersonal hygiene, particularly hand hygiene before and after all patient contacts, will minimize risk for transmitting enteric pathogens to patients. However, H C P who contract an acute diarrheal illness accompanied by fever, cramps, or bloody stools are likely to excrete substantial numbers of infective organisms in their feces. Excluding these H C P from care of patients until the illness has been evaluated and treated can prevent transmission (3).\n\n# Poliomyelitis\n\n# Background\n\n# Epidemiology and Risk Factors\nIn the United States, the last indigenously acquired cases of poliomyelitis caused by wild poliovirus occurred in 1979, and the Americas were certified to be free of indigenous wild poliovirus in 1994 (319,320). W ith the complete transition from use of oral poliovirus vaccine (OPV) to inactivated poliovirus vaccine (IPV) in 2000, vaccine-associated paralytic poliomyelitis (VAPP) attributable to O PV also has been eliminated (321,322)\n\n# Transmission and Exposure in Health-Care Settings\nPoliovirus can be recovered from infected persons, including from pharyngeal specim ens, feces, urine, and (rarely) cerebrospinal fluid. H C P and laboratory workers might be exposed if they come into close contact with infected persons (e.g., travelers returning from areas where polio is endemic) or with specimens that contain poliovirus.\n\n# Recommendations Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nBoth IPV and OPV are highly immunogenic and effective when administered according to their schedules. In studies conducted in the United States, 3 doses of IPV resulted in 100% serocoversion for types 2 and 3 poliovirus and 96%-100% for type 1 (326). Imm unity is prolonged and might be lifelong. IPV is well tolerated, and no serious adverse events have been associated with its use. IPV is an inactivated vaccine and does not cause VAPP IPV is contraindicated in persons with a history of hypersensitivity to any component of the vaccine, including 2-phenoxyethanol, formaldehyde, neomycin, streptomycin, and polymyxin B. OPV is no longer available in the United States.\n\n# Recommendations\n\n# Vaccination\nBecause the majority of adults born in the United States are likely immune to polio as a result of vaccination during childhood, poliovirus vaccine is not routinely recommended for persons aged >18 years. The childhood recommendation for poliovirus vaccine consists of 4 doses at ages 2, 4, and 6-18 months and 4-6 years.\nHowever, vaccination is recommended for H C P who are at greater risk for exposure to polioviruses than the general population, including laboratory workers who handle specimens that might contain polioviruses and H C P who have close contact with patients who might be excreting wild polioviruses, including H CP who travel to work in areas where polioviruses are circulating.\nUnvaccinated H C P should receive a 3-dose series of IPV, with dose 2 administered 4-8 weeks after dose 1, and dose 3 administered 6-12 months after dose 2. H C P who have previously completed a routine series of poliovirus vaccine and who are at increased risk can receive a lifetime booster dose of IPV if they remain at increased risk for exposure. Available data do not indicate the need for more than a single lifetime booster dose with IPV for adults.\n\n# Controlling the Spread of Poliovirus\nStandard precautions always should be practiced when handling biologic specim ens. Suspect cases require an immediate investigation including collection of appropriate laboratory specimens and control measures. All suspect or confirmed cases should be reported immediately to the local or state health department.\n\n# Other Vaccines Recom m ended\nfor Adults Certain vaccines are recommended for adults based on age or other individual risk factors but not because of occupational exposure (327). Vaccine-specific ACIP recommendations should be consulted for details on schedules, indications, contraindications, and precautions for these vaccines.\n- to be at increased risk for hepatitis A virus infection because of occupational exposure, including persons exposed to sewage. Hepatitis A vaccine is recommended for person w ith chronic liver disease, international travelers, and certain other groups at increased risk for exposure to hepatitis A.\n\n# Catch-Up and Travel Vaccination\n\n# Catch-Up Programs\nManagers of health-care facilities should implement catch-up vaccination programs for HCP who already are employed, in addition to developing policies for achieving high vaccination coverage among newly hired HCP HCP vaccination records could be reviewed annually during the influenza vaccination season or concurrent with annual TB testing. This strategy could help prevent outbreaks of vaccine-preventable diseases. Because education, especially when combined with other interventions such as reminder/recall systems and low or no out-of-pocket costs, enhances the success of many vaccination programs, informational materials should be available to assist in answering questions from HCP regarding the diseases, vaccines, and toxoids as well as the program or policy being implemented (120,328). Conducting educational workshops or seminars several weeks before the initiation of a catch-up vaccination program might promote acceptance of program goals.\n\n# Travel\nHospital personnel and other H C P who perform research or health-care work in foreign countries might be at increased risk for acquiring certain diseases that can be prevented by vaccines recommended in the United States (e.g., hepatitis B, influenza, M M R , T dap , poliovirus, varicella, and meningococcal vaccines) and travel-related vaccines (e.g., hepatitis A, Japanese encephalitis, rabies, typhoid, or yellow fever vaccines) (329). Elevated risks for acquiring these diseases might stem from exposure to patients in health-care settings (e.g., poliomyelitis and meningococcal disease) but also might arise from circumstances unrelated to patient care (e.g., high endemicity of hepatitis A or exposure to arthropod-vector diseases ). All H C P should seek the advice of a health-care provider familiar with travel medicine at least 4-6 weeks before travel to ensure that they are up to date on routine vaccinations and that they receive vaccinations recommended for their destination (329). Although bacille Calmette-Guérin vaccination is not recommended routinely in the United States, H C P should discuss potential beneficial and other consequences of this vaccination with their health care provider.\n\n# Work Restrictions\nW ork restrictions for susceptible H C P (i.e., no history of vaccination or documented lack of immunity) exposed to or infected with certain vaccine-preventable diseases can range from restricting individual HCP from patient contact to complete exclusion from duty (Table 5). A furloughed employee should be considered in the same category as an employee excluded from the facility. Specific recommendations concerning work restrictions in these circumstances have been published previously (3,11). The risk for rubella vaccine-associated malformations in the offspring o f women pregnant when vaccinated or who become pregnant w ithin 1 month after vaccination is negligible.11 Such women should be counseled regarding the theoretical basis o f concern for the fetus.\n\n# vaccine.\nSee table footnotes on page 41 111 Commercial assays can be used to assess disease-induced immunity, but they often lack sensitivity to detect vaccine-induced im m unity (i.e., they m ight yield false-negative results). § § § Verification o f history or diagnosis o f typical disease can be provided by any health-care provider (e.g., school or occupational clinic nurse, nurse practitioner, physician assistant, or physician). For persons reporting a history of, or reporting with, atypical or mild cases, assessment by a physician or their designee is recommended, and one o f the following should be sought: 1) an epidemiologic link to a typical varicella case or to a laboratory-confirm ed case or 2) evidence o f laboratory confirmation if it was performed at the tim e o f acute disease. When such documentation is lacking, persons should not be considered as having a valid history o f disease because other diseases m ight mimic mild atypical varicella. 111 For example, immunocompromised patients or pregnant women. Those who develop acute respiratory symptoms w ith o u t fever should be considered for evaluation by occupational health to determine appropriateness o f contact with patients and can be allowed to work unless caring for patients in a protective environment; these personnel should be considered for temporary reassignment or exclusion from work for 7 days from symptom onset or until the resolution o f all noncough symptoms, whichever is longer. If symptoms such as cough and sneezing are still present, HCP should wear a facemask during patient care activities. The im portance of performing frequent hand hygiene (especially before and after each patient contact) should be reinforced.\nMeasles"},"raw_text":{"kind":"string","value":"This report updates the previously published summary o f recommendations for vaccinating health-care personnel (HCP) in the United States (CDC. Immunization o f health-care workers: recommendations o f the Advisory Committee on Immunization Practices [ACIP] and the Hospital Infection Control Practices Advisory Committee [HICPAC]. M M W R 1997;46[No. RR-18J). This report was reviewed by and includes input from the Healthcare (formerly Hospital) Infection Control Practices Advisory Committee. These updated recommendations can assist hospital administrators, infection-controlpractitioners, employee health clinicians, and HCP in optimizing infection prevention and control programs. The recommendations for vaccinating HCP are presented by disease in two categories: 1) those diseases for which vaccination or documentation o f immunity is recommended because o f risks to HCP in their work settings for acquiring disease or transmitting to patients and 2) those for which vaccination might be indicated in certain circumstances. Background information for each vaccine-preventable disease and specific recommendations for use ofeach vaccine are presented. Certain infection-control measures that relate to vaccination also are included in this report. In addition, ACIP recommendations for the remaining vaccines that are recommended for certain or all adults are summarized, as are considerations for catch-up and travel vaccinations and for work restrictions. This report summarizes all current ACIP recommendations for vaccination o f HCP and does not contain any new recommendations or policies.# Immunization of Health-Care Personnel\n\n# Recom m endations of the A dvisory Committee on Im m unization Practices (ACIP)\nThis report updates the previously published summary o f recom m endations o f the A dvisory C om m ittee on Immunization Practices (ACIP) and the Healthcare (formerly Hospital) Infection Control Practices Advisory Committee (HICPAC) for vaccinating health-care personnel (HCP) in the United States (1). The report, which was reviewed by and includes input from HICPAC, summarizes all current ACIP recommendations for vaccination of H C P and does not contain any new recommendations or policies that have not been published previously. These recommendations can assist hospital administrators, infection-control practitioners, employee health clinicians, and H C P in optimizing infection prevention and control programs.\nH C P are defined as all paid and unpaid persons working in health-care settings who have the potential for exposure to patients and/or to infectious materials, including body substances, contaminated medical supplies and equipment, contaminated environmental surfaces, or contaminated air. H C P might include (but are not lim ited to) physicians, nurses, nursing assistants, therapists, technicians, emergency medical service personnel, dental personnel, pharmacists, laboratory personnel, autopsy personnel, students and trainees, contractual staff not employed by the health-care facility, and persons (e.g., clerical, dietary, housekeeping, laundry, security, maintenance, administrative, billing, and volunteers) not directly involved in patient care but potentially exposed to infectious agents that can be transmitted to and from HCP and patients (2).\nBecause of their contact with patients or infective material from patients, many HCP are at risk for exposure to (and possible transmission of) vaccine-preventable diseases. Employers and Introduction vaccination records for H C P so records can be retrieved easily as needed (3). Each record should reflect im m unity status for indicated vaccine-preventable diseases (i.e., documented disease, vaccination history, or serology results) as well as vaccinations adm inistered during em ploym ent and any documented episodes of adverse events after vaccination (4).\nFor each vaccine, the record should include date of vaccine administration (including for those vaccines that might have been received prior to employment), vaccine manufacturer and lot number, edition and distribution date of the languageappropriate Vaccine Information Statement (VIS) provided to the vaccinee at the time of vaccination, and the name, address, and title of the person administering the vaccine (4). Accurate vaccination records can help to rapidly identify susceptible H C P (i.e., those with no history of vaccination or lack of documentation of immunity) during an outbreak situation and can help reduce costs and disruptions to health care operations (5)(6)(7). H C P should be provided a copy of their vaccination records and encouraged to keep it with their personal health records so they can readily be made available to future employers. HICPAC has encouraged any facility or organization that provides direct patient care to formulate a comprehensive vaccination policy for all HCP (3). The American Hospital Association has endorsed the concept of vaccination programs for both hospital personnel and patients (8). To ensure that all H C P are up to date with respect to recommended vaccines, facilities should review H C P vaccination and immunity status at the time ofhire and on a regular basis (i.e., at least annually) with consideration of offering needed vaccines, if necessary, in conjunction with routine annual disease-prevention measures (e.g., influenza vaccination or tuberculin testing). These recommendations (Tables 2 and 3) should be considered during policy development. Several states and health-care facilities have established requirements relating to assessment of vaccination status and/or administration of one or more vaccines for H C P (9,10). Disease-specific outbreak control measures are described in this report and elsewhere (3,11,12). All HCP should adhere to all other recommended infectioncontrol guidelines, whether or not they are individually determined to have immunity to a vaccine-preventable disease.\n# Methods\nIn 2008, the ACIP Immunization of Health-Care Personnel Work Group (the W ork Group) was formed as a subgroup of the ACIP Adult Immunization W ork Group to update the previously published recommendations for im m unization of HCP. The W ork Group comprised professionals from academic medicine (pediatrics, family medicine, internal medicine, occupational and environmental medicine, and infectious disease); federal and state public health professionals; and liaisons from the Society for Healthcare Epidemiology of America and HICPAC. The W ork Group met monthly, developed an outline for the report, worked closely with subject matter experts at C D C (who developed, revised, and updated sections of the report), and provided subsequent critical review of the draft documents. The approach of the Work Group was to summarize previously published ACIP recommendations and not to m ake new recom m endations or policies; a comprehensive list of publications containing the various vaccine-specific recommendations is provided (Table 1). In February 2011, the updated report was presented to ACIP, which voted to approve it.\nThe recommendations for vaccination of HCP are presented below by disease in two categories: 1) those diseases for which routine vaccination or documentation of immunity is recommended for H C P because of risks to H C P in their work settings and, should H CP become infected, to the patients they serve and 2) those diseases for which vaccination of HCP might be indicated in certain circumstances. Vaccines recommended in the first category are hepatitis B, seasonal influenza, measles, mumps, and rubella, pertussis, and varicella vaccines. Vaccines in the second category are meningococcal, typhoid, and polio vaccines. Except for influenza, all of the diseases prevented by these vaccines are notifiable at the national level (13). Main changes from the 1997 ACIP recommendations have been summarized (Box).\n# Diseases for W hich Vaccination Is\nRecom m ended O n the basis of docum ented nosocomial transmission, H C P are considered to be at substantial risk for acquiring or transm itting hepatitis B, influenza, measles, mumps, rubella, pertussis, and varicella. Current recommendations for vaccination are provided below.\n# Hepatitis B\n\n# Background\n\n# Epidemiology and Risk Factors\nHepatitis B is an infection caused by the hepatitis B virus (HBV), which is transm itted through percutaneous (i.e., breaks in the skin) or mucosal (i.e., direct contact with mucous membranes) exposure to infectious blood or body fluids. The virus is highly infectious; for nonimmune persons, disease transmission from a needlestick exposure is up to 100 times more likely for exposure to hepatitis B e antigen (HBeAg)-positive blood than to HIV-positive blood (14). HBV infection is a well recognized occupational risk for U.S. HCP and globally. The risk for HBV is associated with degree of contact with blood in the work place and with the hepatitis B e-antigen status of the source persons (15). The virus is also environmentally stable, remaining infectious on environmental surfaces for at least 7 days (16).\nIn 2009 in the United States, 3,371 cases of acute HBV infection were reported nationally, and an estimated 38,000 new cases of HBV infection occurred after accounting for underreporting and underdiagnosis (17). O f 4,519 persons reported with acute HBV infection in 2007, approximately 40% were hospitalized and 1.5% died (18). HBV can lead to chronic infection, which can result in cirrhosis of the liver, liver failure, liver cancer, and death. An estimated 800,000- 1.4 million persons in the United States are living with chronic HBV infection; these persons serve as the main reservoir for continued HBV transmission (19).\nVaccines to prevent hepatitis B became available in the United States in 1981; a decade later, a national strategy to eliminate HBV infection was implemented, and the routine vaccination of children was recommended (20). During 1990During 2009, the rate of new HBV infections declined approximately 84%, from 8.5 to 1.1 cases per 100,000 population (17); the decline was greatest (98%) among persons aged <19 years, for whom recommendations for routine infant and adolescent vaccination have been applied. Although hepatitis B vaccine coverage is high in infants, children, and adolescents (91.8% in infants aged 19-35 months and 91.6% in adolescents aged 13-17 years) (21,22), coverage remains lower (41.8% in 2009) for certain adult populations, including those with behavioral risks for HBV infection (e.g., men who have sex with men and persons who use injection drugs) (23).\n# Hepatitis B in Health-Care Settings\nDuring 1982, when hepatitis B vaccine was first recommended for HCP, an estimated 10,000 infections occurred among persons employed in a medical or dental field. By 2004, the number of HBV infections among HCP had decreased to an estimated 304 infections, largely resulting from the im plem entation of routine preexposure vaccination and improved infection-control precautions (24)(25)(26).\nThe risk for acquiring HBV infection from occupational exposures is dependent on the frequency of percutaneous and mucosal exposures to blood or body fluids (e.g., semen, saliva, and wound exudates) containing HBV, particularly fluids containing HBeAg (a marker for high HBV replication and viral load) (27)(28)(29)(30)(31). The risk is higher during the professional BOX. Summary of main changes* from 1997 Advisory Comm ittee on Immunization Practices/Hospital (now Healthcare) Infection Control Practices Advisory Comm ittee recommendations for immunization of health-care personnel (HCP)\n# Hepatitis B\n• H C P and trainees in certain populations at high risk for chronic hepatitis B (e.g., those born in countries with high and intermediate endemicity) should be tested for HBsAg and anti-HBc/anti-HBs to determine infection status.\n# Influenza\n• Emphasis that all HCP, not just those with direct patient care duties, should receive an annual influenza vaccination • Comprehensive programs to increase vaccine coverage among H C P are needed; influenza vaccination rates among HCP within facilities should be measured and reported regularly. Measles, mumps, and rubella (MMR) • History of disease is no longer considered adequate presumptive evidence of measles or mumps immunity for HCP; laboratory confirmation of disease was added as acceptable presumptive evidence of immunity. History of disease has never been considered adequate evidence of immunity for rubella. • The footnotes have been changed regarding the recommendations for personnel born before 1957 in routine and outbreak contexts. Specifically, guidance is provided for 2 doses of M M R for measles and mumps protection and 1 dose of M M R for rubella protection. Pertussis • HCP, regardless of age, should receive a single dose of Tdap as soon as feasible if they have not previously received Tdap.\n• The minimal interval was removed, and Tdap can now be administered regardless of interval since the last tetanus or diphtheria-containing vaccine. • Hospitals and ambulatory-care facilities should provide Tdap for HCP and use approaches that maximize vaccination rates. Varicella Criteria for evidence of immunity to varicella were established. For H C P they include • written documentation with 2 doses of vaccine, • laboratory evidence of immunity or laboratory confirmation of disease, • diagnosis of history of varicella disease by health-care provider, or diagnosis of history of herpes zoster by health-care provider.\n# Meningococcal\n• H C P with anatomic or functional asplenia or persistent complement component deficiencies should now receive a 2-dose series of meningococcal conjugate vaccine. H C P with H IV infection who are vaccinated should also receive a 2 dose series. • Those HCP who remain in groups at high risk are recommended to be revaccinated every 5 years.\nAbbreviations: HBsAg = Hepatitis B surface antigen; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; Tdap = tetanus toxoid, reduced diptheria toxoid and acellular pertussis vaccine; HIV = human immunodeficiency virus. training period and can vary throughout a person's career (1). Depending on the tasks performed, health-care or public safety personnel m ight be at risk for HBV exposure; in addition, personnel providing care and assistance to persons in outpatient settings and those residing in long-term-care facilities (e.g., assisted living) might be at risk for acquiring or facilitating transmission of HBV infection when they perform procedures that expose them to blood (e.g., assisted bloodglucose monitoring and wound care) (32)(33)(34).\nA Federal Standard issued in D ecem ber 1991 under the O ccupational Safety and H ealth Act m andates that hepatitis B vaccine be made available at the employer's expense to all health-care personnel who are exposed occupationally to blood or other potentially infectious materials (35). The Federal Standard defines occupational exposure as reasonably anticipated skin, eye, m ucous m em brane, or parenteral contact with blood or other potentially infectious materials that might result from the performance of an employee's duties (35 \n# Vaccine Effectiveness\nThe 3-dose vaccine series administered intramuscularly at 0, 1, and 6 months produces a protective antibody response in approximately 30% -55% of healthy adults aged <40 years after the first dose, 75% after the second dose, and >90% after the third dose (40)(41)(42). After age 40 years, <90% of persons vaccinated with 3 doses have a protective antibody response, and by age 60 years, protective levels of antibody develop in approximately 75% of vaccinated persons (43). Smoking, obesity, genetic factors, and immune suppression also are associated with dim inished im m une response to hepatitis B vaccination (43-46).\n# Duration of Immunity\nProtection against symptomatic and chronic HBV infection has been docum ented to persist for >22 years in vaccine responders (47). Im m unocom petent persons who achieve hepatitis B surface antibody (anti-HBs) concentrations of >10 mIU/mL after preexposure vaccination have protection against both acute disease and chronic infection. Anti-HBs levels decline over time. Regardless, responders continue to be protected, and the majority of responders will show an anamnestic response to vaccine challenge (47)(48)(49)(50)(51). Declines might be somewhat faster among persons vaccinated as infants rather than as older children, adolescents, or adults and among those administered recombinant vaccine instead of plasma vaccine (which has not been commercially available in the United States since the late 1980s). Although immunogenicity is lower among immunocompromised persons, those who achieve and maintain a protective antibody response before exposure to HBV have a high level of protection from infection (52).\nAmong persons who do not respond to a primary 3-dose vaccine series (i.e., those in whom anti-HBs concentrations of >10 mIU/mL were not achieved), 25% -50% respond to an additional vaccine dose, and 44% -100% respond to a 3-dose revaccination series using standard or high dosage vac cine (43,(53)(54)(55)(56)(57)(58). Persons who have measurable but low (i.e., 1-9 mIU/mL) levels of anti-HBs after the initial series have better response to revaccination than persons who have no anti-HBs (49,53,54). Persons who do not have protective levels of anti-HBs 1-2 months after revaccination either are infected with HBV or can be considered primary nonresponders; for the latter group, genetic factors might be associated with nonresponse to hepatitis B vaccination (54,58,59). ACIP does not recommend more than two vaccine series in nonresponders (52).\n# Vaccine Safety\nHepatitis B vaccines have been demonstrated to be safe when administered to infants, children, adolescents, and adults (52,60,61). Although rare cases of arthritis or alopecia have been associated temporally with hepatitis B vaccination, recent data do not support a causal relationship between hepatitis B vaccine and either arthritis or alopecia (61)(62)(63). During 1982During 2004, an estimated 70 million adolescents and adults and 50 million infants and children in the United States received >1 dose of hepatitis B vaccine (52). The most frequently reported side effects in persons receiving hepatitis B vaccine are pain at the injection site (3% -29% ) and temperature of >99.9 F (>37.7 C) (1% -6% ) (64-67). However, in placebo-controlled studies, these side effects were reported no more frequently among persons receiving hepatitis B vaccine than among persons receiving placebo (40,41,(64)(65)(66)(67). Revaccination is not associated with an increase in adverse events. Hepatitis B vaccination is contraindicated for persons with a history of hypersensitivity to yeast or any vaccine component (4,(64)(65)(66). Persons with a history of serious adverse events (e.g., anaphylaxis) after receipt of hepatitis B vaccine should not receive additional doses. As with other vaccines, vaccination of persons with moderate or severe acute illness, with or without fever, should be deferred until illness resolves (4). Vaccination is not contraindicated in persons with a history of multiple sclerosis, Guillain-Barre Syndrome, autoim m une disease (e.g., systemic lupus erythematosis and rheumatoid arthritis), or other chronic diseases. Pregnancy is not a contraindication to vaccination; limited data suggest that developing fetuses are not at risk for adverse events when hepatitis B vaccine is administered to pregnant women (4,68). Available vaccines contain noninfectious hepatitis B surface antigen (HBsAg) and do not pose any risk for infection to the fetus. \n# Postexposure\nThe need for postexposure prophylaxis should be evaluated immediately after H C P experience any percutaneous, ocular, m ucous-m em brane or nonintact skin exposure to blood or body fluid in the workplace. Decisions to administer postexposure prophylaxis should be based on the HBsAg status of the source and the vaccination history and vaccine-response status of the exposed H C P (Table 4) (72).\n# Unvaccinated and Incompletely Vaccinated HCP and Trainees\n• Unvaccinated or incompletely vaccinated persons who experience a workplace exposure from persons known to be HBsAg-positive should receive 1 dose of hepatitis B immune globulin HBIG (i.e., passive vaccination) as soon as possible after exposure (preferably within 24 hours).\nThe effectiveness of HBIG when administered >7 days after percutaneous or permucosal exposures is unknown (Table 4). • Hepatitis B vaccine should be administered in the deltoid muscle as soon as possible after exposure; HBIG should be administered at the same time at another injection site. The 3-dose hepatitis B vaccine series should be completed for previously unvaccinated and incompletely vaccinated persons who have needlestick or other percutaneous exposures, regardless of the HBsAg status of the source and w hether the status o f the source is known. To document protective levels of anti-HBs (>10mIU/mL), postvaccination testing of persons who received HBIG for postexposure prophylaxis should be performed after anti-HBs from HBIG is no longer detectable (4-6 months after administration).\n# Vaccinated HCP and Trainees\n• Vaccinated H C P with documented immunity (anti-HBs concentrations of >10 mIU/mL) require no postexposure prophylaxis, serologic testing, or additional vaccination. • Vaccinated H C P with docum ented nonresponse to a 3-dose vaccine series should receive 1 dose of HBIG and a second 3-dose vaccine series if the source is HBsAgpositive or known to be at high risk for carrying hepatitis.\nIf the source is known or determ ined to be HBsAgnegative, these previously nonresponding H C P should com p lete the rev accin atio n series and undergo postvaccination testing to ensure that their response status is docum ented ( Influenza causes an estim ated average of >200,000 hospitalizations and 3,000-49,000 deaths annually in the United States (74)(75)(76). The majority of influenza-related severe illnesses and deaths occur among persons with chronic medical conditions, infants and young children, seniors, and pregnant women (74)(75)(76)(77)(78). Reducing the risk for influenza among persons at higher risk for complications is a major focus of influenza prevention strategies (77).\n# Influenza Transmission in Health-Care Settings\nHCP are exposed to patients with influenza in the workplace and are thus at risk of occupationally acquired influenza and of transmitting influenza to patients and other HCP. In a cross sectional survey of hospital house staff (physicians in training), 37% reported influenza-like illness during September-April, and 9% reported more than one respiratory illness. Length of illness varied (range: 1-10 days; mean: 7 days), as did days of work missed (range: 0-10 days; mean: 0.7 days) (79). Infected HCP who continue to work while ill might transmit influenza to patients, many of whom are at increased risk for severe outcomes from influenza. H C P are therefore recommended for routine annual influenza vaccination (77).\nFew randomized trials of the effect that influenza vaccination has on illness in H CP have been conducted. In one randomized trial of 427 HCP, influenza vaccination of H C P failed to decrease episodes of respiratory infection or duration of illness but was associated with a 28% decrease in absenteeism (from 1.4 days to 1.0 day) attributable to respiratory infections (80). No laboratory confirmation of influenza was obtained in this study. In another randomized trial among HCP, vaccination was associated with a significantly lower rate of serological evidence of influenza infection, with a vaccine efficacy rate of 88% for influenza A and 89% for influenza B (p<0.05) (81); however, no significant differences were noted in days of febrile respiratory illness or absenteeism.\nInfluenza can cause outbreaks of severe respiratory illness among hospitalized persons and long-term-care residents (82)(83)(84)(85)(86)(87)(88)(89)(90). Influenza outbreaks in hospitals (86)(87)(88) and long-termcare facilities (91) have been associated with low vaccination rates among HCP. One nonrandomized study demonstrated an increase in H C W vaccination rates and decrease in nosocomially acquired, laboratory-confirmed influenza in a hospital after a mobile cart-based H C P vaccination program was introduced (86). Several randomized controlled studies of the impact of H C P vaccination on morbidity and mortality in long-term care facilities have been performed (92)(93)(94)(95). These studies have demonstrated substantial decreases in all cause mortality (92)(93)(94)(95) and influenza-like illness (92,94,95). However, studies which examine and demonstrate efficacy in preventing more specific outcomes (e.g., laboratory-confirmed influenza illness and mortality) are lacking. Recent systematic reviews suggest that vaccination of HCP in settings in which patients also were vaccinated provided significant reductions in deaths among elderly patients from all causes and deaths from pneumonia, but also note that additional randomized controlled trials are warranted (96,97), as are examination of more specific outcomes.\nPreventing influenza among HCP who might serve as sources of influenza virus transmission provides additional protection to patients at risk for influenza complications. Vaccination of H C P can specifically benefit patients who cannot receive vaccination (e.g., infants aged <6 months or those with severe allergic reactions to prior influenza vaccination), patients who respond poorly to vaccination (e.g., persons aged >85 years and immune-compromised persons), and persons for whom antiviral treatment is not available (e.g., persons with medical contraindications). Although annual vaccination has long been recommended for H C P and is a high priority for reducing morbidity associated with influenza in health-care settings (98)(99)(100), national survey data have demonstrated that the vaccination coverage level during the 2008-09 season was 52.9% (101).\n# Considerations Regarding Influenza Vaccination of HCP\nBarriers to H C P aceptance of influenza vaccination have included fear of vaccine side effects (particularly influenza like symptoms), insufficient time or inconvenience, perceived ineffectiveness of the vaccine, perceived low likelihood of contracting influenza, avoidance of medications, and fear of needles (79,(102)(103)(104)(105)(106)(107)(108)(109). Factors demonstrated to increase vaccine acceptance include a desire for self-protection, previous receipt of influenza vaccine, a desire to protect patients, and perceived effectiveness of vaccine (79,105,106,(109)(110)(111)(112). Strategies that have demonstrated improvement in H C P vaccination rates have included campaigns to emphasize the benefits of H C P vaccination for staff and patients, vaccination of senior medical staff or opinion leaders, removing administrative barriers (e.g., costs), providing vaccine in locations and at times easily accessible by HCP, and monitoring and reporting H C P influenza vaccination rates (99,(113)(114)(115)(116)(117)(118)(119)(120). Intranasally administered live attenuated influenza vaccine (LAIV) is an option for healthy, nonpregnant adults aged <50 years who dislike needles.\nThe practice of obtaining signed declinations from HCP offered influenza vaccination has been adopted by some institutions but has not yet been demonstrated to exceed coverage rates of >70% -80% (99,115,(121)(122)(123). Institutions that require declination statements from H C P who refuse influenza vaccination should educate and counsel these HCP about benefits of the vaccine.\nEach health-care facility should develop a comprehensive influenza vaccination strategy that includes targeted education about the disease, including disease risk among H C P and patients, and about the vaccine. In addition, the program should establish easily accessible vaccination sites and inform H C P about their locations and schedule. Facilities that employ H C P should provide influenza vaccine at no cost to personnel (124). The most effective combination of approaches for achieving high influenza vaccination coverage among H C P likely varies by institution. Hospitals and health-care organizations in the United States traditionally have employed an immunization strategy that includes one or more of the following components: education about influenza, easy access to vaccine, incentives to encourage immunization, organized campaigns, institution of declination policies, and legislative and regulatory efforts (e.g., vaccination requirements) (99,115,(121)(122)(123)(124)(125)(126).\nBeginning January 1, 2007, the Joint Comm ission on A ccreditation o f H ealth-C are O rganizations required accredited organizations to offer influenza vaccinations to staff, including volunteers and licensed independent practitioners and to report coverage levels among HCP (127). Standards are available for measuring vaccination coverage among HCP as a measure of program performance within a health care setting (128). Beginning January 2013, the Centers for Medicaid Services will require acute care hospitals to report HCP influenza vaccine as part of its hospital inpatient quality reporting program.*\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nEffectiveness of influenza vaccines varies from year to year and depends on the age and health status of the person getting the vaccine and the similarity or \"match\" between the viruses or virus in the vaccine and those in circulation. Vaccine strains are selected for inclusion in the influenza vaccine every year based on international surveillance and scientists' estimations about which types and strains of viruses will circulate in a given year. Annual vaccination is recommended because the predom inant circulating influenza viruses typically change from season to season and, because immunity declines over time postvaccination (77).\nIn placebo-controlled studies am ong adults, the most frequent side effect o f vaccination was soreness at the vaccination site (affecting 10% -64% of patients) that lasted <2 days (129,130). These injection-site reactions typically were mild and rarely interfered with the recipient's ability to conduct usual daily activities. The main contraindication to influenza vaccination is a history of anaphylactic hypersensitivity to egg or other components of the vaccine. A history of Guillain-Barre Syndrome within 6 weeks following a previous dose of influenza vaccine is considered to be a precaution for use of influenza vaccines (77 \n# Vaccination\nAnnual influenza vaccination is recommended for all persons aged >6 m onths who have no medical contraindication; therefore, vaccination of all HCP who have no contraindications is recommended. The influenza vaccine is evaluated annually with one or more vaccine strains updated almost every year. In addition, antibody titers decline during the year after vaccination. T hus, annual vaccination w ith the current season's formulation is recommended. Annual vaccination is appropriate and safe to begin as early in the season as vaccine is available. HCP should be among the groups considered for prioritized receipt of influenza vaccines when vaccine supply is limited.\nTwo types of influenza vaccines are available. LAIV is administered intranasally and is licensed for use in healthy nonpregnant persons aged 2-49 years. The trivalent inactivated vaccine (TIV) is administered as an intramuscular injection and can be given to any person aged >6 months. Both vaccine types contain vaccine virus strains that are selected to stimulate a protective immune response against the wild-type viruses that are thought to be most likely in circulation during the upcoming season. Use of LAIV for H C P who care for patients housed in protective inpatient environments has been a theoretic concern, but transmission of LAIV in health-care settings has not been reported. LAIV can be used for HCP who work in any setting, except those who care for severely immunocompromised hospitalized persons who require care in a protective environment. H C P who themselves have a condition that confers high risk for influenza complications, who are pregnant, or who are aged >50 years should not receive LAIV and should be administered TIV instead. An inactivated trivalent vaccine containing 60 mcg of hemagglutinin antigen per influenza vaccine virus strain (Fluzone High-Dose [sanofi pasteur]) is an alternative inactivated vaccine for persons aged >65 years. Persons aged >65 years may be administered any of the standard-dose TIV preparations or Fluzone High-Dose (77). The majority of T IV preparations are administered intramuscularly. An intradermally administered T IV was licensed in May 2011 and is an alternative to other TIV preparations for persons aged 18-64 years (131).\n# Use of Antiviral Drugs for Treating Exposed Persons and Controlling Outbreaks\nUse of antiviral drugs for chemoprophylaxis or treatment of influenza is an adjunct to (but not a substitute for) vaccination. Oseltamivir or zanamivir are recommended currently for chemoprophylaxis or treatment of influenza (132,133). TIV Recommendations can be administered to exposed, unvaccinated H C P at the same time as chemoprophylaxis, but LAIV should be avoided because the antiviral medication will prevent viral replication needed to stimulate a vaccine response (77). Antivirals are used often among patients during outbreaks in closed settings such as long-term-care facilities but also can be administered to unvaccinated H C P during outbreaks, when an exposure to a person with influenza occurs, or after exposure when vaccination is not thought to be protective against the strain to which a vaccinated H C P was exposed. Chemoprophylaxis consists of 1 dose (of either antiviral drug) daily for 10 days, and treatment consists of 1 dose twice daily for 5 days. In many instances of H C P exposure, watchful waiting and early initiation of treatment if symptoms appear is preferred rather than use of antiviral chemoprophylaxis immediately after exposure. The intensity and duration of the exposure and the underlying health status of the exposed worker are important factors in clinical judgm ents about w hether to provide chemoprophylaxis. If chemoprophylaxis is used, the provider should base choice of the agent on whether the circulating strain or strains of influenza have demonstrated resistance to particular antivirals.\n# Program Evaluation\n• Health-care adm inistrators should include influenza vaccination coverage among H C P as a measure of quality of care (124). • Influenza vaccination rates among HCP within facilities should be regularly measured and reported, and ward-, unit-, and specialty-specific coverage rates should be provided to staff and adm inistration (124). Such information might be useful to promote compliance with vaccination policies.\n# Measles\n\n# Background\n\n# Epidemiology and Risk Factors\nMeasles is a highly contagious rash illness that is transmitted by respiratory droplets and airborne spread. Severe complications, w hich m ight result in death, include pneum onia and encephalitis. Before the national measles vaccination program was im plem ented in 1963, almost every person acquired measles before adulthood; an estimated 3-4 million persons in the U nited States acquired measles each year (134). Approximately 500,000 persons were reported to have had measles annually, of whom 500 persons died, 48,000 were hospitalized, and another 1,000 had permanent brain damage from measles encephalitis (134).\nThrough a successful 2-dose measles vaccination program (i.e., a first dose at age 12-15 months and a second dose between ages 4 -6 years) (135) and better measles control throughout the region o f the Americas (136), endemic transmission of measles was interrupted in the United States, and measles was declared eliminated from the country in 2000 (137). However, measles remains widespread in the majority of countries outside the Western Hemisphere, with an estimated 20 m illion measles cases occurring worldwide (138) and approximately 164,000 related deaths (139). Thus, the United States continues to experience international importations that might lead to transmission among U.S. residents and limited outbreaks, especially in unvaccinated populations (140)(141)(142)(143).\nDuring 2001-2008, a total of 557 confirmed measles cases were reported in the United States from 37 states and the District of Columbia (annual median: 56; range: 37 in 2004 to 140 in 2008), representing an annual incidence ofless than one case per million population (144). O fthe 557 reported case-patients, 126 (23%) were hospitalized (annual median: 16; range: 5-29); of these, at least five case-patients were admitted to intensive care. Two deaths were reported, both in 2003 (144).\nO f the 557 reported case-patients during 2001-2008, a total of 223 (40%) were adults, including 156 (28%) aged 20-39 years and 67 (12%) aged >40 years. O f the 438 measles cases among U.S. residents, 285 (65%) cases were considered preventable (i.e., occurred among persons who were eligible for vaccination but were unvaccinated) (144). The remaining 153 (35%) cases were considered nonpreventable. Cases were defined as nonpreventable if they occurred among U.S. resident case-patients who had received >1 dose of measles-containing vaccine, if patients were vaccinated as recommended if traveling internationally, or if they were not vaccinated but had other evidence of im m unity (i.e., were born before 1957 and therefore presumed immune from natural disease in childhood, had laboratory evidence of immunity, or had documentation of physician-diagnosed disease) or for whom vaccination is not recommended. During 2001-2008, a total of 12.5% (one of eight) of measles cases reported to CD C among H C P occurred in persons born before 1957; the other seven cases occurred among H C P born after 1957.\nMeasles-mumps-rubella (MMR) vaccination policies have been enforced with variable success in United States health care facilities over the past decade. Even though medical settings were a primary site of measles transmission during the 1989-1991 measles resurgence (145,146), as of September 2011, only three states (New York, Oklahoma, and Rhode Island) had laws mandating that all hospital personnel have proof of measles immunity and did not allow for religious or philosophic exemptions (147).\nVaccine coverage in the United States is high; in 2010, a total of 91 \n# Measles Transmission and the Costs of Mitigating Measles Exposures in Health-Care Settings\nHealth-care-associated cases of measles are of public health concern. Because of the severity of measles, infected persons are likely to seek medical care in primary health-care facilities, emergency departments, or hospitals (141,149,150). Medical settings played a prominent role in perpetuating outbreaks of measles transmission during the 1989-1991 measles resurgence (145,146) and were a primary site of measles transmission in a health-care-associated outbreak in 2008 (149). During 2001 2008, a total of 27 reported measles cases were transmitted in U.S. health-care facilities, accounting for 5% of all reported U.S. measles cases.\nBecause of the greater opportunity for exposure, HCP are at higher risk than the general population for becoming infected with measles. A study conducted in 1996 in medical facilities in a county in Washington state indicated that HCP were 19 times more likely to develop measles than other adults (151). During 2001During -2008, in the 23 health-care settings in which measles transmission was reported, eight cases occurred among HCP, six (75%) of whom were unvaccinated or had unknown vaccination status. One health-care provider was hospitalized in an intensive care unit for 6 days from severe measles complications (142). During a health-care-associated measles outbreak in Arizona in 2008 with 14 cases, six cases were acquired in hospitals, and one was acquired in an outpatient setting. One unvaccinated health-care worker developed measles and infected a hospital emergency room patient who required intensive care following hospital admission for measles (149).\nHigh costs also are involved in evaluating and containing exposures and outbreaks in health-care facilities, as well as a substantial disruption of regular hospital routines when control measures are instituted, especially if hospitals do not have readily available data on the measles immunity status of their staff and others included in the facility vaccination program. In 2005 in Indiana, one hospital spent more than $113,000 responding to a measles outbreak (142), and in 2008 in Arizona, two hospitals spent $799,136 responding to and containing cases in their facilities (149). The Arizona outbreak response required rapid review of measles documentation of 14,844 H C P at seven hospitals and emergency vaccination of approximately 4,500 H C P who lacked documentation of measles immunity. Serologic testing at two hospitals among 1,583 H C P without documented history of vaccination or without documented laboratory evidence of measles immunity revealed that 138 (9%) of these persons lacked measles IgG antibodies (149).\n# Vaccine Effectiveness, Duration of Immunity and Seroprevalence Studies, and Vaccine Safety\nVaccine Effectiveness M M R vaccine is highly effective in preventing measles with a 1-dose vaccine effectiveness of 95% when administered on or after age 12 months and a 2-dose vaccine effectiveness of 99% (135).\n# Duration of Immunity and Seroprevalence Studies\nTwo doses of live measles vaccine are considered to provide long-lasting immunity (135). Although antibody levels decline following vaccination, a study examining neutralizing antibody levels up to 10 years following the second dose of M M R vaccine in children indicates that antibodies remain above the level considered protective (152).\nStudies among H C P in the United States during the measles resurgence in the late 1980s through early 1990s demonstrated that 4% -10% of all H C P lacked measles IgG antibodies (153)(154)(155)(156). During the 2008 Arizona outbreak, of the 1,077 health-care providers born during or after 1957 without documented measles immunity, 121 (11%) were seronegative (149). In a study of measles seroprevalence among 469 newly hired H C P at a hospital in N orth Carolina who were born before 1957, and thus considered immune by age, who could not provide written evidence of immunity to measles, serologic testing indicated that six (1.3%) lacked measles IgG antibodies (157). Other serologic studies of hospital-based H C P indicate that 2%-9% of those born before 1957 lacked antibodies to measles (156,(158)(159)(160).\nA survey co n d u cted d u rin g 1999-2004 foun d a seroprevalence of measles antibodies of 95.9% among persons in the U.S. population aged 6-49 years (161). The survey indicated that the lowest prevalence, 92.4% , was among adults born during 1967-1976 (161). A 1999 study of U.S. residents aged >20 years determined that 93% had antibodies to measles virus (162).\n# Vaccine Safety\nMeasles vaccine is administered in combination with the mumps and rubella components as the M M R vaccine in the United States. Monovalent measles vaccine rarely has been used in the United States in the past 2 decades and is no longer available. After decades of use, evidence demonstrates that M M R vaccine has an excellent safety profile (134).\nT he m ajority of docum ented adverse events occur in children. In rare circumstances, M M R vaccination of adults has been associated w ith the following adverse events: anaphylaxis (approximately 1.0-3.5 occurrences per million doses administered) (134), thrombocytopenia from the measles component or rubella component (a rate of three to four cases for every 100,000 doses) ( 134), and acute arthritis from the rubella component (arthralgia develops among approximately 25% of rubella-susceptible postpubertal females after M M R vaccination, and approximately 10% have acute arthritis-like signs and symptoms) (135). W hen joint symptoms occur, they generally persist for 1 day-3 weeks and rarely recur (135). Chronic joint symptoms attributable to the rubella component of the M M R vaccine are reported very rarely, if they occur at all. Evidence does not support an association between M M R vaccination and any of the following: hearing loss, retinopathy, optic neuritis, Guillain-Barre Syndrome, type 1 diabetes, Crohn's disease, or autism (135,(163)(164)(165)(166)(167)(168)(169).\nA woman can excrete the rubella vaccine virus in breast milk and transmit the virus to her infant, but the infection remains asymptomatic (135) Presumptive evidence of immunity to measles for persons who work in health-care facilities includes any of the following:\n.\n• written documentation of vaccination with 2 doses of live measles or M M R vaccine administered at least 28 days apart,'!' • laboratory evidence of immunity, § • laboratory confirmation of disease, or • birth before 1957.J\n# Prevaccination Testing\nPrevaccination antibody screening before M M R vaccination for an employee who does not have adequate presumptive evidence of im m unity is not necessary unless the medical facility considers it cost effective (134,(170)(171)(172) although no recent studies have been conducted. For H C P who have 2 documented doses of M M R vaccine or other acceptable evidence of immunity to measles, serologic testing for immunity is not recommended. In the event that a H C P who has 2 documented doses of M M R vaccine is tested serologically and determined to have negative or equivocal measles titer results, it is not recommended that the person receive an additional dose of M M R vaccine. Such persons should be considered to have presumptive evidence of measles immunity. Documented ageappropriate vaccination supersedes the results of subsequent serologic testing. Because rapid vaccination is necessary to halt disease transmission, during outbreaks of measles, serologic screening before vaccination is not recommended.\n# Use of Vaccine and Immune Globulin for Treating Exposed Persons and Controlling Outbreaks\nFollowing airborne infection-control precautions and implementing other infection-control measures are important to control the spread of measles but might fail to prevent all nosocomial transmission, because transmission to other susceptible persons might occur before illness is recognized. Persons infected with measles are infectious 4 days before rash onset through 4 days after rash onset. W hen a person who is suspected of having measles visits a health-care facility, airborne infection-control precautions should be followed stringently. The patient should be asked immediately to wear a medical mask and should be placed in an airborne-infection isolation room (i.e., a negative airpressure room) as soon as possible. If an airborne-infection isolation room is not available, the patient should be placed in a private room with the door closed and be asked to wear a mask. If possible, only staff with presumptive evidence of immunity should enter the room of a person with suspect or confirmed measles. Regardless of presumptive immunity status, all staff entering the room should use respiratory protection consistent with airborne infection-control precautions (i.e., use of an N95 respirator or a respirator with similar effectiveness in preventing airborne transmission) (3,150).\nBecause of the possibility, albeit low (~1%), of measles vaccine failure in H C P exposed to infected patients (173), all H C P should observe airborne precautions in caring for patients with measles. H C P in whom measles occurs should be excluded from work until >4 days following rash onset. Contacts w ith measles-compatible sym ptom s should be isolated, and appropriate infection-control measures (e.g., rapid vaccination of susceptible contacts) should be implemented to prevent further spread (174).\nIf measles exposures occur in a health-care facility, all contacts should be evaluated immediately for presumptive evidence of measles immunity. HCP without evidence of immunity should be offered the first dose of M M R vaccine and excluded from work from day 5-21 following exposure (135). HCP without evidence of immunity who are not vaccinated after exposure should be removed from all patient contact and excluded from the facility from day 5 after their first exposure through day 21 after the last exposure, even if they have received postexposure intramuscular immune globulin of 0.25 mL/kg (40 mg IgG/ kg) (135). Those with documentation of 1 vaccine dose may remain at work and should receive the second dose.\nC ase-patient contacts who do not have presum ptive evidence of measles immunity should be vaccinated, offered intramuscular immune globulin of 0.25 mL/kg (40 mg IgG/ kg), which is the standard dosage for nonimmunocompromised persons (135), or quarantined until 21 days after their exposure to the case-patient. Contacts with measles-compatible symptoms should be isolated, and appropriate infectioncontrol measures should be implemented to prevent further spread. If immune globulin is administered to an exposed person, observations should continue for signs and symptoms of measles for 28 days after exposure because immune globulin might prolong the incubation period.\nAvailable data suggest that live virus measles vaccine, if administered within 72 hours of measles exposure, will prevent, or modify disease (134). Even if it is too late to provide effective postexposure prophylaxis by administering MMR, the vaccine can provide protection against future exposure to all three infections. Identifying persons who lack evidence ofmeasles immunity during contact investigations provides a good opportunity to offer M M R vaccine to protect against measles as well as mumps and rubella, not only for HCP who are part of an organization' s vaccination program, but also for patients and visitors. If an exposed person is already incubating measles, M M R vaccination will not exacerbate symptoms. In these circumstances, persons should be advised that a measles-like illness occurring shortly after vaccination could be attributable either to natural infection or to the vaccine strain.\nIn such circumstances, specimens should be submitted for viral strain identification.\n# Mumps\n\n# Background\n\n# Epidemiology and Risk Factors\nMumps is an acute viral infection characterized by fever and inflammation of the salivary glands (usually parotitis) (175). The spectrum of illness ranges from subclinical infection (20% -40%) to nonspecific respiratory illness, sialadenitis including classic parotitis, deafness, orchitis, and meningoencephalitis; severity increases with age (175). In the prevaccine era, mumps was a common childhood illness, with approximately 186,000 mumps cases reported in the United States per year (176). After the introduction of the Jeryl Lynn strain mumps vaccine in 1967 and the implementation of the 1-dose mumps vaccine policy for children in 1977 (177), reports of mumps cases in the United States declined 99% (178). During 1986-1987, an increase in reported mumps cases occurred, primarily affecting unvaccinated adolescents and young adults. In the late 1980s, sporadic outbreaks continued to occur that affected both unvaccinated and 1-dose vaccinated adolescents and young adults (178). In 1989, a second dose of M M R vaccine was recommended nationwide for better measles control among school-aged children (179). Historically low rates of mumps followed with only several hundred reported cases per year in the United States during 2000-2005.\nIn 1998, a national goal to eliminate mumps was set for 2010 (180). However, in 2006, a total of 6,584 mumps cases were reported in the United States, the largest U.S. mumps outbreak in nearly 20 years (181-183). Whereas overall national mumps incidence was 2.2 per 100,000 population, eight states in the Midwest were the most affected, with 2.5-66.1 cases per 100.000 population (183). The highest incidence (31.1 cases per 100,000 population) was among persons aged 18-24 years (e.g., college-aged students), the majority of whom had received 2 doses of mumps-containing vaccine. O f the 4,017 case-patients for whom age and vaccination status were known, 1,786 (44%) were aged >25 years (incidence: 7.2 cases per 100.000 persons); of these 1,786 patients, 351 (20%) received at least 2 doses, 444 (25%) received 1 dose, 336 (19%) were unvaccinated, and 655 (37%) had unknown vaccination status.\nSince the 2006 resurgence, two additional large U.S. mumps outbreaks have occurred, both during 2009-2010, one among members o f a religious com m unity w ith cases occurring throughout the northeastern United States (184) and the other in Guam ( 185 \n# Mumps Transmission and the Costs of Mitigating Mumps Exposures in Health-care Settings\nAlthough health-care-associated transmission of mumps is infrequent, it might be underreported because of the high percentage (~20%-40%) of infected persons who might be asymptomatic (186)(187)(188)(189). In a survey of 9,299 adults in different professions conducted in 1968, before vaccine was used routinely, the rate of mumps acquisition was highest among dentists and HCP, with rates of 18% among dentists and 15% among physicians (37% for pediatricians), compared with 9% among primary and secondary school teachers and 2% among university staff members (190).\nIn the postvaccine era, m um ps transm ission also has been documented in medical settings (191)(192)(193). During a Tennessee mumps outbreak during 1986-1987, a total of 17 (12%) of 146 hospitals and three (50%) of six long-term-care facilities reported one or more practices that could contribute to the spread of mumps, including not isolating patients with mumps, assigning susceptible staff to care for patients with mumps, and not immunizing susceptible employees. Health care-associated transmission resulted in six cases of mumps infections among health-care providers and nine cases of mumps infections among patients (191). In Utah in 1994, two health-care providers in a hospital developed mumps after they had contact with an infected patient (192). During the 2006 outbreak, one health-care facility in Chicago experienced ongoing mumps transmission lasting 4 weeks (193).\nDuring the 2006 multistate U.S. outbreak, 144 (8.5%) of 1,705 adult case-patients in Iowa for whom occupation was known were health-care providers (Iowa D epartm ent o f Public H ealth, unpublished data, 2006). W hether transmission occurred from patients, coworkers, or persons in the community is unknown. During the 2009-2010 outbreak in the northeastern region of the United States, seven (0.2%) of the 3,400 case-patients were health-care providers, six of whom likely were infected by patients because they had no other known exposure.\nExposures to mumps in health-care settings also can result in added economic costs because of furlough or reassignment of staff members from patient-care duties or closure of wards (194). In 2006, a Kansas hospital spent $98,682 containing a mumps outbreak (195). During a mumps outbreak in Chicago in 2006, one health-care facility spent $262,788 controlling the outbreak (193).\n# Vaccine Effectiveness, Duration of Immunity and Seroprevalence Studies, and Vaccine Safety\nVaccine Effectiveness M M R vaccine has a 1-dose vaccine effectiveness in preventing mumps of 80% -85% (range: 75% -91% ) (175,(196)(197)(198)(199) and a 2-dose vaccine effectiveness of 79% -95% (199)(200)(201)(202). In a study conducted on two Iowa college campuses during the 2006 mumps outbreak among a population that was primarily vaccinated with 2 doses, 2-dose vaccine effectiveness ranged from 79% to 88% (202).\n# Duration of Immunity and Seroprevalence Studies\nMumps antibody levels wane over time following the first or second dose of vaccination (203,204), but the correlates of im m unity to m um ps are poorly understood and the significance of these waning antibody levels is unclear. A study on a university campus in Nebraska in 2006 indicated lower levels of mumps neutralizing antibodies among students who had been vaccinated with a second M M R dose >15 years previously than among those who had been vaccinated 1-5 years previously, but the difference was not statistically significant (p>0.05) (205). In a 2006 study on a university campus in Kansas, students with mumps were more likely to have received a second dose of M M R vaccine >10 years previously than were their roommates without mumps (206). However, another 2006 study from an Iowa college campus identified no such association (202).\nDuring 1999-2004, national seroprevalence for mumps antibodies for persons aged 6 -4 9 years was 90% (95% confidence interval [CI]: 88.8-91.1) (207). In the Nebraska study, 414 (94%) of the 440 participants were seropositive for mumps antibodies (205). A study in Kansas in 2006 indicated that 13% of hospital employees lacked antibodies to the mumps virus (195). In a recent study on mumps seroprevalence among 381 newly hired health-care personnel at a hospital in North Carolina who were born before 1957 and thus considered immune by age and who could not provide written evidence of immunity to mumps, serologic testing indicated that 14 (3.7%) lacked IgG antibodies to mumps (157). For HCP who do not have adequate presumptive evidence of mum ps imm unity, prevaccination antibody screening before M M R vaccination is not necessary (135,175). For H C P who have 2 documented doses of M M R vaccine or other acceptable evidence of immunity to mumps, serologic testing for im m unity is not recommended. In the event that a health-care provider who has 2 docum ented doses of M M R vaccine is tested serologically and determined to have negative or equivocal mumps titer results, it is not recommended that the person receive an additional dose of M M R vaccine. Such persons should be considered immune to mumps. Documented age-appropriate vaccination supersedes the results of subsequent serologic testing. Likewise, during outbreaks of mumps, serologic screening before vaccination is not recommended because rapid vaccination is necessary to halt disease transmission.\n# Controlling Mumps Outbreaks in Health-Care Settings\nPlacing patients in droplet precautions and implementing other infection-control measures is important to control the spread of mumps but might fail to prevent all nosocomial transmission, because transmission to other susceptible persons might occur before illness is recognized (208). W hen a person suspected of having mumps visits a health-care facility, only H C P with adequate presum ptive evidence of im m unity should be exposed to the person, and in addition to standard precautions, droplet precautions should be followed. The index case-patient should be isolated, and respiratory precautions ** The first dose of mumps-containing vaccine should be administered on or after the first birthday; the second dose should be administered no earlier than 28 days after the first dose.\nMumps immunoglobulin (IgG) in the serum; equivocal results should be considered negative. § § The majority of persons born before 1957 are likely to have been infected naturally between birth and 1977, the year that mumps vaccination was recommended for routine use, and may be presumed immune, even if they have not had (gown and gloves) should be used for patient contact. Negative pressure rooms are not required. The patient should be isolated for 5 days after the onset of parotitis, during which time shedding of virus is likely to occur (209).\nIf mumps exposures occur in a health-care facility, all contacts should be evaluated for evidence of mumps immunity. HCP with no evidence of mumps immunity who are exposed to patients with mumps should be offered the first dose of M M R vaccine as soon as possible, but vaccine can be administered at any interval following exposure; they should be excluded from duty from day 12 after the first unprotected exposure through day 25 after the most recent exposure. H C P with documentation of 1 vaccine dose may remain at work and should receive the second dose. HCP with mumps should be excluded from work for 5 days from the onset of parotitis (209).\nAntibody response to the mumps com ponent of M M R vaccine generally is believed not to develop soon enough to provide effective prophylaxis after exposure to suspected mum ps (191,210), but data are insufficient to rule out a prophylactic effect. N onetheless, the vaccine is not recom m ended for prophylactic purposes after exposure. However, identifying persons who lack presumptive evidence of mumps immunity during contact investigations provides a good opportunity to offer M M R vaccine to protect against mumps as well as measles and rubella, not only for HCP who are part of an organization's vaccination program, but also for patients and visitors. If an exposed person already is incubating mumps, M M R vaccination will not exacerbate the symptoms. In these circumstances persons should be advised that a mumps-like illness occurring shortly after vaccination is likely to be attributable to natural infection. In such circumstances, specimens should be submitted for viral strain identification to differentiate between vaccine and wild type virus. Immune globulin is not routinely used for postexposure protection from mumps because no evidence exists that it is effective (135).\n# Rubella\n\n# Background\n\n# Epidemiology and Risk Factors\nRubella (German measles) is a viral disease characterized by rash, low-grade fever, lym phadenopathy, and malaise (211). A lthough rubella is considered a benign disease, transient arthralgia and arthritis are observed commonly in infected adults, particularly among postpubertal females. Chronic arthritis has been reported after rubella infection, but such reports are rare, and evidence of an association is weak (212). O ther complications that occur infrequently are thrombocytopenia and encephalitis (211). Infection is asymptomatic in 25%-50% of cases (213). Clinical diagnosis of rubella is unreliable and should not be considered in assessing immune status. Many rash illnesses might mimic rubella infection and many rubella infections are unrecognized. The only reliable evidence of previous rubella infection is the presence of serum rubella IgG antibody (211).\nO f primary concern are the effects that rubella can have when a pregnant woman becomes infected, especially during the first trimester, which can result in miscarriages, stillbirths, therapeutic abortions, and congenital rubella syndrome (CRS), a constellation of birth defects that often includes blindness, deafness, mental retardation, and congenital heart defects (211,213). Postnatal rubella is transmitted through direct or droplet contact from nasopharyngeal secretions. The incubation period ranges from 12 to 23 days (214,215). An ill person is most contagious when the rash first appears, but the period of maximal communicability extends from a few days before to 7 days after rash onset (213). Rubella is less contagious than measles.\nIn the prevaccine era, rubella was an endemic disease globally with larger epidemics that occurred; in the United States, rubella epidemics occurred approximately every 7 years (211). During the 1964-1965 global rubella epidemic, an estimated 12.5 million cases of rubella occurred in the United States, resulting in approximately 2,000 cases of encephalitis, 11,250 fetal deaths attributable to spontaneous or surgical abortions, 2,100 infants who were stillborn or died soon after birth, and 20,000 infants born with CRS. The economic impact of this epidemic in the United States alone was estimated at $1.5 billion in 1965 dollars ($10 billion in 2010 dollars) (216).\nAfter the rubella vaccine was licensed in the United States in 1969, reported rubella cases decreased from 57,686 in 1969 to 12,491 in 1976 (216), and CRS cases reported nationwide decreased from 68 in 1970 to 23 in 1976 (217). Declines in rubella age-specific incidence occurred in all age groups, including adolescents and adults, but the greatest declines were among children aged <15 years (216) As of September 2011, only three states (i.e., New York, Oklahoma, and Rhode Island) had laws mandating that all hospital personnel have proof of rubella immunity and did not allow for religious or philosophical exemptions (147). Additional states had requirements for specific types of facilities or for certain employees within those facilities, but they did not have universal laws mandating proof of rubella immunity for all hospital personnel (147). \n.\n# Rubella Transmission and the Costs of Mitigating Rubella Exposures in Health-Care Settings\nNo documented transmission of rubella to HCP or other hospital staff or patients in U.S. health-care facilities has occurred since elimination was declared. However, in the decades before elimination, rubella transmission was documented in at least 10 U.S. medical settings (221)(222)(223)(224)(225)(226)(227)(228)(229)(230)(231) and led to outbreaks with serious consequences, including pregnancy terminations, disruption of hospital routine, absenteeism from work, expensive containment measures, negative publicity, and the threat of litigation (232). In these outbreaks, transmission occurred from HCP to susceptible coworkers and patients, as well as from patients to HCP and other patients. No data are available on whether HCP are at increased risk for acquiring rubella compared with other professions.\n# Vaccine Effectiveness, Duration of Immunity and Seroprevalence Studies, and Vaccine Safety\n\n# Vaccine Effectiveness\nVaccine effectiveness of the RA 27/3 rubella vaccine against clinical rubella is 95% (85%-99% CI) and >99% for clinical laboratory confirmed rubella (211,233). Antibody responses to rubella as part of M M R vaccine are equal (i.e., >99%) to those seen after the single-antigen RA 27/3 rubella vaccine (211,234).\n# Duration of Immunity and Seroprevalence Studies\nIn clinical trials, 97% -99% of susceptible persons who received a single dose of the RA 27/3 rubella vaccine when they were aged >12 months developed antibody (211,235,236). Two studies have demonstrated that vaccine-induced rubella antibodies might wane after 12-15 years (237,238); however, rubella surveillance data do not indicate that rubella and CRS are increasing among vaccinated persons.\nN ational seroprevalence for rubella antibodies among persons aged 6-49 years during 1999-2004 was 91% (239). During 1986-1990, serologic surveys in one hospital indicated that 5% of H C P (including persons born in 1957 or earlier) did not have detectable rubella antibody (240). Earlier studies indicated that up to 14%-19% of U.S. hospital personnel, including young women of childbearing age, lacked detectable rubella antibody (225,241,242). In a recent study on rubella seroprevalence among 477 newly hired HCP at a hospital in N orth Carolina who were born before 1957, and thus considered immune by age, who could not provide written evidence of immunity to rubella, serologic testing revealed that 14 (3.1%) lacked detectable levels of antibody to rubella (157).\nBecause of the potential for contact with pregnant women in any type of health-care facility, all HCP should have documented presumptive evidence of immunity to rubella. History of disease is not considered adequate evidence of immunity. As a result of the theoretic risk to the fetus, women should be counseled to avoid becoming pregnant for 28 days after receipt of a rubella-containing vaccine (243). However, receipt of rubella-containing vaccine during pregnancy should not be a reason to consider termination of pregnancy; data from 18 years of following to term 321 known rubella-susceptible women who were vaccinated within 3 months before or 3 m onths after conception indicated that none of the 324 infants born to these mothers had malformations compatible with congenital rubella syndrome, but five had evidence of subclinical rubella infection (244). The estimated risk for serious malformations to fetuses attributable to the mother receiving RA 27/3 vaccine is considered to range from zero to 1.6% (135,244).\nEvidence does not support a link between M M R vaccination and any of the following: hearing loss, retinopathy, optic neuritis, Guillain-Barre Syndrome, type 1 diabetes, Crohn's disease, or autism (135,(163)(164)(165)(166)(167)(168)(169).\nA woman can excrete the rubella vaccine virus in breast milk and transmit the virus to her infant, but the infection remains asymptomatic (135) Presumptive evidence of immunity to rubella for persons who work in health-care facilities includes any of the following:\n.\n• written documentation of vaccination with 1 dose of live rubella or M M R vaccine, • laboratory evidence of im m unity,• laboratory confirmation of rubella infection or disease, or • birth before 1957*** (except women of childbearing potential who could become pregnant, although pregnancy in this age group would be exceedingly ra re^).\n# Prevaccination Testing\nFor HCP who do not have adequate presumptive evidence of rubella im m unity, prevaccination antibody screening before M M R vaccination is not necessary unless the medical facility considers it cost effective (135). For HCP who have 1 documented dose of M M R vaccine or other acceptable evidence of immunity to rubella, serologic testing for immunity is not recommended. In the event that a health-care provider who has at least 1 documented dose of rubella-containing vaccine is tested serologically and determined to have negative or equivocal rubella titer results, receipt of an additional dose of M M R vaccine for prevention of rubella is not recommended. Such persons should be considered im m une to rubella. However, if the provider requires a second dose of measles or mumps vaccine, then a second dose of M M R should be adm inistered. D ocum ented age-appropriate vaccination supersedes the results of subsequent serologic testing. Likewise, during outbreaks of rubella, serologic screening before vaccination is not recommended because rapid vaccination is necessary to halt disease transmission.\n# Controlling Rubella Outbreaks\nTo prevent transmission of rubella in health-care settings, patients suspected to have rubella should be placed in private rooms. In addition to standard precautions, droplet precautions Because rubella can occur in some persons born before 1957 and because congenital rubella and congenital rubella syndrome can occur in the offspring of women infected with rubella virus during pregnancy, birth before 1957 is not acceptable evidence of rubella immunity for women who could become pregnant.\nshould be followed until 7 days after onset of symptoms. Room doors can remain open, and special ventilation is not required. Any exposed HCP who do not have adequate presumptive evidence of rubella immunity should be excluded from duty beginning 7 days after exposure to rubella and continuing through either 1) 23 days after the most recent exposure or 2) 7 days after rash appears if the provider develops rubella (213)(214)(215). Exposed H C P who do not have adequate presum ptive evidence of im m unity who are vaccinated postexposure should be excluded from duty for 23 days after the most recent exposure to rubella because no evidence exists that postexposure vaccination is effective in preventing rubella infection (244).\nN either rubella-containing vaccine (244) nor im m une globulin (IG) (211,244) is effective for postexposure prophylaxis of rubella. Although intramuscular administration of 20 mL of immune globulin within 72 hours of rubella exposure might reduce the risk for rubella, it will not eliminate the risk (135,245); infants with congenital rubella have been born to women who received IG shortly after exposure (213). In addition, administration of IG after exposure to rubella might modify or suppress symptoms and create an unwarranted sense of security with respect to transmission.\nIf exposure to rubella does not cause infection, postexposure vaccination with M M R vaccine should induce protection against subsequent infection of rubella, as well as measles and mumps. If the exposure results in infection, no evidence indicates that administration of M M R vaccine during the presymptomatic or prodromal stage of illness increases the risk for vaccine-associated adverse events (213).\n# Pertussis\n\n# Background\n\n# Epidemiology and Risk Factors\nPertussis is a highly contagious bacterial infection. Secondary attack rates among susceptible household contacts exceed 80% (246,247). Transmission occurs by direct contact with respiratory secretions or large aerosolized droplets from the respiratory tract of infected persons. The incubation period is generally 7-10 days but can be as long as 21 days. The period of communicability starts with the onset of the catarrhal stage and extends into the paroxysmal stage. Symptoms of early pertussis (catarrhal phase) are indistinguishable from other upper respiratory infections.\nVaccinated adolescents and adults, whose immunity from childhood vaccinations wanes 5-10 years after the most recent dose of vaccine (usually administered at age 4-6 years), are an important source of pertussis infection for susceptible infants. Infants too young to be vaccinated are at greatest risk for severe pertussis, including hospitalization and death. The disease can be transmitted from adults to close contacts, especially unvaccinated children.\nVaccination coverage am ong infants and children for diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine remains high. In 2010, coverage for children aged 19-35 months who have received >4 doses of DTaP/diphtheria and tetanus toxoids and pertussis vaccine (DTP)/diphtheria and tetanus toxoids vaccine (DT) was 84% (21). Among children entering kindergarten for the 2009-2010 school year, DTaP coverage was 93% (148). Vaccination coverage for tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine was 68.7% among adolescents in 2010 and <7% among adults in 2009 (22,248). Tdap vaccination coverage among H C P was 17.0% in 2009 (248).\n# Disease in Health-Care Settings and Impact on Health Care Personnel and Patients\nIn hospital settings, transmission of pertussis has occurred from hospital visitors to patients, from HCP to patients, and from patients to H C P (249-252). Although of limited size (range: 2-17 patients and 5-13 staff), documented outbreaks were costly and disruptive. In each outbreak, H C P were evaluated for cough illness and required diagnostic testing, prophylactic antibiotics, and exclusion from work.\nD uring outbreaks that occur in hospitals, the risk for contracting pertussis among patients or staff is often difficult to quantify because exposure is not well defined. Serologic studies conducted among hospital staff indicate that exposure to pertussis is much more frequent than suggested by attack rates of clinical disease (246,(249)(250)(251)(252)(253)(254). In one outbreak, seroprevalence of pertussis agglutinating antibodies among H C P correlated w ith the degree of patient contact and was highest among pediatric house staff (82%) and ward nurses (71%) and lowest among nurses with administrative responsibilities (35%) (251).\nA model to estimate the cost of vaccinating H CP and the net return from preventing nosocomial pertussis was constructed using probabilistic methods and a hypothetical cohort of 1,000 H C P with direct patient contact followed for 10 years (255). Baseline assumptions, determined from data in the literature, included incidence of pertussis in HCP, ratio of identified exposures per HCP case, symptomatic percentage of seroconfirmed pertussis infections in HCP, cost of infectioncontrol measures per exposed person, vaccine efficacy, vaccine coverage, employment turnover rate, adverse events, and cost of vaccine (255). In a 10-year period, the cost of infection control would be $388,000 w ithout Tdap vaccination of HCP compared with $69,000 with such a program (255). Introduction of a vaccination program would result in a net savings as high as $535,000 and a benefit-cost ratio of 2.38 (i.e., for every dollar spent on the vaccination program, the hospital would save $2.38 on control measures) (255).\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nA prelicensure im m unogenicity and safety study in adolescents and adults of a vaccine containing acellular pertussis estimated vaccine efficacy to be 92% (256). Recent postlicensure studies ofTdap demonstrate vaccine effectiveness at 78% and 66% (257,258). Duration of im m unity from vaccination has yet to be evaluated. D ata from pre-and postlicensure studies support the safety ofTdap in adolescents and adults (259)(260)(261)(262)(263).\nSince the 2005 Tdap recommendations for HCP, one study tried to determine if postexposure prophylaxis following pertussis exposure was necessary for Tdap-vaccinated H C P (264). During the study period, 116 exposures occurred among 94 HCP. Pertussis infection occurred in 2% of those who received postexposure prophylaxis compared with 10% of those who did not, suggesting a possible benefit of postexposure prophylaxis among Tdap-vaccinated HCP (264). Because Tdap coverage is suboptimal among HCP, and the duration of protection afforded by Tdap is unknown, vaccination status does not change the approach to evaluate the need for postexposure prophylaxis in exposed H CP Postexposure prophylaxis is necessary for HCP in contact with persons at risk for severe disease. Other HCP either should receive postexposure prophylaxis or be monitored for 21 days after pertussis exposure and treated at the onset of signs and symptoms of pertussis. Recommended postexposure prophylaxis antibiotics for HCP exposed to pertussis include azithromycin, clarithroymycin, or erythromycin. HCP are not at greater risk for diphtheria or tetanus than the general population.\n# Recommendations\n\n# Vaccination\nRegardless of age, H C P should receive a single dose ofTdap as soon as feasible if they have not previously received Tdap and regardless of the time since their most recent Td vaccination. Vaccinating HCP with Tdap will protect them against pertussis and is expected to reduce transmission to patients, other HCP, household members, and persons in the community. Tdap is not licensed for multiple administrations; therefore, after receipt of Tdap, H C P should receive Td for future booster vaccination against tetanus and diphtheria. Hospitals and ambulatory-care facilities should provide Tdap for H C P and use approaches that maximize vaccination rates (e.g., education about the benefits of vaccination, convenient access, and the provision of Tdap at no charge).\n# Prevaccination Testing\nPrevaccination serologic testing is not recommended.\n# Demonstrating Immunity\nIm m unity cannot be dem onstrated through serologic testing because serologic correlates of protection are not well established.\n# Controlling Pertussis Outbreaks in Health-Care Settings\nPrevention of pertussis transmission in health-care settings involves diagnosis and early treatment of clinical cases, droplet isolation of infectious patients who are hospitalized, exclusion from work of H C P who are infectious, and postexposure prophylaxis. Early diagnosis of pertussis, before secondary transmission occurs, is difficult because the disease is highly communicable during the catarrhal stage, when symptoms are still nonspecific. Pertussis should be considered in the differential diagnoses for any patient with an acute cough illness with severe or prolonged paroxysmal cough, particularly if characterized by posttussive vomiting, whoop, or apnea. Nasopharyngeal specimens should be taken, if possible, from the posterior nasopharynx with a calcium alginate or Dacron swab for cultures and/or polymerase chain reaction (PCR) assay.\nHealth-care facilities should maximize efforts to prevent transmission of Bordetella pertussis. Precautions to prevent respiratory droplet transmission or spread by close or direct contact should be employed in the care of patients admitted to hospital with suspected or confirmed pertussis (265). These precautions should remain in effect until patients are improved clinically and have completed at least 5 days of appropriate antimicrobial therapy. HCP in whom symptoms (i.e., unexplained rhinitis or acute cough) develop after known pertussis exposure might be at risk for transmitting pertussis and should be excluded from work until 5 days after the start of appropriate therapy (3).\nData on the need for postexposure prophylaxis in Tdapvaccinated H C P are inconclusive (264). Certain vaccinated H C P are still at risk for B. pertussis. Tdap might not preclude the need for postexposure prophylaxis. Postexposure antimicrobial prophylaxis is recommended for all HCP who have unprotected exposure to pertussis and are likely to expose a patient at risk for severe pertussis (e.g., hospitalized neonates and pregnant women). O ther H C P should either receive postexposure antimicrobial prophylaxis or be monitored daily for 21 days after pertussis exposure and treated at the onset of signs and symptoms of pertussis.\n# Varicella\n\n# Background\n\n# Epidemiology and Risk Factors\nVaricella is a highly infectious disease caused by primary infection with varicella-zoster virus (VZV). VZV is transmitted from person to person by direct contact, inhalation of aerosols from vesicular fluid of skin lesions of varicella or herpes zoster (HZ), a localized, generally painful vesicular rash commonly called shingles, or infected respiratory tract secretions that also might be aerosolized (266). The average incubation period is 14-16 days after exposure to rash (range: 10-21 days). Infected persons are contagious an estimated 1-2 days before rash onset until all lesions are crusted, typically 4 -7 days after rash onset (266). Varicella secondary attack rates can reach 90% among susceptible contacts. Typically, primary infection with VZV results in lifetime immunity. VZV remains dormant in sensory-nerve ganglia and can reactivate at a later time, causing H Z. Before the U.S. childhood varicella vaccination program began in 1995, approximately 90% ofvaricella disease occurred among children aged <15 years (266). During 1997-2009, national varicella vaccine coverage among children aged 19-35 months increased from 27% to 90%, leading to dramatic declines of >85% in varicella incidence, hospitalizations, and deaths (267)(268)(269). The decline in disease incidence was greatest among children for whom vaccination was recommended; however, declines occurred in every age group including infants too young to be vaccinated and adults, indicating reduced communitywide transmission of VZV.\nC urrent incidence of varicella am ong adults is low (<0.1/1,000 population), and adult cases represent <10% of all reported varicella cases (270). National seroprevalence data from 1999-2004 demonstrated that, in the early vaccine era, adults continued to have high immunity to varicella (271). In this study, 98% of persons aged 20-49 years had VZV-specific IgG antibodies. However, with declining likelihood of exposure to VZV, children and adolescents who did not receive 2 doses of varicella vaccine could remain susceptible to VZV infection as they age into adulthood, when varicella can be more severe.\nThe clinical presentation of varicella has changed since the implementation of the varicella vaccination program, with more than half of varicella cases reported in 2008 occurring among persons who were vaccinated previously, the majority of them children. Varicella disease in vaccinated children (breakthrough varicella) usually has a modified or atypical presentation; the rash is typically mild, with <50 lesions that are more likely to be predominantly maculopapular than vesicular (266). Fever is less common, and the duration of illness is shorter. Nevertheless, breakthrough varicella is infectious. One study indicated that vaccinated children with varicella with <50 lesions were only one third as infectious as unvaccinated children whereas those with >50 lesions were as infectious as unvaccinated children (272). Because the majority of adults are immune and few need vaccination, fewer breakthrough cases have been reported among adults than among children, and breakthrough varicella in adults has tended to be milder than varicella in unvaccinated adults (273,274).\nThe epidemiology of varicella in tropical and subtropical regions differs from that in the United States. In these regions, a higher proportion ofVZV infections are acquired later in life. Persons emigrating from these regions might be more likely to be susceptible to varicella compared to U.S.-born persons and, therefore, are at a higher risk for developing varicella if unvaccinated and exposed (275,276).\n# Disease in Health-Care Settings and Impact on Health Care Personnel and Patients\nA lthough relatively rare in the U nited States since introduction of varicella vaccine, nosocomial transmission of VZV is well recognized and can be life-threatening to certain patients (277)(278)(279)(280)(281)(282)(283)(284)(285)(286)(287)(288)(289). In addition to hospital settings, nosocomial VZV transmission has been reported in longterm-care facilities and a hospital-associated residential facility (290,291). Sources of nosocomial exposure that have resulted in transmission include patients, HCP, and visitors with either varicella or H Z. Both localized and disseminated H Z in immunocompetent as well as immunocompromised patients have been identified as sources of nosocomial transmission of VZV. Localized H Z has been demonstrated to be much less infectious than varicella; disseminated H Z is considered to be as infectious as varicella (266). Nosocomial transmission has been attributed to delays in the diagnosis or reporting of varicella or H Z and in failures to implement control measures promptly. In hospitals and other health-care settings, airborne transmission of VZV from patients with either varicella or H Z has resulted in varicella in HCP and patients who had no direct contact with the index case-patient (284)(285)(286)(287)(288)291). Although all susceptible patients in health-care settings are at risk for severe varicella disease with complications, certain patients without evidence of immunity are at increased risk: pregnant women, premature infants born to susceptible mothers, infants born at <28 weeks' gestation or who weigh <1,000 grams regardless of maternal immune status, and immunocompromised persons of all ages (including persons who are undergoing immunosuppressive therapy, have malignant disease, or are immunodeficient).\nVZV exposures among patients and HCP can be disruptive to patient care, time-consuming, and costly even when they do not result in VZV transmission (281,282,292). Studies ofVZV exposure in health-care settings have documented that a single provider with unrecognized varicella can result in the exposure of >30 patients and >30 employees (292). Identification of susceptible patients and staff, medical management of susceptible exposed patients at risk for complications of varicella, and furloughing of susceptible exposed HCP are time-consuming and costly (281,282). W ith the overall reduction in varicella disease attributable to the success of the vaccination program, the risk for exposure to VZV from varicella cases in health-care settings is likely declining. In addition, an increasing proportion of varicella cases occur in vaccinated persons who are less contagious. Diagnosis of varicella has become increasingly challenging as a growing proportion of cases occur in vaccinated persons in whom disease is mild, and HCP encounter patients with varicella less frequently. Although not currently routinely recommended for the diagnosis and management of varicella, laboratory testing of suspected varicella cases is likely to become increasingly useful in health-care settings, especially as the positive predictive value of clinical diagnosis declines.\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\n\n# Vaccine Effectiveness\nFormal studies to evaluate vaccine efficacy or effectiveness have not been performed among adults. Studies of varicella vaccine effectiveness performed among children indicated good performance of 1 dose for prevention of all varicella (80% -85%) and >95% effectiveness for prevention of moderate and severe disease (266,293). Studies have indicated that a second dose among children produces an improved humoral and cellular immune response that correlates with improved protection against disease (266,294).\nVaricella vaccine effectiveness is expected to be lower in adults than in children. Adolescents and adults require 2 doses to achieve seroconversion rates similar to those seen in children after 1 dose (266). A study of adults who received 2 doses of varicella vaccine 4 or 8 weeks apart and were exposed subsequently to varicella in the household estimated an 80% reduction in the expected number of cases (295).\n# Duration of Immunity\nSerologic correlates of protection against varicella using commercially available assays have not been established for adults (266). In clinical studies, detectable antibody levels have persisted for at least 5 years in 97% of adolescents and adults who were administered 2 doses of varicella vaccine 4-8 weeks apart, but boosts in antibody levels were observed following exposures to varicella, which could account for the long-term persistence of antibodies after vaccination in these studies (295). Studies have demonstrated that whereas 25%-31% of adult vaccine recipients who seroconverted lost detectable antibodies 1-11 years after vaccination (273,296), vaccine-induced VZV-specific T-cell proliferation (marker for cell-mediated immunity [CMI]) was maintained in 94% of adults 1 and 5 years postvaccination (297). Disease was mild in vaccinated persons who developed varicella after exposure to VZV, even among vaccinees who did not seroconvert or who lost detectable antibody (273,274). Severity of illness and attack rates among vaccinated adults did not increase over time. These studies suggest that VZV-specific CMI affords protection to vaccinated adults, even in the absence of detectable antibody response.\n# Vaccine Safety\nThe varicella vaccine has an excellent safety profile. In clinical trials, the most common adverse events among adolescents and adults were injection-site complaints (24.4% after the first dose and 32.5% after the second dose) (266,295). Varicella-like rash at the injection site occurred in 3% of vaccine recipients after the first dose and in 1% after the second. A nonlocalized rash occurred in 5.5% of vaccine recipients after the first dose and in 0.9% after the second, with a median number of lesions of five, at a peak of 7-21 and 0-23 days postvaccination, respectively (295). Data on serious adverse events among adults after varicella vaccination are limited, but the proportion of serious adverse events among all adverse events reported to the Vaccine Adverse Events Reporting System during 1995-2005 was low (5%) among both children and adults (298). Serious adverse events reported among children included pneumonia, hepatitis, H Z (some hospitalized), meningitis with H Z, ataxia, encephalitis, throm bocytopenic purpura. N ot all adverse events reported after varicella vaccination have been laboratory confirmed to be attributable to the vaccine strain VZV (266,298).\nRisk for transmission of vaccine virus was assessed in placebo recipients who were siblings of vaccinated children and among healthy siblings of vaccinated leukemic children (266). The findings suggest that transmission of varicella vaccine virus from healthy persons to susceptible contacts is very rare. The risk might be increased in vaccinees in whom a varicella-like rash develops after vaccination. However, this risk is also low. The benefits of vaccinating HC P without evidence of immunity outweigh this extremely low potential risk. Since implementation of the varicella vaccine program, transmission of vaccine virus has been documented from eight persons (all of whom had a rash after vaccination) resulting in nine secondary infections among household and long-term-care facility contacts (299). No transmission has been documented from vaccinated HCP.\n# Recommendations\n\n# Vaccination\nHealth-care institutions should ensure that all HCP have evidence of immunity to varicella. This information should be documented and readily available at the work location. HCP without evidence of immunity to varicella should receive 2 doses of varicella vaccine administered 4-8 weeks apart. If >8 weeks elapse after the first dose, the second dose may be administered without restarting the schedule. Recently vaccinated HCP do not require any restriction in their work activities; however, HCP who develop a vaccine-related rash after vaccination should avoid contact with persons without evidence of immunity to varicella who are at risk for severe disease and complications until all lesions resolve (i.e., are crusted over) or, if they develop lesions that do not crust (macules and papules only), until no new lesions appear within a 24-hour period.\nEvidence of immunity for HCP includes any of the following (266):\n• written documentation of vaccination with 2 doses of varicella vaccine, • laboratory evidence o f im m unity § § § or laboratory confirmation of disease, • diagnosis or verification of a history of varicella disease by a health-care provider,JJJ or • diagnosis or verification of a history of H Z by a health-care provider. In health-care settings, serologic screening before vaccination of personnel without evidence of immunity is likely to be cost effective. Key factors determining cost-effectiveness include sensitivity and specificity of serologic tests, the nosocomial transmission rate, seroprevalence of VZV antibody in the personnel population, and policies for managing vaccine recipients developing postvaccination rash or who are § § § Commercial assays can be used to assess disease-induced immunity, but they often lack sensitivity to detect vaccine-induced immunity (i.e., they might yield false-negative results). JJJ Verification of history or diagnosis of typical disease can be provided by any health-care provider (e.g., a school or occupational clinic nurse, nurse practitioner, physician assistant, or physician). For persons reporting a history of, or reporting with, atypical or mild cases, assessment by a physician or their designee is recommended, and one of the following should be sought: 1) an epidemiologic link to a typical varicella case or to a laboratoryconfirmed case or 2) evidence of laboratory confirmation if it was performed at the time of acute disease. W hen such documentation is lacking, persons should not be considered as having a valid history of disease because other diseases might mimic mild atypical varicella.\nexposed subsequently to VZV. Institutions may elect to test all unvaccinated HCP, regardless of disease history, because a small proportion of persons with a positive history of disease might be susceptible. For the purpose of screening HCP, a less sensitive and more specific commercial ELISA should be considered. The latex agglutination test can produce falsepositive results, and HCP who remained unvaccinated because of false test results subsequently contracted varicella (289).\nRoutine testing for varicella im m unity after 2 doses of vaccine is not recommended. Available commercial assays are not sensitive enough to detect antibody after vaccination in all instances. Sensitive tests that are not generally available have indicated that 92% -99% of adults develop antibodies after the second dose (266). Seroconversion does not always result in full protection against disease and, given the role of CMI for providing long-term protection, absence of antibodies does not necessarily mean susceptibility. Documented receipt of 2 doses of varicella vaccine supersedes results of subsequent serologic testing.\nHealth-care institutions should establish protocols and recommendations for screening and vaccinating HCP and for management of H CP after exposures in the work place. Institutions also should consider precautions for H C P in whom rash occurs after vaccination, although they should also consider the possibility of wild-type disease in HCP with recent exposure to varicella or HZ.\nA vaccine to prevent H Z is available and recommended for all persons aged >60 years without contraindications to vaccination. H Z vaccine is not indicated for HCP for the prevention of nosocomial transmission, but HCP aged >60 years may receive the vaccine on the basis of the general recom m endation for H Z vaccination, to reduce their individual risk for HZ.\n# Varicella Control Strategies\nAppropriate measures should be implemented to manage cases and control outbreaks (300).\n# Patient Care\nOnly HCP with evidence of immunity to varicella should care for patients who have confirmed or suspected varicella or HZ. Airborne precautions (i.e., negative air-flow rooms) and contact precautions should be employed for all patients with varicella or disseminated H Z and for immunocompromised patients with localized H Z until disseminated infection is ruled out. These precautions should be kept in place until lesions are dry and crusted. If negative air-flow rooms are not available, patients should be isolated in closed rooms and should not have contact with persons without evidence of immunity to varicella. For immunocompetent persons with localized HZ, standard precautions and complete covering of the lesions are recommended.\n# Postexposure Management of HCP and Patients\nExposure to V ZV is defined as close contact w ith an infectious person, such as close indoor contact (e.g., in the same room) or face-to-face contact. Experts differ regarding the duration of contact; some suggest 5 minutes, and others up to 1 hour; all agree that it does not include transitory contact (301).\nAll exposed, susceptible patients and H C P should be identified using the criteria for evidence of immunity. An additional criterion of evidence of immunity only for patients who are not immunocompromised or pregnant is birth in the United States before 1980. Postexposure prophylaxis with vaccination or varicella-zoster immunoglobulin, depending on immune status, of exposed HCP and patients without evidence of immunity is recommended (266).\nHCP who have received 2 doses of vaccine and who are exposed to VZV (varicella, disseminated H Z, and uncovered lesions of a localized HZ) should be monitored daily during days 8-21 after exposure for fever, skin lesions, and systemic symptoms suggestive of varicella. H C P can be monitored directly by occupational health program or infection-control practitioners or instructed to report fever, headache, or other constitutional symptoms and any atypical skin lesions immediately. HCP should be excluded from a work facility immediately if symptoms occur. H C P who have received 1 dose of vaccine and who are exposed to VZV (varicella, disseminated H Z, and uncovered lesions of a localized HZ) (in the community or health-care setting/workplace) should receive the second dose within 3-5 days after exposure to rash (provided 4 weeks have elapsed after the first dose). After vaccination, management is similar to that of 2-dose vaccine recipients. Those who did not receive a second dose or who received the second dose >5 days after exposure should be excluded from work for 8-21 days after exposure.\nUnvaccinated HCP who have no other evidence of immunity who are exposed to VZV (varicella, disseminated H Z, and uncovered lesions of a localized HZ) are potentially infective from days 8-21 after exposure and should be furloughed during this period. They should receive postexposure vaccination as soon as possible. Vaccination within 3-5 days of exposure to rash might modify the disease if infection occurred. Vaccination >5 days postexposure is still indicated because it induces protection against subsequent exposures (if the current exposure did not cause infection). For HCP at risk for severe disease for whom varicella vaccination is contraindicated (e.g., pregnant or immunocomprosed HCP), varicella-zoster immune globulin after exposure is recommended. The varicella-zoster immune globulin product currently used in the United States, VariZIG (Cangene Corporation, Winnipeg, Canada), is available under an Investigational New Drug Application Expanded Access protocol; a sample release form is available at http://www.fda. gov/downloads/BiologicsBloodVaccines/SafetyAvailability/ UCM 176031.pdf. Varicella-zoster immune globulin might prolong the incubation period by a week, thus extending the time during which personnel should not work from 21 to 28 days. In case of an outbreak, H C P without evidence of immunity who have contraindications to vaccination should be excluded from the outbreak setting through 21 days after rash onset of the last identified case-patient because of the risk for severe disease in these groups. If the VZV exposure was to localized H Z with covered lesions, no work restrictions are needed if the exposed HCP had previously received at least 1 dose of vaccine or received the first dose within 3-5 days postexposure. A second dose should be administered at the appropriate interval. H C P should be monitored daily during days 8-21 after exposure for fever, skin lesions, and systemic symptoms suggestive of varicella and excluded from a work facility if symptoms occur. If at least 1 dose was not received, restriction from patient contact is recommended.\n# Diseases for W hich Vaccination Might\nBe Indicated in Certain Circum stances Health-care facilities and other organizations should consider including in their vaccination programs vaccines to prevent meningococcal disease, typhoid fever, and polio for H CP who have certain health conditions or who work in laboratories or regions outside the United States where the risk for workrelated exposure exists.\n# Meningococcal Disease\n\n# Background\n\n# Epidemiology and Risk Factors\nMeningococcal disease is rare among adults in the United States and incidence has decreased to historic lows; during 1998-2007 the average annual incidence of meningococcal disease was 0.28 (range: 0.26-0.31) cases per 100,000 population among persons aged 25-64 years (302).\nRoutine vaccination with meningococcal conjugate vaccine is recommended by ACIP for adolescents aged 11-18 years, with the primary dose at age 11-12 years and the booster dose at age 16 years. In 2010, coverage with meningococcal conjugate vaccine among persons aged 13-17 years was 62.7% (22). Nosocomial transmission of Neisseria meningitidis is rare, but H C P have become infected after direct contact with respiratory secretions of infected persons (e.g., managing of an airway during resuscitation) and in a laboratory setting. HCP can decrease the risk for infection by adhering to precautions to prevent exposure to respiratory droplets (303,304) and by taking antimicrobial chemoprophylaxis if exposed directly to respiratory secretions.\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nTwo quadrivalent (A, C, W-135, Y) conjugate meningococcal vaccines (MCV4) are licensed for persons aged through 55 years (305,306). Both protect against two of the three serogroups that cause the majority of meningococcal disease in the United States and against 75% of disease among adults. Available data indicate that the majority of persons do not have enough circulating functional antibody to be protected >5 years after a single dose of MCV4. Both vaccines had similar safety profiles in clinical trials. Quadrivalent (A, C, W -135, Y) meningococcal polysaccharide vaccine (MPSV4) is available for use in persons aged >55 years. No vaccine for serogroup B meningococcal disease is licensed in the United States.\n# Recommendations\n\n# Vaccination\n\n# M CV4 is not recommended routinely for all HCP\n\n# HCP Recommended to Receive Vaccine to Prevent Meningococcal Disease\nA 2-dose vaccine series is recommended for H C P with know n asplenia or persistent com plem ent com ponent deficiencies, because these conditions increase the risk for meningococcal disease. HCP traveling to countries in which meningococcal disease is hyperendemic or epidemic also are at increased risk for infection and should receive vaccine. Those with known asplenia or persistent complement component deficiencies should receive a 2-dose vaccine series. All other HCP traveling to work to high-risk areas should receive a single dose of M CV4 before travel if they have never received it or if they received it >5 years previously. Clinical microbiologists and research microbiologists who might be exposed routinely to isolates of N. meningitides should receive a single dose of M CV4 and receive a booster dose every 5 years if they remain at increased risk. Health-care personnel aged >55 years who have any of the above risk factors for meningococcal disease should be vaccinated with MPSV4 (305).\n# HCP Who May Elect to Receive Vaccine to Prevent Meningococcal Disease\nH CP with known HIV infection are likely at increased risk for meningococcal disease and may elect vaccination. If these HCP are vaccinated, they should receive a 2-dose vaccine series (307).\n# Booster Doses\nH CP who receive the 2-dose M CV4 vaccine series and/or remain in a group at increased risk should receive a booster dose every 5 years (306).\n# Postexposure Management of Exposed HCP\nPostexposure prophylaxis is advised for all persons who have had intensive, unprotected contact (i.e., without wearing a mask) with infected patients (e.g., via m outh-to-m outh resuscitation, endotracheal intubation, or endotracheal tube management), including HCP who have been vaccinated with either the conjugate or polysaccharide vaccine (3).\nA ntim icrobial prophylaxis can eradicate carriage o f N. meningitidis and prevent infections in persons who have unprotected exposure to patients w ith m eningococcal infections (305). Rifampin, ciprofloxacin, and ceftriaxone are effective in eradicating nasopharyngeal carriage of N. meningitidis. In areas of the United States where ciprofloxacinresistant strains of N. meningitidis have been detected (as of August 30, 2011, only parts of Minnesota and North Dakota), ciprofloxacin should not be used for chemoprophylaxis (308). Azithromycin can be used as an alternative. Ceftriaxone can be used during pregnancy. Postexposure prophylaxis should be administered within 24 hours of exposure when feasible; postexposure prophylaxis administered >14 days after exposure is of limited or no value (305). H C P not otherwise indicated for vaccination may be recommended to be vaccinated with meningococcal vaccine in the setting of a com m unity or institutional outbreak of meningococcal disease caused by a serogroup contained in the vaccine.\n# Typhoid Fever\n\n# Background\n\n# Epidemiology and Risk Factors\nThe incidence of typhoid fever declined steadily in the United States during 1900-1960 and has since remained low. During 1999-2006, on average, 237 cases were reported annually to the National Typhoid and Paratyphoid Fever Surveillance System (309). The median age of patients was 22 years and 54% were male; 79% reported foreign travel during the 30 days before onset of symptoms. Among international travelers, the risk for Salmonella Typhi infection appears to be highest for those who visit friends and relatives in countries in which typhoid fever is endemic and for those who visit (even for a short time) the most highly endemic areas (e.g., the Indian subcontinent) (310).\nIncreasing resistance to flu o ro q u in o lo n es such as ciprofloxacin, which are used to treat multidrug-resistant. S. Typhi, has been seen particularly among travelers to south and southeast Asia (311). Isolates with decreased susceptibility to ciprofloxacin (DCS) do not qualify as resistant according to current Clinical and Laboratory Standards Institute criteria but are associated with poorer clinical outcomes (311,312). Resistance to nalidixic acid, a quinolone, is a marker for DCS and increased from 19% in 1999 to 59% in 2008 (313). Nine isolates resistant to ciprofloxacin also were seen during this time period (313).\nAlthough overall S. Typhi infections have declined in the United States, increased incidence and antimicrobial resistance including resistance to fluoroquinolones have been seen for paratyphoid fever caused by Paratyphi A (314). No vaccines that protect against Paratyphi A infection are available.\n# Transmission and Exposure in Health-Care Settings\nDuring 1985-1994, seven cases oflaboratory-acquired typhoid fever were reported among persons working in microbiology laboratories, only one of whom had been vaccinated (315). Additionally, S. Typhi might be transmitted nosocomially via the hands of infected persons (315).\n# Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nTwo typhoid vaccines are distributed in the United States: oral live-attenuated Ty21a vaccine (one enteric-coated capsule taken on alternate days for a total of four capsules) and the capsular polysaccharide parenteral vaccine (1 0.5 mL intramuscular dose). Both vaccines protect 50% -80% of recipients. To maintain immunity, booster doses of the oral vaccine are required every 5 years, and booster doses of the injected vaccine are required every 2 years. Complication rates are low for both types of S. Typhi vaccines. During 1994-1999, serious adverse events requiring hospitalization occurred in an estimated 0.47 to 1.3 per 100,000 doses, and no deaths occurred (310). However, live-attenuated Ty21a vaccine should not be used among immunocompromised persons, including those infected with HIV (316). Theoretic concerns have been raised about the immunogenicity of live, attenuated Ty21a vaccine in persons concurrently receiving antimicrobials (including antimalarial chemoprophylaxis), viral vaccines, or immune globulin (317). A third type of vaccine, a parenteral heat-inactivated vaccine associated with higher reactogenicity, was discontinued in 2000 (310,318).\n# Vaccination\nM icrobiologists and others who work frequently with S. Typhi should be vaccinated with either of the two licensed and available vaccines. Booster vaccinations should be administered on schedule according to the manufacturers' recommendations.\n# Controlling the Spread of Typhoid Fever\nPersonal hygiene, particularly hand hygiene before and after all patient contacts, will minimize risk for transmitting enteric pathogens to patients. However, H C P who contract an acute diarrheal illness accompanied by fever, cramps, or bloody stools are likely to excrete substantial numbers of infective organisms in their feces. Excluding these H C P from care of patients until the illness has been evaluated and treated can prevent transmission (3).\n# Poliomyelitis\n\n# Background\n\n# Epidemiology and Risk Factors\nIn the United States, the last indigenously acquired cases of poliomyelitis caused by wild poliovirus occurred in 1979, and the Americas were certified to be free of indigenous wild poliovirus in 1994 (319,320). W ith the complete transition from use of oral poliovirus vaccine (OPV) to inactivated poliovirus vaccine (IPV) in 2000, vaccine-associated paralytic poliomyelitis (VAPP) attributable to O PV also has been eliminated (321,322) \n# Transmission and Exposure in Health-Care Settings\nPoliovirus can be recovered from infected persons, including from pharyngeal specim ens, feces, urine, and (rarely) cerebrospinal fluid. H C P and laboratory workers might be exposed if they come into close contact with infected persons (e.g., travelers returning from areas where polio is endemic) or with specimens that contain poliovirus.\n# Recommendations Vaccine Effectiveness, Duration of Immunity, and Vaccine Safety\nBoth IPV and OPV are highly immunogenic and effective when administered according to their schedules. In studies conducted in the United States, 3 doses of IPV resulted in 100% serocoversion for types 2 and 3 poliovirus and 96%-100% for type 1 (326). Imm unity is prolonged and might be lifelong. IPV is well tolerated, and no serious adverse events have been associated with its use. IPV is an inactivated vaccine and does not cause VAPP IPV is contraindicated in persons with a history of hypersensitivity to any component of the vaccine, including 2-phenoxyethanol, formaldehyde, neomycin, streptomycin, and polymyxin B. OPV is no longer available in the United States.\n# Recommendations\n\n# Vaccination\nBecause the majority of adults born in the United States are likely immune to polio as a result of vaccination during childhood, poliovirus vaccine is not routinely recommended for persons aged >18 years. The childhood recommendation for poliovirus vaccine consists of 4 doses at ages 2, 4, and 6-18 months and 4-6 years.\nHowever, vaccination is recommended for H C P who are at greater risk for exposure to polioviruses than the general population, including laboratory workers who handle specimens that might contain polioviruses and H C P who have close contact with patients who might be excreting wild polioviruses, including H CP who travel to work in areas where polioviruses are circulating.\nUnvaccinated H C P should receive a 3-dose series of IPV, with dose 2 administered 4-8 weeks after dose 1, and dose 3 administered 6-12 months after dose 2. H C P who have previously completed a routine series of poliovirus vaccine and who are at increased risk can receive a lifetime booster dose of IPV if they remain at increased risk for exposure. Available data do not indicate the need for more than a single lifetime booster dose with IPV for adults.\n# Controlling the Spread of Poliovirus\nStandard precautions always should be practiced when handling biologic specim ens. Suspect cases require an immediate investigation including collection of appropriate laboratory specimens and control measures. All suspect or confirmed cases should be reported immediately to the local or state health department.\n# Other Vaccines Recom m ended\nfor Adults Certain vaccines are recommended for adults based on age or other individual risk factors but not because of occupational exposure (327). Vaccine-specific ACIP recommendations should be consulted for details on schedules, indications, contraindications, and precautions for these vaccines.\n• to be at increased risk for hepatitis A virus infection because of occupational exposure, including persons exposed to sewage. Hepatitis A vaccine is recommended for person w ith chronic liver disease, international travelers, and certain other groups at increased risk for exposure to hepatitis A.\n# Catch-Up and Travel Vaccination\n\n# Catch-Up Programs\nManagers of health-care facilities should implement catch-up vaccination programs for HCP who already are employed, in addition to developing policies for achieving high vaccination coverage among newly hired HCP HCP vaccination records could be reviewed annually during the influenza vaccination season or concurrent with annual TB testing. This strategy could help prevent outbreaks of vaccine-preventable diseases. Because education, especially when combined with other interventions such as reminder/recall systems and low or no out-of-pocket costs, enhances the success of many vaccination programs, informational materials should be available to assist in answering questions from HCP regarding the diseases, vaccines, and toxoids as well as the program or policy being implemented (120,328). Conducting educational workshops or seminars several weeks before the initiation of a catch-up vaccination program might promote acceptance of program goals.\n# Travel\nHospital personnel and other H C P who perform research or health-care work in foreign countries might be at increased risk for acquiring certain diseases that can be prevented by vaccines recommended in the United States (e.g., hepatitis B, influenza, M M R , T dap , poliovirus, varicella, and meningococcal vaccines) and travel-related vaccines (e.g., hepatitis A, Japanese encephalitis, rabies, typhoid, or yellow fever vaccines) (329). Elevated risks for acquiring these diseases might stem from exposure to patients in health-care settings (e.g., poliomyelitis and meningococcal disease) but also might arise from circumstances unrelated to patient care (e.g., high endemicity of hepatitis A or exposure to arthropod-vector diseases [e.g., yellow fever]). All H C P should seek the advice of a health-care provider familiar with travel medicine at least 4-6 weeks before travel to ensure that they are up to date on routine vaccinations and that they receive vaccinations recommended for their destination (329). Although bacille Calmette-Guérin vaccination is not recommended routinely in the United States, H C P should discuss potential beneficial and other consequences of this vaccination with their health care provider.\n# Work Restrictions\nW ork restrictions for susceptible H C P (i.e., no history of vaccination or documented lack of immunity) exposed to or infected with certain vaccine-preventable diseases can range from restricting individual HCP from patient contact to complete exclusion from duty (Table 5). A furloughed employee should be considered in the same category as an employee excluded from the facility. Specific recommendations concerning work restrictions in these circumstances have been published previously (3,11). The risk for rubella vaccine-associated malformations in the offspring o f women pregnant when vaccinated or who become pregnant w ithin 1 month after vaccination is negligible.11 Such women should be counseled regarding the theoretical basis o f concern for the fetus.\n# vaccine.\nSee table footnotes on page 41 111 Commercial assays can be used to assess disease-induced immunity, but they often lack sensitivity to detect vaccine-induced im m unity (i.e., they m ight yield false-negative results). § § § Verification o f history or diagnosis o f typical disease can be provided by any health-care provider (e.g., school or occupational clinic nurse, nurse practitioner, physician assistant, or physician). For persons reporting a history of, or reporting with, atypical or mild cases, assessment by a physician or their designee is recommended, and one o f the following should be sought: 1) an epidemiologic link to a typical varicella case or to a laboratory-confirm ed case or 2) evidence o f laboratory confirmation if it was performed at the tim e o f acute disease. When such documentation is lacking, persons should not be considered as having a valid history o f disease because other diseases m ight mimic mild atypical varicella. 111 For example, immunocompromised patients or pregnant women. Those who develop acute respiratory symptoms w ith o u t fever should be considered for evaluation by occupational health to determine appropriateness o f contact with patients and can be allowed to work unless caring for patients in a protective environment; these personnel should be considered for temporary reassignment or exclusion from work for 7 days from symptom onset or until the resolution o f all noncough symptoms, whichever is longer. If symptoms such as cough and sneezing are still present, HCP should wear a facemask during patient care activities. The im portance of performing frequent hand hygiene (especially before and after each patient contact) should be reinforced. \nMeasles\n# Acknowledgments\nThe following persons contributed to this report: Rachel J. Wilson, GeoffA. Beckett, M PH, Division ofViral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC; LaDora O. Woods, BS, Carter Consulting, Inc., Atlanta, Georgia."},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":290,"cells":{"id":{"kind":"string","value":"11201a428de3597e55a15b5132d853a4e8b5050d"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"for their support in typing and preparing the document for pub I¡cation. Table 1-1.-Respirator recommendations Average work shift concentration gf radon progeny (WL) Respirator recommendations 0 to 0.083 (1/12) No respirator required >0.083 to 0.42 to i 0.83 Any air-purifying half-mask respirator equipped with a HEPA filter Any SAR equipped with a half mask and operated in a demand (negative-pressure) mode Any more protective respirator >0.83 to 2.08 to 4.15 to 83.0 to 166.0 or unknown concentration or emergency entry Any SCBA equipped with a full facepiece and operated in a pressure demand or other positive pressure mode 2.9 10.0 Any SAR equipped with a full facepiece operated in a pressure demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in a pressure demand or other positive pressure mode 2.9 10.0 Emergency escape Any self-contained self-rescuer (SCSR) NA NA As estimated using the sampling techniques described in Appendix IV. jNA=Not applicable. §HEPA = high-efficiency particulate air. \" S e e appropriated credit factors below. SAR = supplied-air respirator. 'TPAPR = powered air-purifying respirator. *Adapted from Schiager et a l . 1981. 'Used in an instant working level monitor. English 28 13.27 2.11 These studies contain limitations in study design, radon progeny exposure records, smoking history information, followup, etc. Comparisons between these studies, especially for the purposes of risk assessment. 'p<0.05 (some p-values were estimated from the observed lung cancer deaths and the Poisson frequency distribution); rate ratios depend on lung cancer mortality in the comparison population and are sensitive to error in rates that are based on a small number of expected deaths. §The expected number of deaths was estimated from the rate ratios provided by the authors. *Not applicable. The 95% confidence limits of the rate ratios range from 14.4 to infinity. 13. Edling C, Axelson 0. Quantitative aspects of radon daughter exposure and lung cancer in underground miners. Br J Ind Med 1983;40:182-7. 14. Whittemore AS, McMillan A. Lung cancer mortality among U.S. uranium miners: A reappraisal.# FOREWORD\nAs Director of the National Institute for Occupational Safety and Health (NIOSH), I am accustomed to making decisions on difficult issues, but few issues have presented the legislative, scientific, and public health dilemmas that accompany recommending criteria to control the exposure of workers to radon progeny in underground mines.\nThe development of this criteria document is subject to the provisions of two legislative mandates. First, the Occupational Safety and Health Act of 1970 requires safe and healthful working conditions for every working person. The Act further requires NIOSH to preserve our human resources by providing medical and other criteria that will ensure, insofar as practicable, that no worker will suffer diminished health, functional capacity, or life expectancy as a result of work experience . The Act also authorizes NIOSH to recommend new criteria to further improve working conditions Sections 22(c) and (d)].\nIn addition, the Federal Coal Mine Health and Safety Act of 1969 and the Federal Mine Safety and Health Amendments Act of 1977 require NIOSH to develop and revise recommended occupational safety and health standards for mine workers. Specifically, the Secretary of Health, Education, and Welfare (now the Secretary of Health and Human Services) is required to consider, \"in addition to the attainment of the highest degree of health protection for the miner . . . the latest available scientific data in the field, the technical feasibility of the standards, and experience gained under this and other health statutes\" Title 1,Section 101(d)]. These mandates have required NIOSH to weigh its obligation to assure the highest degree of health protection for miners against the technical feasibility of the recommended standard in the development of recommendations for controlling radon progeny exposure in underground mines.\nThe control of exposure to radon progeny presents an unprecedented problem because of the ubiquitous yet variable nature of their presence in mines and the ambient environment. To complicate this matter further, recent reports indicate that an exposure-related health risk may exist at background exposure levels.\nThe full ramifications of this dilemma can easily be appreciated by considering two points. The first is that dilution ventilation (the primary engineering approach to reducing the concentration of radon progeny in mines) is accomplished by the exchange of mine air with air from the outside environment. Obviously, this approach is not a viable option for the total elimination of radon progeny in underground mines because the outside air is also contaminated with radon progeny.\nIn addition, this approach would not be a prudent community environmental public health measure in some situations because it involves releasing an additional burden of radon progeny to the ambient environment and thereby contributing to the background level in the immediate area of the mine. Thus ventilation cannot be used to totally eliminate exposure to radon progeny in mines.\nThe second point to consider in this dilemma is that the variable nature of radon progeny exposure in the ambient environment precludes recommending an annual cumulative exposure limit that includes both occupational and ambient contributions. Because ambient exposure varies, such a recommendation would result in an occupational exposure limit and associated risk that would vary with the locale. This approach is obviously undesirable, for it would lead to a nightmare of confusion and complicated enforcement requirements and would probably result in unequal protection of miners.\nData from both human and animal studies clearly demonstrate a direct link between lung cancer and radon exposure. Specific epidemiological studies provide a basis for quantitatively estimating human risk at various exposure levels. Such analyses clearly show that a radon exposure of 4 WLM (4 working level months) per year over a 30-year working lifetime (the current Mine Safety and Health Administration standard) poses a significant and unacceptable risk of lung cancer. This risk must be substantially reduced.\nIn recommending an exposure limit for radon progeny, NIOSH considered not only the results of its own risk assessment and the technical feasibility of the recommended standard, but also the uncertainty of the data available on risk. Uncertainties are inherent in both the risk assessment methods and the scientific data on which the risk assessment is based. This fact must be understood and acknowledged. Some of the factors involved in these uncertainties include the choice of risk assessment method and model, the measurement methods used for data collection, and risk estimates derived from data that are heavily weighted with higher exposures.\nThe first of these factors in risk uncertainty involves the choice of a risk assessment method and/or model (such as the Cox proportional hazards model used in the NIOSH risk assessment study). NIOSH has attempted to develop a mathematical model that best describes the lung cancer risk in miners exposed to radon progeny. The use of a risk assessment model is merely a practical way to work with a very complex problem. There are modeling approaches other than the one chosen for this study. Each choice would result in a somewhat different description of the relationship between radon progeny exposure and lung cancer risk. NIOSH has attempted to compare the alternatives that are available and applicable. NIOSH scientists have considered the differences that might arise through a review of the available scientific literature and discussions with other scientists who have evaluated this exposure-related lung cancer risk.\nAlthough alternative models might yield minimally different quantitative risk estimates, none of them would lead the Institute to a qualitatively different risk assessment (i.e., that exposures to radon progeny at the current standard are associated with excesses of lung cancer).\nThe second factor involved in risk uncertainty is the measurement method used for data collection. This study involves a follow-up period of more than 35 years, more than 3,000 miners, and thousands of measurements. The older data are subject to greater uncertainty than the more recent data because of improvements in the entire measurement process over the course of the study.\nThe third factor involved in risk uncertainty is the process of generating risk estimates at lower exposure levels. One consideration is that such risk estimates are derived from data heavily weighted by higher exposures (note that the annual cumulative exposures of most miners in this study are higher than either the current MSHA standard or the proposed NIOSH recommended exposure limit ). Another consideration is the desirability of placing occupational risk in the context of background exposure risk. However, the latter has not been evaluated and would have to be estimated on the basis of occupational data. We therefore do not believe that it is currently possible to contrast these two types of risks. Nonetheless, EPA has generated some initial information on background exposure risk in A Citizen's Guide to Rad o n . This document indicates that action should be taken to lower radon progeny levels in homes with measured concentrations of 0.02 WL or greater. NIOSH estimates that this concentration would probably result in a cumulative exposure that is less than 1 WLM but within an order of magnitude of that value. New information is clearly needed on background exposure levels and the hazards associated with such exposure before occupational and nonoccupational risks can be reliably quantified and validly contrasted. Until these data are available, the final target exposure limits cannot be identified for control of this hazard in our total environment. The uncertainties in the data and a recent study commissioned by the Bureau of Mines on the feasibilities of controlling radon progeny levels in mines have been weighed along with the available evidence and the obligations of NIOSH. This process has resulted in an REL of 1 WLM per year. Our own quantitative risk assessment clearly shows that significant health risks are posed by an exposure level of 1 WLM per year over a 30-year working lifetime. NIOSH therefore regards this REL as an upper limit and further recommends that mine operators limit exposure to radon progeny to the lowest levels possible.\nIn addition, NIOSH wishes to emphasize that this recommended standard contains many important provisions in addition to the annual exposure limit. These include recommendations for limited work shift concentrations of radon progeny, sampling and analytical methods, recordkeeping, medical surveillance, posting of hazardous information, respiratory protection, worker education and notification, and sanitation. All of these recommendations help minimize risk.\nIn summary, NIOSH has the legislative, scientific, and public health responsibility to protect the health of miners by developing recommendations that eliminate or minimize occupational risks, recommended exposure limit of 1 WLM per year, I of the recommended standard fully satisfies the Although I am approving the do not feel that this part Institute's commitment to protect the health of all of the Nation's miners.\nFuture research may provide evidence of new and more effective methods for reducing occupational exposures to radon progeny, more reliable risk estimates at low exposure levels, and improved risk assessment methods.\nIf new information demonstrates that a lower exposure limit constitutes both prudent public health and a feasible engineering policy, NIOSH will revise its recommended standard.\n\n# I. RECOMMENDATIONS FOR A RADON PROGENY STANDARD\nThe National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to radon progeny in underground mines be controlled by compliance with this recommended standard, which is designed to protect the health of underground miners over a working lifetime of 30 years. Mine operators should regard the recommended exposure limit for radon progeny as the upper boundary for exposure; they should make every effort to limit radon progeny to the lowest possible concentrations. This recommended standard will be reviewed and revised as necessary.\nRadon progeny (also known as radon daughters) are the short-lived decay products of radon, an inert gas that is one of the natural decay products of uranium. The short-lived radon progeny (i.e., polonium-210, lead-214, bismuth-214, and polonium-214) are solids and exist in air as free ions or as ions attached to dust particles. The NIOSH recommended exposure limit (REL) is based on (1) evidence that a substantial risk of lung cancer is associated with an occupational exposure to radon progeny, and (2) the technical feasibility of reducing exposures.\nIn this document, NIOSH presents recommendations that will protect miners employed year-round at any mine work area for as long as 30 years (the period of time used by MSHA as a miner's working lifetime). The exposure limit contained in this recommended standard is measurable by techniques that are valid, reproducible, and available to industry and government agencies. NIOSH has concluded that current technology is sufficient to achieve compliance with the recommended standard.\nBecause knowledge of the carcinogenic process is incomplete and no data exist to demonstrate a safe level of exposure to carcinogens, NIOSH maintains that occupational exposure to carcinogens such as radon progeny should be reduced to the lowest level technically achievable. Compliance with this standard does not relieve mine operators from complying with other applicable standards.\n\n# S ection 1 -D e fin itio n s ( a ) Miner\nMiners include all mine personnel who are involved with any underground operation (e.g., drilling, blasting, haulage, and maintenance).\n\n# (b ) Working Level\nOne working level (WL) is any combination of short-lived radon progeny in 1 liter (L) of air that will ultimately release 1.3 x 10^ million electron volts (MeV) of alpha energy during decay to lead-210.\n\n# ( c ) Working Level Month\nA working level month (WLM) is the product of the radon progeny concentration in WL and the exposure duration in months. For example, if a miner is exposed at a concentration of 0.083 WL for 1 month 1 (170 hours ),- then the cumulative exposure for the month is 0.083 WLM.\nIf the cumulative exposure of the same miner is 0.083 WLM for each of 12 consecutive months (2,040 hr), then the cumulative exposure for the year is 1 WLM.\n\n# (d ) Work Area\nA work area is any stope, drift heading, travelway, haulageway, shop, station, lunchroom, or any other underground location where miners work, travel, or congregate.\n\n# ( e ) Average Work S h if t C oncentration\nThe average work shift concentration is the average concentration of radon progeny present during a work shift in a given area. This concentration is used to represent the miner's breathing zone exposure to radon progeny.\n\n# Section 2 -Environment (Workplace A i r ) ( a ) Recommended Exposure L im it (REL)\nExposure to radon progeny in underground mines shall not exceed 1 WLM per year, and the average work shift concentration shall not exceed 1/12 of 1 WL (or 0.083 WL). The REL of 1 WLM per year is an upper limit of cumulative exposure, and every effort shall be made to reduce exposures to the lowest levels possible.\n\n# (b ) Sampling and A nalysis\nGrab samples for radon progeny in the workplace shall be taken and analyzed using working level monitors, the Kusnetz method, or any other method at least equivalent in accuracy, precision, and sensitivity. Sampling and analytical methods are described in Chapter II. Details of the recommended sampling strategy are contained in Appendix IV. The recommended sampling strategy allows the use of grab samples for estimating the average work shift concentration of radon progeny.\n\n# Section 3 -M onitoring and Recording Exposures ( a )\nExposure M onitoring All operators of underground mines shall perform environmental evaluations in all work areas to determine exposures to radon progeny.\n(1) An initial environmental evaluation shall be conducted in each work area to determine the average work shift concentration of radon progeny.\n*Note that Mine Safety and Health Administration (MSHA) regulations are based on 173 hr per month.\n(2) Periodic environmental evaluations shall be conducted at intervals (as described in Appendix IV) in each work area. An alternative sampling strategy may be used if the mine operator can demonstrate that it effectively monitors exposure to radon progeny.\n(3) If environmental monitoring in a work area indicates that the average work shift concentration of radon progeny exceeds 1/12 WL (as described in Appendix IV), the mine operator shall prepare an action plan describing the types of engineering controls and work practices that will be implemented to reduce the average work shift concentration in that area.\n\n# (b ) Exposure M onitoring Records\nThe mine operator shall determine and record the exposure to radon progeny.\nEach miner's exposure shall be calculated using monitoring data obtained for the areas in which the miner worked. These records shall include (1) locations, dates, and times of measurements, (2) sampling and analytical methods used, (3) the number, duration, and results of the samples taken, and (4) all items required by Sections 3(b) (2) and (3). All records shall be retained at the mine site or nearest mine office as described in Section 10.\n( 1 ) C a lc u la tin g the M in e r's D a ily Exposure\nThe average work shift concentration of radon progeny for each work area shall be used to calculate each miner's daily exposure.\nIf no monitoring has been conducted in a work area on a particular day, the daily average work shift concentration for that area shall be determined by averaging the results obtained on the last day of monitoring with the results from the next day that monitoring is conducted.\nA miner's exposure (in WLM) for a given area is calculated as foI lows:\nWLM = WL x T 170 hr\nwhere WL is the average work shift concentration of radon progeny, T is the total time (hours) spent in the area, and 170 is the number of hours worked per month.\nA miner's total cumulative exposure for the year is the sum of the daily exposures (as calculated above) for all work areas in which time was spent during the work shift.\n\n# ) Uranium Mines\nExposure to radon progeny shall be recorded daily for each uranium miner. These records shall include the miner's name, social security number, the time spent in each work area, estimated exposure to radon progeny for each work area as determined in Section 3(b) (3), and (if applicable) the type of respiratory protection and duration of its use.\n(3) Nonuranium Mines Exposure to radon progeny shall be recorded daily for all miners assigned to work in areas where environmental monitoring for radon progeny is required as described in Appendix IV. These exposure monitoring records shall include the miner's name, social security number, time the miner has spent in each work area, estimated exposure to radon progeny for each work area as determined in Section 3(b) (3), and (if applicable) the type of respiratory protection used and the duration of its use.\n(4) Respirator Credit\nThe type of respirator worn and the credit given for wearing it (see Section 7) shall be recorded for each miner. Mine operators shall record both the average work shift concentration of radon progeny and the adjusted exposure concentration calculated by using the respirator credit. The adjusted exposure concentration shall be used to determine the miner's cumulative exposure for compliance with the REL of 1.0 WLM/year. Section 4 -Medical Surveillance (a) General (1) The mine operator shall institute a medical surveillance program for all miners.\n(2) The mine operator shall ensure that all medical examinations and procedures are performed by or under the direction of a Iicensed physician.\n(3) The mine operator shall provide the required medical surveillance at a reasonable time and place without loss of pay or cost to the miners.\n(4) The mine operator shall provide the following information to the physician performing or responsible for the medical surveillance program: a copy of the radon progeny standard, the miner's duration of employment, the miner's cumulative exposure to radon progeny (or an estimate of potential exposure to radon progeny if the miner is a new employee), a description of the miner's duties as they relate to his exposure, and a description of any protective equipment the miner has used or may be required to use.\n(5) The mine operator or physician shall counsel tobacco-smoking miners about their increased risk of developing lung cancer from the combined exposure to tobacco smoke and radon progeny. The mine operator or physician shall encourage the miner to participate in a smoking cessation program. The mine operator shall enforce a policy prohibiting smoking at the mine site. (6) The physician shall provide the mine operator and the miner with a written statement describing any medical conditions found during the preplacement or periodic medical examinations that may increase the miner's health risk when exposed to radon progeny. This written statement shall not reveal specific findings, but shall include any recommended limitations on the miner's exposure to radon progeny or ability to use respirators and other personal protective equipment.\n\n# (b ) Preplacement Medical Examination\nThe preplacement medical examination of each miner shall include the foI lowing:\n(1) A comprehensive medical and work history (including smoking history) that emphasizes the identification of existing medical conditions and attempts to elicit information about previous occupational exposure to radon progeny.\n(2) A thorough examination of the miner's respiratory system, including pulmonary function tests. The initial and subsequent pulmonary function tests shall include determination of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV-j) using the current American Thoracic Society (ATS) recommendations on instrumentation, technician training, and interpretation. A prospective miner with symptomatic, spirometric, or radiographic evidence of pulmonary impairment should be counseled about the risks of continued exposure.\n(3) A posterio-anterior chest X-ray using the current ATS recommendations on instrumentation, technician training, and interpretat ion.\n(4) Other tests deemed appropriate by the physician.\n\n# ( c ) P e rio d ic Medical Examination\nThe periodic medical examination for each miner shall include the fotlowing:\n(1) An annual update of medical and work histories (including smoking history).\n(2) An evaluation of the miner's respiratory system. Because of the potential for chronic respiratory disease, this evaluation shall include spirometry at intervals determined by the physician.\nMiners that have spirometric or radiographic evidence or symptoms of pulmonary impairment should be counseled by the physician regarding the risks of continued exposure.\n(3) A posterio-anter¡or chest X-ray at intervals determined by the physician using the current ATS recommendations on instrumentation, technician training, and interpretation. Periodic chest X-rays are recommended for monitoring miners exposed to fibrogenic respiratory hazards (e.g., quartz). Ordinarily, chest X-rays may be obtained every 5 years for the first 15 years of employment and every 2 years thereafter, depending on the nature and intensity of exposures and their related health risks. A recent X-ray obtained for other purposes (e.g., upon hospitalization) may be substituted for the periodic X-ray if it is of acceptable quality.\n(4) Other tests deemed appropriate by the physician.\n\n# Section 5 -Posting\nAll warning signs shall be printed in both English and the predominant language of non-Eng Iish-reading miners. Miners unable to read the posted signs shall be informed verbally about the hazardous areas of the mine and the instructions printed on the signs.\n(a) Readily visible signs containing the following information shall be posted at mine entrances or in work areas that require environmental monitoring for radon progeny as described in Appendix IV:\n\n# AUTHORIZED PERSONNEL ONLY DANGER! POTENTIAL RADIATION HAZARD RADON PROGENY\n(b) If respiratory protection is required, the following statement shall be added in large letters to the sign required in Section 5(a):\n\n# RESPIRATORY PROTECTION REQUIRED IN THIS AREA Section 6 -Work P ra c tic e s and Engineering C ontrols\nEffective work practices and engineering controls shall be instituted by the mine operator to reduce the concentration of radon progeny to the lowest technically achievable limit. Since there is no typical mine and each operation has some unique features, the work practices and engineering controls in this section may need to be adapted for use in particular si tuat ions. Examples of effective ore extraction and handling procedures include the following: minimizing the number of ore faces simultaneously exposed, performing retreat mining toward intake air, limiting the underground storage and handling of ore, locating ore transfer points away from ventilation intakes, removing dust spilled from ore cars, minimizing ore spillage by maintaining roadways and carefully loading haulage vehicles, and covering ore until it is moved to the surface.\n( 2 ) B la s tin g\nBlasting should be performed at the end of the work shift whenever possible. Miners shall be evacuated from exhaust drifts until environmental sampling confirms that the average work shift concentration of radon progeny does not exceed 1/12 WL. Refer to Section 7 if respiratory protection is required for subsequent reentry.\n( 3 ) Worker R o tatio n\nThe mine operator shall not use the planned rotation of miners to maintain an individual's exposure below the REL of 1.0 WLM per year. NIOSH acknowledges, however, that some miners may inadvert ently be exposed to short-term high concentrations of radon progeny. For example, such exposures may occur when engineering controls fail. To ensure that the miners' cumulative exposure remains below the REL in such circumstances, it may be necessary to transfer them to other jobs or work areas that have lower concentra tions of radon progeny. Miners transferred under these circum stances shall retain their pay as prescribed for coal miners under Section 203(b) of the Federal Coal Mine Safety and Health Act of 1977.\n\n# (b ) Engineering C o ntrols\nMechanical exhaust ventilation used alone or in combination with other engineering controls and work practices can effectively reduce exposures to radon progeny. Ventilation systems discharging outside the mine shall conform with applicable local, State, and Federal air pollution regulations and shall not constitute a hazard to miners or to the general population.\n(1) Ductwork shall be kept in good repair to maintain designed airflows. The effectiveness of mechanical ventilation systems shall be determined periodically and as soon as possible after any significant changes have been made in production or control. A log shall be kept showing designed airflow and the results of all airflow measurements.\n(2) Fans shall be operated continuously in the work areas of an active mine and before the opening of a previously inactive mine or inactive section until environmental sampling confirms that the average work shift concentrations of radon progeny do not exceed 1/12 WL. Refer to Section 7 if respiratory protection is required.\n*Code of Federal Regulations. See CFR in references.\n(3) Fresh air shall be provided to miners in dead end areas near the working faces.\n(4) Bulkheads, backfill, and sealants shall be used to control exposures as appropriate.\nAppendix III provides a general discussion of engineering control methods.\nS ection 7 -R e s p ira to r S e le c tio n and C re d it fo r R e s p ira to r Use ( a ) General C onsiderations NIOSH has determined that a radon progeny exposure limit of 1.0 WLM per year is technically achievable in mines through the use of effective work practices and engineering controls. Over a 30-year working lifetime, this exposure limit will reduce but not eliminate the risk of lung cancer associated with exposure to radon progeny. NIOSH considers respirators to be one of the last options for worker protection. Work practices and engineering controls are more effective means for limiting exposures and providing a safe environment for all workers. Respirator use in underground mines is not always practical for a number of reasons, including the additional physiological burden and safety hazards they pose. NIOSH therefore recommends that engineering controls and work practices be used where technically achievable to control the exposure of miners to radon progeny.\nCompliance with an exposure limit of 1.0 WLM per year requires an average exposure of 1/12 WL throughout the year to ensure that the miner can work for an entire year (i.e., 2,040 hr). For average work shift concentrations above 1/12 WL, NIOSH recommends mandatory respirator use as well as the implementation of engineering controls and work practices to reduce exposure to radon progeny.\nOccupational exposure to radon progeny above background concentrations has been associated with excess lung cancer risk. Therefore, regardless of the exposure concentration, NIOSH advises the use of respirators to further reduce exposure and decrease the risk of lung cancer.\nRespiratory protection shall be used by miners (1) when work practices and engineering controls are not adequate to limit average work shift concentrations of radon progeny to 1/12 WL, (2) when entering a mine area where concentrations of radon progeny are unknown, or (3) during emergencies. Use only those respirators approved by NIOSH or the Mine Safety and Health Administration (MSHA).\n\n# (b ) R e s p ira to r P ro te c tio n Program\nWhenever respirators are used, a complete respiratory protection program shall be instituted. This program must follow the recommendations contained in ANSI Z88. (published by the American National Standards Institute) and the respirator-use criteria in 30 CFR 57.5005.\nThe respiratory protection program described in ANSI Z88.2-1969 requires the following:\n(1) A written program for respiratory protection that contains standard operating procedures governing the selection and use of respi rators.\n(2) Periodic worker training in the proper use and limitations of respi rators.\n(3) Evaluation of working conditions in the mine.\n(4) An estimate of anticipated exposure.\n(5) An estimate of the physical stress that will be placed on the miner. A detailed medical examination of each miner shall be conducted according to the guidelines set forth in Appendix V. (6) Routine inspection, maintenance, disinfection, proper storage, and evaluation of respirators. (7) Information concerning the manufacturers' instructions for respirator fit-testing and proper use.\n\n# ( c ) R e s p ira to r S e le c tio n\nNIOSH makes the following recommendations for respirator selection:\n(1) A respirator is not required for exposure to average work shift concentrations less than or equal to 1/12 WL.\n(2) For exposure to average work shift concentrations greater than 1/12 WL, NIOSH recommends those respirators listed in Table 1-1. (3) For entry into areas where radon progeny concentrations are unknown or exceed 166 WL, or for emergency entry, NIOSH recommends only the most protective respirators (any full-facepiece, positive-pressure, self-contained breathing apparatus or full-facepiece, positive-pressure, supplied-air respirator and SCBA combinat ion).\nThese recommendations are based on the fact that radon progeny exist as particulates and that miners are not exposed to hazardous concentrations of nonparticulate contaminants.\nIf protection against nonparticulate contaminants is required, different types of respirators must be selected.\n\n# (d ) C re d it fo r R e s p ira to r Use\nWhen respirators are worn properly, the miner's average work shift exposure can be reduced by a factor that depends on the class of respirator worn. Table 1-1 provides the credit factors for the various classes of respirators. For example, if a miner wears a helmet-type, powered, air-purifying respirator (PAPR) for 65% of the work shift and the radon progeny concentration in the work area is 0.3 WL, then the miner's exposure can be adjusted by dividing 0.3 WL by 2.7, the credit factor for this class of respirator. This results in an adjusted exposure of 0.11 WL for that miner. Respirator credit is discused in detaiI in Chapter 11.\n\n# S ection 8 -Inform ing Workers o f the Hazards o f Radon Progeny ( a ) N o tific a t io n o f Hazards\nThe mine operator shall provide all miners with information about workplace hazards before job assignment and at least annually thereafter.\n( b ) T ra in in g (1) The mine operator shall institute a continuing education program conducted by persons with expertise in occupational safety and health. The purpose of this program is to ensure that all miners have current knowledge of workplace hazards, effective work practices, engineering controls, and the proper use of respirators and other personal protective equipment. This program shall also include a description of the general nature of the environmental and medical surveillance programs and the advantages of participating in them. This information shall be kept on file and be readily available to miners for examination and copying. The mine operator shall maintain a written plan of these training and surveillance programs.\n(2) Miners shall be instructed about their responsibilities for following proper work practices and sanitation procedures necessary to protect their health and safety.\n\n# S ection 9 -S a n ita tio n ( a ) E ating and D rinking\nThe preparation, storage, dispensing (including vending machines), or consumption of food shall be prohibited in any area where a toxic material is present. The mine operator shall provide facilities so that miners can wash their hands and faces thoroughly with soap or mild detergent and water before eating or drinking.\n\n# (b ) Smoki ng\nSmoking shall be prohibited in underground work areas.\n\n# ( c ) To i I e t Fac i I i t i es\nThe mine operator shall provide an adequate number of toilet facilities and encourage the miners to wash their hands thoroughly with soap or mild detergent and water before and after using these facilities.\n\n# (d ) Change Rooms\n(1) The mine operator shall provide clean change rooms for the miners.\n(2) The mine operator shall provide storage facilities such as lockers to permit the miners to store street clothing and personal i terns.\n\n# ( e ) Showers\nThe mine operator shall provide showers and encourage the miners to shower at the end of the work shift.\n\n# ( f ) Laundering\n(1) The mine operator shall provide for the cleaning, laundering, or disposal of contaminated work clothing and equipment.\n(2) The mine operator shall ensure that contaminated work clothing or equipment that is to be cleaned, laundered, or disposed of is placed in a closed container to prevent dispersion of dust.\n(3) Any person who cleans or launders this contaminated work clothing or equipment must be informed by the operator that it may be contaminated with radioactive materials.\n\n# S ection 10 -Recordkeeping Requirements\n( a ) Record R etention (1) The mine operator shall retain all records of the monitoring required in Section 3(b).\n(2) All monitoring records shall be retained for at least 40 years after termination of employment.\n(3) The mine operator shall retain the medical records required by Section 4. These records shall be retained for at least 40 years after termination of employment.\n\n# (b ) A v a il a b i l it y o f Records\nThe miner shall have access to his medical records and be permitted to obtain copies of them. Records shall also be made available to former miners, or their representative and to the designated representatives of the Secretary of Labor and the Secretary of Health and Human Services.\n\n# ( c ) T ran s fer o f Records\n(1) Upon termination of employment, the mine operator shall provide the miner with a copy of his records specified in Section 10(a).\n(2) Whenever the mine operator transfers ownership of the mine, all records described in this section shall be transferred to the new operator, who shall maintain them as required by this standard.\n(3) Whenever a mine operator ceases to do business and there is no successor, the mine operator shall notify the miners of their rights of access to those records at least 3 months before cessation of business.\n(4) The Director of NIOSH shall be notified in writing before (a) a mine operator ceases to do business and there is no successor to maintain records, and (b) the mine operator intends to dispose of those records.\n(5) No records shall be destroyed until the Director of NIOSH responds in writing to the mine operator.\nII.\n\n# INTRODUCTION\n\n# A. Scope\nRadon is a gas that diffuses continuously from surrounding rock and broken ore into the air of underground mines, where it may accumulate; radon may also be carried into mines through groundwater containing dissolved radon . Radon gas may be inhaled and immediately exhaled without appreciably affecting the respiratory tissues. However, when attached or unattached radon progeny are inhaled, they may be deposited on the epithe lial tissues of the tracheobronchial airways. Alpha radiation may subse quently be emitted into those tissues from polonium-218 and polonium-214, thus posing a cancer risk to miners who inhale radon progeny.\nThis document presents the criteria and recommendations for an exposure standard that is intended to decrease the risk of lung cancer in miners occupationally exposed to short-lived, alpha-emitting decay products of radon (radon progeny) in underground mines. The REL for radon progeny applies only to the workplace and is not designed to protect the population at large. The REL is intended to ( 1) protect miners from the development of lung cancer, (2) be measurable by techniques that are valid, reproducible, and available to industry and government agencies, and (3) be technically ach i evabIe.\n\n# B. Current Standard\nMSHA has established radiation protection standards for workers in underground metal and nonmetal mines . This standard limits a miner's radon progeny exposure to a concentration of 1.0 WL and an annual cumulative exposure of 4 WLM. Each WLM is determined as a 173-hr cumulative, time-weighted exposure . Smoking is prohibited in all areas of a mine where radon progeny exposures must be determined; respiratory protection is required in areas where the concen tration of radon progeny exceeds 1.0 WL.\nAccording to current MSHA regulations, the exhaust air of underground mines must be sampled to determine the concentration of radon progeny.\n\n# Uran i um M ines\nIf the concentration of radon progeny in the exhaust air of a uranium mine exceeds 0.1 WL, samples representative of a miner's breathing zone must be taken at random times every 2 weeks in each work area (i.e., stopes, drift headings, travelways, haulageways, shops, stations, lunchrooms, or any other place where miners work, travel, or congregate).\nIf concentrations of radon progeny exceed 0.3 WL in a work area, sampling must be done weekly until the concentration has been reduced to 0.3 WL or less for 5 consecutive weeks. Uranium mine operators must calculate, record, and report to MSHA the radon progeny exposure of each underground miner. The records must include the miner's time in each work area and the radon progeny concentration measured in each of those areas.\n\n# Nonuranium Mines\nIf the concentration of radon progeny in the exhaust air of nonuranium mines exceeds 0.1 WL, and if concentrations are between 0.1 and 0.3 WL in an active working area, samples representative of a worker's breathing zone must be taken at least every 3 months at random times until the concentrations of radon progeny are less than 0.1 WL in that area. Samples must be taken annually thereafter.\nIf the concentration of radon progeny exceeds 0.3 WL in a working area, samples must be taken at least weekly until the concentration has been reduced to 0.3 WL or less for 5 consecutive weeks. Operators of nonuranium mines must calculate, record, and report to MSHA the radon progeny exposures of miners assigned to areas with concentrations of radon progeny exceeding 0.3 WL. The records must include the miner's time in each work area and the radon progeny concentration measured in each of those areas.\n\n# C. Uranium Decay S e ries\nFigure 11-1 shows the sequence by which the most abundant isotope of uranium (238u) decays to a radioactively stable isotope of lead (206pb). Radon (222Rn) is an inert gas with a radiologic half-life of 3.8 days; it is a product of the natural decay of radium (226Ra ). When radon decays, alpha particles and gamma radiation are emitted, and an isotope of polonium (218p0 ) ¡s formed. Polonium-218 (218p0 ) anc| j ts decay productslead-214 (214pb), bismuth-214 (214b ' i ), and polonium-214 (214p0 )-are commonly referred to as short-lived radon progeny because they have half-lives of 27 minutes or less (see . Both polonium-218 and polonium-214 emit alpha particles as they decay. The short-lived progeny are solids and exist in air as free ions (unattached progeny) or as ions adsorbed to dust particles (attached progeny).\nBecause it is a gas, radon diffuses through rock or soil and into the air of underground mines, where it may accumulate; radon may also be carried into mines through groundwater containing dissolved radon . Radon may be inhaled and immediately exhaled without appreciably affecting the respiratory tissues. However, when the radon progeny (either attached or unattached) are inhaled, they may be deposited in the epithelial tissues of the tracheobronchial airways, where alpha radiation from polonium-218 and polonium-214 may be subsequently emitted. The quantity of mucus in those airways and the efficiency of its clearance (retrograde ciliary action) into the esophagus are important factors that affect the total radiation absorbed at a specific site within the respiratory tract.\nAlpha particles are energetic helium nuclei. As they pass through tissue, they dissipate energy by the excitation and ionization of atoms in the tissue; it is this process that damages cells. Because alpha particles travel less than 100 micrometers in tissue, intense ionization occurs close to the site of deposition of the inhaled alpha-emitting radon progeny. Beta particles (electrons) and gamma radiation (shortwave electromagnetic radiation) can also cause ionization in tissues, but they travel farther through tissues and dissipate less energy per unit path length than do alpha particles . The beta parti cles and gamma radiation emitted by radon progeny make a negligible contri bution to the radiation dose in the lung .\n\n# D-U n its o f Measure\nThe common unit of radioactivity is the curie (Ci), which is the rate at which the atoms of a radioactive substance decay; 1 Ci equals 3.7 x 10^® disintegrations per second (dps). The picocurie (pCi) corresponds to 3.7 x 10~2 dps. The International System of Units (SI) unit of radio activity is the becquerel (Bq), which is equivalent to 1 dps. Therefore, 1 pCi is equivalent to 0.037 Bq.\nWhen radon gas and radon progeny are inhaled, the radiation exposure is primarily caused by the short-lived radon progeny (polonium-218, lead-214, bismuth-214, and polonium-214, which are deposited in the lung) rather than by the radon gas. Because it was not feasible to routinely measure the individual radon progeny, the U.S. Public Health Service introduced the concept of the working level, or WL . The WL unit represents the amount of alpha radiation emitted from the short-lived radon progeny. One WL is any combination of short-lived radon progeny in 1 liter (L) of air that will ultimately release 1.3 x 10^ million electron volts (MeV) of alpha energy during decay to lead-210. The SI unit of measure for potential alpha energy concentration is joules per cubic meter of air (J/m3 ); 1 WL is equal to 2.08 x 10\"5 J/m3 ,\nThe equilibrium between radon gas and radon progeny must be known in order to convert units of radioactivity (Ci or Bq) to a potential alpha energy concentration (WL or J/m3 ). The equilibrium factor (F) is defined as the ratio of the equilibrium-equivalent concentration of the short-lived radon progeny to the actual concentration of radon in air . When the equilibrium factor approaches 1.0, it means that the concentration of radon progeny is increasing relative to the concentration of radon. At complete radioactive equilibrium (F=1.0), the rate of radon progeny decay equals the rate at which the progeny are produced. Thus the radioactivity of the decay products equals the radioactivity of the radon .\nIn under ground mines, the equilibrium factor mainly depends on the ventilation rate and the aerosol concentration . Values of F ranging from 0.08 to 0.65 are typical in underground mines . Radioactivity and potential alpha energy concentration values at various equilibria are presented in Table 11-1. The common unit of measure for human exposure to radon progeny is the working level month (WLM). One WLM is defined as the exposure of a worker to radon progeny at a concentration of 1.0 WL for a working period of 1 month (170 hr).- The SI unit for WLM is joule-hour per cubic meter of air (J-h/m3 ); 1 WLM is equal to 3.6 x 10-3 J-h/m3 . *Note that MSHA regulations are based on 173 hr per month. *F is defined as the quotient of the equilibrium-equivalent radon progeny activity divided by the radon activity.\nThe rad (radiation absorbed dose) is the unit of measure for the absorbed dose of ionizing radiation. One rad corresponds to the energy transfer of 6.24 x 107 MeV per gram of any absorbing material . The rem (roentgen equivalent man) is the unit of measure for the dose equivalent of any ionizing radiation in man. One rem is equivalent to one rad multiplied by a radiation quality factor (QF). The radiation QF expresses the relative effectiveness of radiation with differing Iinear-energy-transfer (LET) values to produce a given biological effect. The radiation QFs for beta particles and gamma radiation are each approximately 1; the radiation QF for alpha radiation varies from 10 to 20 .\nFor equal doses of absorbed radiation (rads), the dose equivalent (rems) attributed to alpha particles is 10 to 20 times greater than the dose equiva lent attributed to high-energy beta particles or gamma radiation. The SI unit of measure for the dose equivalent is the sievert (Sv). One rem is equal to 0.01 Sv .\n\n# E. Worker Exposure\nIn 1986, 22,499 workers were employed in 427 metal and nonmetal mines in the United States.\nIn the past few years, the number of underground uranium mines operating in the United States has decreased dramatically from 300 in 1980 to 16 in 198416 in . Accordingly, the number of miners employed in these mines has also decreased from 9,076 in 19799,076 in , and to 448 in 1986.\nTable II-2 shows the range in concentrations of airborne radon progeny measured in U.S. underground metal and nonmetal mines from 1976 through 1985 . As illustrated in 38 of the 254 operating underground nonuranium mines sampled during fiscal year 1985 contained concentrations of airborne radon progeny equal to or greater than 0.1 WL in . With an estimated average of 55 workers per mine, approximately 2,090 nonuranium miners were at risk of exposure to radon progeny concentrations equal to or greater than 0. 1 WL in 1985. The gamma radiation exposures of U.S. uranium miners are generally regarded to be less than the whole-body occupational exposure limit of 5 rem (50 mSv) per year .\n\n# F. Measurement Methods fo r A irborne Radon Progeny\n\n# D escrip tio n o f Measurement Methods\n\n# a . Grab Samp I i ng Methods\nGrab sampling methods for measuring airborne radon progeny involve drawing a known volume of air through a filter and counting the alpha or beta radioactivity on the filter during or after sampling. Grab sampling methods used in underground mines are listed in Table II-5.\nIn one-count grab sampling methods such as those used with instant working-level monitors, the radioactivity is determined over a single counting period using a scintillation counter.\nIn two-count methods, the radioactivity is determined over two counting periods, and the ratio of these two measurements is used to calculate the radon progeny concentrations.\nIn a three-count method, radon progeny concentrations are derived from the relative changes in the measurements taken at three 30-minute intervals.\nCritically important factors are the proper calibration of radiation detectors and pumps, filters that precisely fit the equipment, and accurate maintenance of the flow rate during the sampling period. It is also important to prevent the accumulation of radionuclides to avoid contamination of the pump, counting equipment, and filters .\nStatistical uncertainties associated with the various grab sampling methods for radon progeny are presented in Data indi cate that the relative precision of the methods is the same. The major differences are the total time period required for sampling and analysis, the capability of determining exposure concentrations at the work site, and the amount of routine maintenance and cali bration required of the instrumentation.\n\n# b. Continuous M onitoring Methods\nIn continuous monitoring methods, air is sampled continuously, and (as with other methods) the alpha or beta radioactivities are determined over the length of the collection period. Continuous monitoring devices and systems have been described elsewhere . The characteristics and statistical uncertainties for some continuous monitoring methods are presented in Table II-7.\nThe U.S. Bureau of Mines has designed an automated continuous monitoring system in which up to 768 detector stations can be linked to a central control unit. The system was designed to trigger an alarm when airborne radon progeny exceed a specified concentration . Although continuous monitoring methods can provide a rapid estimate of exposure concentrations, placement of the instrumentation in active work areas is difficult and may not always be representative of the exposure in the miner's breathing z o n e .\n\n# c . Personal Dosimeters\nPersonal dosimeters for radon progeny are intended to automatically record a miner's cumulative exposure regardless of fluctuations in radon progeny concentrations. Thus these devices eliminate the need to document work area location and occupancy time. Although several personal dosimeters have been tested in U.S. uranium mines, none are in routine use in this country because of problems in calibration and lack of precision .\n\n# . Pass i ve Dos i meters\nPassive dosimeters rely on the natural migration of attached and unattached radon progeny to the detection area of the device without the use of an air pump. Thin plastic foils sensitive to alpha particles are used as detectors. Although passive dosimeters using track etch foi Is have been studied in under ground mines , such devices are still in the developmental stage .\n\n# Act i ve Dos i meters\nActive dosimeters use a mechanical pump to draw a known volume of air through a filter. The alpha radiation emitted by the radon progeny collected on the filter is counted and recorded automatically. The following dosimeter detectors have been tested for use under mining conditions: thermoluminescent detectors , electronic detectors , and track etch detectors . Active track etch dosimeters are used for radiation monitoring in all underground mines in France .\n\n# d. Factors to Consider When S e le c tin g Measurement Methods\nConcentrations of radon progeny have been reported to vary among the different uranium mines and work areas within each mine . These variations have been attributed to the type of mining process, the grade of ore mined, and the effectiveness of the ventila tion to control exposures. Historically, radon progeny exposures in work areas were measured by grab sampling techniques that used the Kusnetz count method or by the instant working-level monitor. More recently, other methods such as continuous monitors and personal dosimeters have also been used in mines. Personal dosimeter methods are clearly more desirable, but they have not been rigorously tested in U.S. mines, and they have been reported to be unreliable for determining exposures over an 8-to 10-hr work shift . Continuous monitoring methods can rapidly detect changes in radon progeny concentrations and can be equipped with an alarm system that will be activated at preset concentrations. These monitors are often stationed at fixed locations within travelways, haulageways, shops, etc. because of the difficulty of moving and restationing them within active mine areas. Although these monitors do not usually provide adequate data for determining worker exposures, they can signal the occurrence of problems in the ventilation system and identify exposure sources.\nNIOSH believes that the use of instant working-level monitors or the Kusnetz count method will provide reliable estimates of exposure to radon progeny. Other methods at least equivalent in accuracy, precision, and sensitivity can be used (see Table II -6). Any method chosen must be capable of meeting the sampling strategy requirements described in Appendix IV.\n\n# G. R e s p ira to r S e le c tio n and C re d it fo r R e s p ira to r Use\n\n# . R e s p ira to r S e le c tio n\nHistorically, NIOSH has recommended the use of the most protective respirators- when workers are exposed to potential occupational carcinogens . Although cumulative exposure to radon progeny may result in cancer, the use of the most protective respirators may not always be technically feasible or safe in routine underground mining operations. Supplied-air respirators (SARs) that are NIOSH/MSHAcertified provide breathing air from compressors or a cascade system of air-supply tanks and are approved only for use with air lines less than 300 ft long. However, the use of SARs may not be practical in under ground mining operations. The reasons are that it is difficult to provide sufficient quantities of breathing air through air lines over long distances and that the air lines are susceptible to crimping and severing from the movement of mining vehicles and haulage cars on tracks. Furthermore, many underground work areas and passageways in mines are too small and cramped with equipment to accommodate air compressors or large air-supply tanks.\nIn addition to being cumbersome in underground mines because of their size, self-contained breathing apparatuses (SCBAs) weigh as much as 35 lb, and SARs weigh approximately 6 lb. Thus when SCBAs or SARs are worn for extended periods, their additional weight can also cause increased physiological burden in the form of heat stress .\nFinally, NIOSH believes that the routine use of SCBAs and SARs may result in increased injuries in underground mining operations. NIOSH is not aware of any studies specifically dealing with injuries or other safety hazards associated with the use of SARs and SCBAs in mines. However, several studies have shown that obstacles introduced into the workplace result in a significantly increased risk of injury from tripping, slipping, or falling . Because mining is currently one of the most dangerous industries in the United States with regard to occupational deaths and injuries (MMWR 1987, BLS 1987, NIOSH believes that this problem would be exacerbated by the routine use of SCBAs and SARs.\nNIOSH believes that there is sufficient safety and health evidence to recommend against the routine use of SARs and SCBAs for reducing exposure to radon progeny during underground mining operations. Table 1-1 lists the respirators that NIOSH recommends for use against exposure to radon progeny. For average work shift concentrations of radon progeny that exceed 1/12 WL, the recommended respirators include air-purifying respirators with high-efficiency particulate air (HEPA) filters. The HEPA filter media are recommended by NIOSH for use with the air-purifying classes of respirators. These filters are the most *E i ther (1) any self-contained breathing apparatus (SCBA) equipped with a full facepiece and operated in a pressure-demand or other positive-pressure mode, or (2) any supplied-air respirator (SAR) equipped with a full face piece and operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary SCBA operated in a pressure-demand or other positive-pressure mode.\nefficient type of particulate filter available, and they are less susceptible than others to performance degradation resulting from humid storage and use conditions .\n\n# . C re d it fo r R e s p ira to r Use\nA miner's exposure to radon progeny may be less than the average work shift concentration in an area, depending on the class of respirator worn and the percentage of time the respirator is worn properly. This reduced exposure for miners who wear respirators can be calculated by dividing the average work shift concentration of radon progeny by the credit factor (CF) for that class of respirator (see Table 1 -1).\nThe credit factors in Table 1-1 were determined by the following equat ion:\nP- = 1/CF = Pw x tw + Pn x tn\nwhere Pf = the total penetration of radon progeny into the respirator facepiece.\nAPF = the assigned protection factor (a complete listing of the APFs for all classes of respirators can be found in the NIOSH Respirator Decision Logic ).\n\n# CF = the credi t factor\nPw = the penetration of radon progeny while wearing the respirator (i.e., 1/APF) tw = the proportion of time during the work shift that the miner wears the respirator properly Pn = the penetration of radon progeny while not wearing a respirator properly (i.e., 100% or 1.0) tn = the proportion of time during the work shift that the miner does not wear the respirator properly (i.e., 1.0 -tw )\nAn unpublished Canadian study evaluated the proportion of time during the work shift that a group of underground uranium miners properly wore their helmet-type, powered, air-purifying respirators If a m i n e operator can verify to MSHA that respirator utilization is greater than 65%, NI0SH recommends a recalculation of the CFs using this higher utilization rate. However, the highest utilization rate that NIOSH recommends is 90%. The CFs for these extremes of utilization rates are listed in Table 1-1.\n\n# III. BASIS FOR THE RECOMMENDED STANDARD\n\n# A. Assessment o f E ffe c ts 1 . Human Studies a . A ssociation o f Radon Exposure w ith Lung Cancer M o r ta lity\nAppendix I contains the report prepared by NIOSH and submitted to MSHA on May 31, 1985, entitled Evaluation of Epidemiologic Studies Examining the Lung Cancer Mortality of Underground Miners. Several of the epidemiologic studies evaluated in that report demonstrate an association between exposure to radon progeny and lung cancer mor tality in underground uranium miners . The relationship between exposure to radon progeny and lung cancer mortality has also been observed in workers in underground metal mines , iron ore mines , tin mines , fluorspar mines , gold mines , and zinc/lead mines .\nIn addition, some of these studies demonstrate a direct exposure-response relationship between lifetime cumulative exposure to radon progeny and lung cancer mortality .\nStatistically significant standardized mortality ratios (SMRs)- above 400% were observed in three studies in which workers accumulated mean lifetime exposures above 100 WLM . Statistically significant SMRs between 140% and 390% were observed in two other studies in which workers accumulated mean lifetime exposures below 100 WLM and in preliminary findings of a third study in which workers accumulated estimated mean lifetime exposures below 100 WLM .\n\n# b. S y n e rg is tic E ffe c ts o f Other Substances\nAlthough the literature consistently demonstrates an association between lung cancer incidence and exposure to radon progeny, it is possible that some of the miners studied were exposed to other substances as well. These substances may have acted synergistically *The standardized mortality ratio (SMR) is the ratio of the mortality rates of two groups being compared. This ratio is expressed as a percentage and is usually adjusted for age or time differences between the two groups.\nwith radon progeny to potentiate the effects of the radon exposure.\n. Substances with synergistic potential include arsenic , hexavalent chromium, nickel, cobalt ; serpentine ; iron ore dust , and diesel exhaust .\nRisk analyses were performed on data from epidemiologic studies of U.S. uranium miners and Swedish iron ore mine workers . These analyses indicate that the risk of mortality from lung cancer among miners who are exposed to radon progeny is greater among those who smoke cigarettes than those who do not smoke.\n\n# c. R e la tio n o f Lung Cancer Risk to Cumulative Radon Exposure\nSince completion of the NIOSH report (Appendix I), Howe et a l .\n published a study of surface and underground mine workers who had worked in Canada in the Eldorado Lodge Uranium Mine between 1948 and 1980. That cohort included 8,487 workers. Based on these stratified categories the risk of death from lung cancer increased linearly with increasing exposure. For the exposure categories of 5 to 24, 25 to 49, and 50 to 99 WLM, the relative risk was elevated, but the difference from the expected risk for an unexposed population was not statistically significant. For all exposure categories above 100 WLM, the relative risk was significantly elevated (p<0.05); note, however, that the first 10 years of followup were excluded from this calculation. For the total cohort, the relative risk coefficient was 3.28% per WLM, and the absolute risk coefficient was 20.8 per 10® person-years per WLM (any excess mortality within the 10 years following initial exposure was excluded from this calculation).\nTwo additional epidemiologic studies that were not included in the 1985 NIOSH report (Appendix I) have also been reported. Pham et a l .\n studied 1,173 iron mine workers in France who were aged 35 to 55 and who had normal chest X-rays at the beginning of the study period in 1975. Thirteen mine workers who had worked underground for a mean of 25.2 years died of lung cancer between 1975 and 1980; only 3.7 deaths were expected from an age-standardized comparison with French males for this same period (SMR = 351; p<0.05). Although exposure records were not available, the authors estimated that some workers may have received lifetime cumulative exposures to radon progeny in the range of 100 to 150 WLM.\nSo 11i et al. observed 318 niobium mine workers in Norway from 1953 through 1981; 77 of these miners were underground workers. This cohort experienced a total of 12 lung cancer deaths, though only 2.96 deaths were expected on the basis of age-specific rates for Norwegian males (SMR = 405; p<0.001). The underground workers experienced 9 lung cancer deaths whereas only 0.81 were expected on the basis of age-specific rates for Norwegian males (SMR = 1,111; p<0.001). From estimates of total exposure to alpha radiation (based on limited measurements of radon and thoron progeny taken in 1959), the authors determined that the risk of lung cancer increased significantly (p<0.05) with increasing alpha radiation for the exposure categories of 1 to 19, 20 to 79, 80 to 119, and greater than or equal to 120 WLM. The excess absolute risk for those exposed workers was reported to be 50 per 10® person-years per WLM.\nThe epidemiologic studies of lung cancer mortality in mine workers exposed to radon progeny (including those studies discussed in Appendix I) are summarized in Tables III-2 and III-3.\n\n# An i maI Stud i es\na . E ffe c ts o f Exposure to Radon Progeny Chameaud et al. studied the effects of exposure to radon progeny in specific pathogen-free (SPF) Sprague-Dawley rats. A total of 1,800 rats were exposed to radon progeny for 1 to 3 hr per day for 14 to 82 days, yielding an accumulated exposure of 20 to 50 WLM. An additional 600 rats were unexposed. The lung cancer incidence in rats was reported to be directly proportional to their lifetime cumulative exposure to radon progeny. The authors con cluded that the amount of radiation needed to double the natural incidence of lung cancer in these rats was 20 WLM. Reduced life spans were not observed for rats in any of the exposure groups.\nb. R e la tio n o f Lung Cancer Incidence to Radon Progeny Exposure Chameaud et al. determined that the lifetime risk coefficient (uncorrected for life span shortening) for the induction of lung cancers in rats was approximately 140 to 850 x 10~® per WLM for exposures ranging from 20 to 4,500 WLM (Table III -4). This is consistent with the lifetime risk coefficient for lung cancer in humans (150 to 450 x 10\"® per WLM) estimated by the International Commission on Radiological Protection (ICRP) . As shown in Table MI-4, lung cancer incidence in rats increased as cumulative exposure to radon progeny increased. In contrast, the lifetime risk of lung cancer per unit of exposure (WLM) decreased with increasing exposure. These findings agree with those of the NI0SH risk assessment (Appendix II), in which the lifetime cumulative risk of lung cancer per unit of exposure decreased as cumulative exposure increased in underground uranium mine workers.\n\n# c . S y n e rg is tic E ffe c ts o f C ig a r e tte Smoke\nChameaud et a l . studied the ability of radon progeny to initiate lung cancer in groups of 50 SPF Sprague-Dawley rats that were subsequently exposed to cigarette smoke. The chamber concentrations of alpha radiation were 0, 300, and 3,000 WL; these concentrations yielded cumulative dose levels of 0, 100, 500, and 4,000 WLM, respectively, over a 2-month period for those groups of animals. Treatment groups were exposed to a total of 352 hr of cigarette smoke (9 cigarettes/500 L of air for 10 to 15 min per day, 4 days per week for 1 year. Exposure to radon progeny alone demonstrated a directly proportional dose-effect relationship for induction of cancer (500 and 4,000 WLM). However, when a similar period of radon exposure was followed by exposure to cigarette smoke, a dose-related, twofold to fourfold increase occurred in lung cancer incidence. The authors stated that the groups receiving high and medium doses of radon and cigarettes had cancers that were not only larger but were more invasive and metastatic compared with the groups exposed to radon alone. Conversely, neither the cigarette smoke alone nor the low-dose radon progeny exposure (100 WLM) alone induced lung cancer.\nIn a parallel lifetime study, Chameaud et a l . related the sequence of exposure to radon progeny and cigarette smoke to the incidence of lung tumors (cancer incidence was not specified) in groups of 50 SPF Sprague-Dawley rats. One group of rats was exposed to radon progeny only (a cumulative exposure of 4,000 WLM); a second group was exposed first to cigarette smoke and then to radon progeny (4,000 WLM); a third group was exposed to radon progeny (4,000 WLM) and then to cigarette smoke; and a fourth group was exposed to cigarette smoke only. Similar incidences of tumors were observed among the rats exposed to radon progeny only (10 tumors) and those exposed first to cigarette smoke and then to radon progeny (8 tumors).\nIn contrast, when the exposure to radon progeny preceded the exposure to cigarette smoke, the effect was potentiated-that is, 32 rats developed tumors. As stated previously, none of the rats exposed to cigarette smoke only developed lung cancer. No statistical analyses were performed on the results of this study.\n\n# d. S ig n ific a n c e o f Animal Studies\nLife span experiments in animals exposed to radon progeny alone have demonstrated that increasing exposures produce increasing incidences of lung cancer. This finding is similar to those of the epidemio logic studies cited in the preceding section (III, A, 1). Because epidemiologic data are available, these animal data contribute relatively little to the final assessment of risk in humans or to the determination of an REL for exposure to radon progeny. Thus this document discusses only selected animal studies of the carcin ogenic potential of radon progeny. Other studies have examined the sequential or concomitant exposures of rats, dogs, and hamsters to substances other than radon progeny (e.g., uranium ore dust, thorium, and tobacco smoke). Several additional studies (critiqued but not described in this document) confirm the adverse health effects of radon progeny on exposed animals . These animal studies generally confirm the risk of lung cancer reported among workers exposed to radon progeny.\n\n# B. Risk Assessment\nNIOSH studied the lung cancer risk of uranium miners by using data from a U.S. Public Health Service (USPHS) study of white male uranium mine workers from the Colorado Plateau area (Colorado, Arizona, New Mexico, and Utah).\nThat NIOSH risk assessment is described in a report entitled Quantitative Risk Assessment of Lung Cancer in U.S. Uranium Miners, which is reproduced in Appendix II. Appendix I contains a detailed discussion of the USPHS data.\nIn the NIOSH risk assessment, data were analyzed for 3,346 workers who had been followed from 1950 through 1982. By 1982, 1,215 workers had died; 256 of these deaths (21.1%) were due to lung cancer. A generalized version of the Cox proportional hazards model was used to estimate the relative risk of death resulting from lung cancer over a 30-year working lifetime at several cumulative exposure values.\n(The 30-year working lifetime was selected to maintain consistency with the working lifetime commonly described by MSHA.) Relative risk is defined as the ratio of lung cancer mortality in a selected exposed group to lung cancer mortality in a comparison group. The quantitative risk assessment model presented in Appendix II did not include the length of time since the end of the mining exposure, which is a significant predictor of relative risk. This term was subsequently added to the generalized Cox model, and new parameter estimates were computed. The estimates in Tables 111-5 and 111-6 are based on this model. The major difference between the two quantitative risk assessment models is that under the new model, the relative risk estimates increase more rapidly during exposure and decrease more rapidly after exposure.\nThe risk of death resulting from lung cancer increased with increasing lifetime cumulative exposure to radon progeny (Table MI -5); this finding is consistent with Appendix II. This direct relationship has been observed in previous epidemiologic studies . As shown in Table MI-5, the relative risk of 1.57 at 30 WLM corresponds to an average exposure of 1 WLM per year for a working lifetime of 30 years. *Estimates are based on a log-relative risk model fitted to age at initial exposure, time since cessation of exposure, and the natural logarithms of the following variables: cumulative mining and background exposure to radon progeny; cumulative cigarette smoking and background smoking; and rate of exposure to radon progeny. +The approximate 95% confidence limits were calculated by applying the parameters from the quantitative risk assessment model together with their variances and covariances to the lung cancer mortality rates in the Colorado Plateau using an actuarial approach.\nIn addition to receiving workplace exposures to radon progeny, workers were assumed to have received average environmental exposures of 0.4 WLM/year. This is the value derived in the NIOSH risk assessment that led to the best fit of the model to the data. This assumed value is consistent with estimates of exposure to radon progeny for persons living near ore-bearing lands in the United States . The average nonoccupational exposure to radon progeny from natural geologic sources for persons in the United States is approximately 0.2 WLM/year .\nRelative risk modeling is common in the epidemiologic literature (especially in studies with lengthy followup) because the dramatic changes that occur in mortality rates with age and calendar year make absolute risk models extremely complicated. Most relative risk models assume that mortality rates in exposed populations are roughly proportional to the rates in unexposed populations at all ages and calendar periods. Because this assumption often approximates reality over a broad range of ages and calendar periods, the relative risk model can be expressed in a less complex form than absolute risk models (i.e., the relative risk model can be expressed without terms involving age and calendar year).\nExcess lifetime risk estimates for lung cancer mortality have been generated (Table III-6) by applying the relative risk estimates in Table III-5 (see also Appendix II) to the lung cancer and all-causes mortality rates for white males in the Colorado Plateau States. Excess risk is defined as the arithmetic difference between the risk of lung cancer mortality in a selected exposed group and the risk of lung cancer mortality in an unexposed comparison group.\nThe estimated excess lung cancer deaths (i.e., excess lifetime risk) in Table 111-6 were computed by approximating the average of the exposuredetermined relative risk function over 5-year age intervals spanning an entire lifetime. These average relative risks and the corresponding mortality rates for lung cancer and for all causes of death among white males in the Colorado Plateau were used to compute the probability of lung cancer mortality during a lifetime using the National Academy of Sciences actuarial method .\nIt is important to understand the limitations of these risk estimates when examining the values in Table III-6. These limitations include the foIlowi n g :\n- A relatively small portion of the cohort had the observed lower levels of cumulative occupational exposure, and the ability to generate precise point-risk estimates at the lower range of occupational exposure is not as strong. Only 7% of the workers in the cohort had lifetime cumulative exposures below 30 WLM, and only 7 of the 256 lung cancer deaths occurred among workers with lower cumulative exposures.\n- The reliability of these excess lifetime risk estimates depends on (1) the accuracy of the original relative risk estimates and (2) the appropriateness of using lung cancer rates for the general white male population in the Colorado Plateau as an estimate of the background lung cancer rate (i.e., that which would occur in populations exposed only to background levels of radon progeny). This cohort contained no unexposed mine workers from which to estimate background lung cancer rates. Although certain limitations exist in using this type of rate , background lung cancer mortality rates from the general U.S. white male population were used to estimate the background rates for the cohort.\n- The background lung cancer rates were not corrected for cigarette smoking. However, the relative risk estimates used to calculate the lifetime risk estimates were adjusted for smoking. This implies that the lifetime risk estimates are only appropriate for a population with a pattern of smoking similar to that of the white male population of the Colorado Plateau.\nIn developing its recommendations, NIOSH has attempted to compare the risk of occupational exposure to radon progeny with the risk of background exposure in homes (i.e., exposure accruing outside the mining environment).\nThe estimated average background exposure to radon progeny is approximately 0. Given this value for background lung cancer risk, another question that must be considered is to what level it would be reasonable to control occupational risk.\nIn its benzene decision, the U.S. Supreme Court gave the following example as the basis for evaluating the occupational risk of chemically induced leukemia: An exposure associated with 1 excess death per million exposed persons might pose an acceptable risk, whereas an exposure associated with 1 excess death per 1,000 exposed persons would pose a significant risk that should be reduced. This example is useful, but it cannot be strictly applied in all cases because it was offered as an illustration and not a fixed rule.\nIn the specific case of lung cancer risk associated with radon progeny exposure, the example cannot be strictly applied because the background risk of lung cancer is much greater than the risk of leukemia at background exposure levels and because cigarette smoking is known to create a confounding effect that greatly increases risk. An excess of 1 lung cancer death per 1,000 would probably not be detectable in a general population if data were subject to considerable uncertainty, since it would necessitate differentiating between 46 and 45 deaths per 1,000.\nAnother important consideration is the technical feasibility of a given exposure limit. As stated earlier, NIOSH has determined that a cumulative exposure limit of 1 WLM per year is achievable (though some argue that it is not feasible on the basis of economics or current technology). NIOSH has found no evidence that any cumulative exposure lower than 1 WLM per year is feasible. As shown in Table III-6, the occupational exposure limit required to reduce expected lifetime risk to 1 excess lung cancer death per 1,000 miners is approximately 0.1 WLM per year. This cumulative exposure would require an occupational exposure concentration that is less than the concentration associated with a cumulative background exposure of 0.4 WLM per year, assuming background expoure is acquired outside the occupational environment. An occupational exposure limit of 0.1 WLM per year would therefore require average mine concentrations lower than the estimated background exposure concentrations.\nIn view of the preceding factors, the level of uncertainty in available data, and the apparent unfeasibility of limiting cumulative exposures to less than 1.0 WLM per year, it does not seem reasonable to recommend exposure limits that would yield only 1 excess lung cancer death per 1,000 miners.. NIOSH has determined that an exposure limit of 1 WLM is feasible in some mines and that such an exposure limit would substantially reduce risks from those associated with the current MSHA standard. An REL of 1 WLM per year is therefore recommended to substantially reduce risk and to stimulate the implementation and development of engineering and mining techniques to reduce exposure. The enforcement of this recommendation combined with additional health and developmental research may facilitate future exposure reductions and thereby reduce lung cancer risk.\n\n# C. Techn i caI Feas i b i I i ty\nIn a report to the U.S. Bureau of Mines, Bloomster et a l . analyzed the technical feasibility of reducing the airborne concentrations of radon progeny in underground uranium mines. The study included data from 14 underground uranium mines operating during the study period (September 1981to May 1984. The authors concluded that some mines could operate at an annual exposure standard of 2 WLM by using dilution ventilation alone if it was introduced early in the development of the mine and if no contamination of inlet air was present. An extensive engineering analysis of 2 of the 14 mines indicated that it might be feasible to meet an operating standard of 1 WLM by using dilution ventilation in combination with other control methods such as bulkheading, air filtration, and use of sealants. The authors expressed doubt about the technical feasibility of operating these uranium mines at a standard of 0.5 WLM. Appendix III provides descriptions of engineering control methods that may be useful in underground mines.\n\n# D. Recommendati ons\nSeveral schemes exist for identifying and classifying a substance as a carcinogen. For example, the National Toxicology Program (NTP) , the International Agency for Research on Cancer (IARC) , and the Occupational Safety and Health Administration (OSHA) have all considered this problem. NIOSH considers the OSHA classification the most appropriate for use in identifying potential occupational carcinogens and supports the following definition:\nA \"potential occupational carcinogen\" is any substance, or combination or mixture of substances, which causes an increased incidence of benign and/or malignant neoplasms, or a substantial decrease in the latency period between exposure and onset of neoplasms in humans or in one or more experimental mammalian species as the result of any oral, respiratory, or dermal exposure, or any other exposure which results in the induction of tumors at a site other than the site of administration .\nThis definition also includes any substance that mammals may potentially metabolize into one or more occupational carcinogens.\nThe epidemiologic data examined by NIOSH demonstrates that occupational exposure to radon progeny in underground mines has the potential for causing lung cancer in miners (see Appendix I) . These human data are supported by a number of studies in which various animal species exposed to radon progeny also developed lung cancer . Furthermore, the NIOSH risk assessment presented in Appendix II, which was based on the human studies, clearly demonstrates that a relationship exists between cumulative radon progeny exposure and the risk of developing lung cancer. The risk assessment shows that as cumulative exposure decreases, the risk of developing cancer decreases.\nIn arriving at an REL, NIOSH attempts to identify that exposure at which no worker will suffer material impairment of health or functional capacity.\nIn the case of radon progeny, this task is difficult because the NIOSH risk assessment shows that even with an exposure of 0.5 WLM per year (15 WLM for a 30-year cumulative exposure) or below, the risk of developing lung cancer increases (see Table III-4 and Appendix II).\nThese results indicate that NIOSH should recommend an annual cumulative exposure limit well below 0.5 WLM, but NIOSH must also consider the technical feasibility of the REL.\nIn previous NIOSH recommendations for the control of carcinogens, technical feasibility has often been interpreted as the ability to quantitate exposure; however, those recommendations were intended for use by nonmining industries where product substitution and engineering and process controls are generally more feasible.\nData from 1984 indicate that 94.4% of the workers in U.S. underground uranium mines accumulated annual radon progeny exposures of less than 2 WLM .\nInformation obtained from the Bureau of Mines indicates that it is now technically feasible to achieve an annual radon progeny concentration of 1.0 WLM. NIOSH therefore recommends that cumulative exposure to radon progeny be limited to 1.0 WLM per year. This recommendation is intended to protect the health of America's underground miners, but it is tempered by the fact that currently it is not technically feasible to achieve annual exposures lower than 1.0 WLM using work practices and engineering controls.\nTo meet the NIOSH recommendation for an annual cumulative exposure of 1 WLM and to assure that mining is a viable year-long occupation, NIOSH believes that the daily average work shift concentration of radon progeny should not exceed 1/12 WL in any work area. Although adherence to the NIOSH REL will significantly reduce the risk of lung cancer in underground mine workers, it will not eliminate it.\nNo effective medical procedure currently exists to treat lung cancer caused by exposure to radon progeny. Furthermore, it has been demonstrated that exposure to both radon progeny and tobacco smoke result in a combined lung cancer risk that is greater than the risk posed by radon progeny or smoke alone. Thus it should be noted that the interaction between radon progeny and smoking is at a minimum additive, and more likely multiplicative. Cigarette smoking should therefore be emphasized as an even greater detriment to mine workers exposed to radon progeny than it is to the general public. The implementation of smoking cessation programs should reduce the incidence of lung cancer in underground mine workers.\nBecause radon progeny are ubiquitous, exposure cannot be totally eliminated. For U.S. residents, the average annual nonoccupational exposure to radon progeny from natural geologic sources is approximately 0.2 WLM, and annual occupational exposures may be considerably higher. The REL of 1 WLM per year is not designed for the population at large, and no extrapolation is warranted beyond occupational exposures in underground metal or nonmetal mines. The REL is designed only for the radon progeny exposures of underground metal and nonmetal mine workers as applicable\n\n# IV. RESEARCH NEEDS\nThe following research is needed to further reduce the risk of lung cancer development from occupational exposure to radon progeny.\n\n# A. Epidem iologic S tudies\nNeeds for epidemiological studies have been identified as follows:\n- A need exists for a followup study of the U.S. miner cohort from the original Public Health Service study to explore the risk of lung cancer among nonsmoking miners exposed to low concentrations of radon progeny. NIOSH is currently resurveying this cohort to update exposure histories and gather additional information on smoking behavior, dietary practices, and tumor cell types.\n- A study is needed to determine whether radon gas itself or other contaminants that might be found in uranium mines are associated with increased morbidity and mortality.\n- An epidemiologic study of injuries is needed in the mining industry to identify safety-related problems, since this industry has one of the highest injury rates in the United States. Particular emphasis should be given to whether or not respirator use is associated with an increased injury and health risk. This investigation should examine slips, trips, falls, and heart attacks.\n\n# B. Engineering C o ntrols and Work P ra c tic e s\nResearch should be conducted to develop more effective control technology methods for reducing exposure to radon progeny to less than 1 WLM. A control technology assessment of the uranium mining industry will assist in this effort by examining existing state-of-the-art technologies and work practices and by recommending new methods for controlling exposure to radon progeny.\n\n# C. R e sp ira to ry P ro te c tio n\nThe following two types of research are recommended for respiratory protect ion:\n- Research should be conducted to determine the extent of gamma radiation emitted from particles trapped on high-efficiency particulate air (HEPA) filters used on air-purifying respirators.\n- A study should also be conducted to evaluate the physiological stress placed on miners who must wear respiratory protection. This study should be conducted both in the laboratory and in the mines.\n\n# D. Environmental (W orkplace) M onitoring\nStudies needed for environmental (workplace) monitoring are as follows:\n- Research should be conducted to characterize and evaluate the importance of particle size, unattached fraction, and condensation nuclei concentrations in estimating the bronchial dose of radon progeny. The dose of alpha radiation affecting the bronchial airways depends on the size of the particles to which it is attached. Recent studies have shown that as particle size decreases, the concentration of radon progeny increases.\n- Continued research is also needed to determine which factors affect the equilibrium between radon progeny and radon gas in mines. These studies should examine how such information may be used to predict the extent of exposure to radon progeny. Additional development and field testing of personal sampling devices is also needed for more complete determination of a miner's daily exposure.\n\n# PUBLIC HEALTH PERSPECTIVE\n\n# V. PUBLIC HEALTH PERSPECTIVE\nIn developing this document, NIOSH has been challenged to carefully consider all of the Institute's legislative, scientific, and moral responsibilities. NIOSH has been required to review diverse scientific data that are subject to uncertainty and then, in keeping with its mandates, to recommend criteria that will attain the highest level of health protection and will at the same time account for other factors such as technical feasibility and insights gained through research and development.\nTo develop a public health perspective on the risk posed by occupational exposure to radon progeny, NIOSH must weigh a number of factors, as follows.\n1. Human and animal data both clearly establish that exposure to radon progeny increases the risk of lung cancer. The human data consist of a number of positive epidemiologic studies, several of which demonstrate an exposure-related health risk that is not accounted for by smoking behavior. The animal studies demonstrate that lung cancer risk increases with exposure in the absence of smoking.\nIt is important to note that smoking by miners appears to greatly exacerbate the risk of lung cancer posed by exposure to radon progeny alone.\n2. The NIOSH risk assessment, based on a USPHS study of uranium miners , demonstrated a significant exposure-response relationship. This analysis indicates that exposure to radon progeny at the current MSHA occupational exposure limit of 4 WLM over a working lifetime will result in 42 excess lung cancers per thousand miners. A miner's working lifetime has been defined as 30 years (MSHA uses 30 years as a miner's working lifetime). Risk declines substantially if a lower annual cumulative exposure is received over the working lifetime. Any risk assessment is subject to uncertainty because risk assessment models may not reflect risk in a completely reliable way and because the data on which they are based are subject to uncertainties and Iimitat ions.\nThe Cox proportional hazards model, which was chosen for the NIOSH risk assessment, is considered one of the strongest analytical approaches for longitudinal epidemiologic data. But it is not clear how accurately the data can be extrapolated to predict risk below the levels of observed exposure. Current biological theory hypothesizes that carcinogenic processes involve an initiation stage that is followed by other stages before an actual malignancy is established. The essential characteristics of all of these stages remain to be delineated. The Cox proportional hazards model is very powerful in describing human risks based on epidemiologic data.\nIts strength is partly due to the model's ability to accommodate long follow-up periods during which changes occur in some of the risk factors, e.g., cumulative exposure. Nevertheless, it is not clear how accurately the Cox model or any other risk assessment model predicts the risk from a multistage cancer process when exposures are below levels that have been studied.\nThe USPHS study on which the NIOSH risk assessment was based is an extensive study, but the risk assessment is subject to uncertainties and limitations because of the nature of the data. For example, more uncertainty would be inherent in the risk estimates at the lower range of exposure because a relatively small proportion of this study population received the lowest cumulative exposures. Approximately 7% of the USPHS uranium miners (which included 7 lung cancers) had received cumulative occupational exposure levels of 30 WLM or less. At lower cumulative exposure levels, even smaller proportions of the cohort and fewer lung cancers were represented. Thus point estimates at these lower cumulative exposure levels would be more subject to the influence of chance occurrences.\nIn addition, exposure levels are subject to measurement error. The uncertainty of exposures have been estimated to range from a relative standard deviation of 38% to as high as 97% (see Appendix II).\n3. Radon progeny and its associated risk are present in our ambient environment as well as in the mining environment and cannot be totally eliminated. Radon progeny are ubiquitous in that they emanate from all ore-bearing deposits containing elements that decay to produce radon gas. The national average exposure to radon progeny has been estimated to be 0.2 WLM . Areas containing large amounts of ore-bearing deposits (e.g., the Colorado Plateau) are likely to have higher-than-average background levels of radon progeny . The NIOSH risk assessment uses a fitted estimate of 0.4 WLM as the background exposure (the average annual cumulative exposure incurred in nonoccupational environments) in the Colorado Plateau. Although no adequate measurement data are available to characterize the level and variability of exposure in the homes of the general population and of miners, it is clear that everyone is exposed and that the degree of exposure depends on each individual's home and work environment. The limits of concentration detection and the accuracy of the measurement techniques become a potential problem when quantifying the very low radon progeny exposure and concentration levels that may be found in the ambient environment (these levels are generally much lower than those found in underground mining environments). Extrapolation of risk to such low levels would become even more problematic than at higher levels because of the reduced accuracy of measuring such concentration levels. The elimination of radon progeny from the ambient and mining environments is not possible.\nThe primary engineering method for controlling radon progeny exposure is dilution ventilation. However, if radon progeny are ubiquitous in our ambient environment, no source of air is free of contamination. The only protective equipment that would eliminate exposure to radon progeny is the self-contained breathing apparatus (SCBA). SCBAs are unaccept able for wear in the ambient environment and represent a significant safety hazard if worn extensively in the mining environment.\nIt is valuable to compare the lung cancer risks associated with the miner's occupational and background exposures. No assessment has yet been made of the lung cancer risk associated with background exposures, either for the general U.S. population or for the population living in the Colorado Plateau. Until studies in homes are completed, it will be impossible to directly contrast the risks of occupational and background exposures.\nNonetheless, it is important to consider occupational risk in the context of the lung cancer risk experienced by the general population. On the basis of State vital statistics records, NIOSH estimates that the lifetime risk of lung cancer in the Colorado Plateau, uncorrected for smoking, is approximately 45 lung cancers per 1,000 white males. Unfortunately, accurate lung cancer rates are not available for nonsmokers in the Colorado Plateau.\nGiven this value for the lung cancer risk of background exposure, another question that must be considered is to what level it would be reasonable to control occupational risk.\nIn its benzene decision, the U.S. Supreme Court gave the following example for the basis of evaluating occupational risk of chemically induced leukemia. The example indicated that an exposure associated with 1 excess death per 1 million exposed persons might pose an acceptable risk, whereas an exposure associated with 1 excess death per 1,000 exposed persons would pose a significant risk that should be reduced. This example is useful but it cannot be strictly applied in all cases, since it was offered as an illustration and not a fixed rule.\nIn the specific case of lung cancer risk associated with radon progeny exposure, the example cannot be strictly applied because the risk of lung cancer is much greater than the risk of leukemia at background exposure levels and because cigarette smoking is known to create a confounding effect that greatly increases risk. An excess of 1 lung cancer death per 1,000 would probably not be detectable in a general population if the data were subject to considerable uncertainty, since it would necessitate differentiating between 46 and 45 deaths per 1,000.\n5. The technical feasibility of achieving lower exposure levels is subject to the limitations of available technology. A report commissioned by the Bureau of Mines [Bloomster et al. 1984a, 1984b has been the primary source for NIOSH's assessment of the technical feasibility of lower exposure levels. On the basis of an extensive engineering analysis of two uranium mines, these investigators indicated that it might be feasible to meet an operating standard of 1 WLM using the best available engineering controls. They expressed doubt about the technical feasibility of operating these uranium mines at a standard of 0.5 WLM. This analysis has been used by NIOSH to define exposure limits that are technically achievable with the best available technology.\nThese are some of the issues that have been considered by NIOSH in developing a recommended standard to prevent lung cancer associated with exposure to radon progeny. This process of weighing risk from a public health perspective parallels the philosophy of risk presented in the 1985 document entitled Risk Assessment and Risk Management of Toxic Substances: A Report to the Secretary .\nIn the process of developing this public health perspective, NIOSH has performed the following actions:\n- NIOSH has identified a public health hazard posed by an occupational exposure. Exposure to radon progeny that occurs in underground mines and the ambient environment has been shown to cause a significant increase in lung cancer among uranium and other underground miners.\n- NIOSH has developed recommendations in a manner that is prudent and in concert with the public need. This process was accomplished by complying with the Institute's legislative mandates to attain the highest level of health protection and at the same time consider other factors such as technical feasibility.\n- NIOSH has sought appropriate public participation by eliciting external reviews. Reviews were requested from more than 60 individuals or groups, including industry, labor, academia, and government representatives. NIOSH has received and considered the comments from more than 30 of these reviewers.\n- NIOSH has communicated risk understandably to both experts and lay persons. NIOSH has expressed risk as relative risk, which most epidemiologists and biostatisticians believe to be the most appropriate mode of expressing human cancer risk. NIOSH has also expressed risk as lifetime excess risk per 1,000 miners, an expression that can easily be interpreted by both experts and lay persons.\n- NIOSH has used all currently available information and the most extensive pertinent set of human data to estimate risk. The USPHS study of uranium miners is the most extensive set of data available in the United States on the radon progeny exposure of underground miners. Unlike other analyses, this study used the entire qualifying cohort in the risk assessment, regardless of exposure level. These investigators felt this was the most valid way to analyze epidemiologic data using the selected model.\n- NIOSH has considered alternative recommendations for risk control that are based on viable exposure limits and engineering controls. The considered options ranged from proposing no REL to prohibiting all occupational exposure to radon progeny. The REL presented in this document was chosen after a thorough weighing of the available data and Institute mandates.\n- NIOSH has advanced the process of risk assessment and policy development by conducting the most thorough risk assessment possible on underground miners exposed to radon progeny. The NIOSH risk assessment permitted estimation of lung cancer risk at the lower range of the observed exposure levels. The assessment also suggested meaningful research areas such as lung cancer risks at low radon exposure levels, synergistic effects of other exposures such as cigarette smoke, effects of radon progeny on late versus early stage cancer, and the need for improved engineering control of exposure.\nAn extensive and complicated process has been used to develop the recommendations in this criteria document. After weighing the conclusions drawn from available data, the mandates of the Institute, and the public health issues, NIOSH recommends an annual cumulative exposure limit of no more than 1 WLM per year. However, as stated earlier, even this exposure poses a significant risk of lung cancer over a working lifetime. Thus NIOSH further recommends that mine operators regard this REL as an upper limit and that they make every effort to limit radon progeny to the lowest possible concentrations.\nIn addition, NIOSH wishes to emphasize the fact that this standard contains many important provisions in addition to the annual exposure limit. These include recommendations for limited work shift concentrations of radon progeny, sampling and analytical methods, recordkeeping, medical surveillance, posting of hazardous information, respiratory protection, worker education and notification, and sanitation. All of these recommendations help minimize risk.\nNIOSH recognizes its commitment to protect the health of the Nation's miners and will continue to reexamine this complex occupational health issue. Research on new and more effective methods for reducing occupational exposures will improve the available control technologies. Additional data on exposure levels and associated health risks will permit firmer estimates of risk and hence better recommendations. NIOSH will revise its recommended standard as important new data become available.\n\n# REFERENCES\nAIF . Exposure of U.S. underground uranium miners to radon daughters in 1982 as reported by 29 underground uranium mine operations, from a survey made April 24, 1984. Unpublished report submitted to Mine Safety and Health Administration by Atomic Industrial Forum.\nAIF . Exposure of U.S. underground uranium miners to radon daughters in 1984 as reported by 20 underground uranium mine operations, from a survey made December 11, 1986 Borak TB, Franco E, Schiager KJ, Johnson JA, Holub HF . Evaluation of recent developments in radon progeny measurements.\nIn: Gomez M, ed. International Conference: Radiation Hazards in Mining. New York, NY: Society of Mining Engineers of American Institute of Mining, Metallurgical, and Petroleum Engineers, Inc., pp. 419-425. Boyd JT, Doll R, Faulds JS, Leiper J . Cancer of the lung in iron ore (haematite) miners. Br J Ind Med 27:97-105. Breslin A J , George AC, Weinstein MS .\nInvestigation of the radiological characteristics of uranium mine atmospheres. New York, NY: Atomic Energy Commission, New York Operations Office, Health and Safety Laboratory. HASL-220, December 1969. Brookins DG [1986.\nIndoor and soil Rn measurements in the Albuquerque, New Mexico, area. Health Phys 51:529-533 In fifteen epidemiologic studies, researchers reported excess lung cancer deaths among underground miners who worked in mines where radon progeny were present.\nIn addition, several studies show a dose-response relationship between radon progeny exposure and lung cancer mortality.\nIn two recent studies, investigators report excess lung cancer deaths due to mean cumulative radon progeny exposures below 100 Working Level Months (WLM) (specifically, at 40-90 WLM and 80 WLM).\nThe health risks from other exposures (i.e., arsenic, diesel exhaust, smoking, chromium, nickel, and radiation) in the mining environment can affect lung cancer risks due to radon progeny exposure. Unfortunately, the literature contains limited information about other exposures found in mines. The available information, concerning whether cigarette smoke and radon progeny exposures act together in an additive or multiplicative fashion is inconclusive; nevertheless, a combined exposure to radon progeny and cigarette smoke results in a higher risk than exposure to either one alone.\nX-ray surveillance and sputum cytology appear to be ineffective in the prevention of radon progeny-induced lung cancers in individual miners; therefore, these techniques are not recommended. Also, at this point, there is insufficient evidence to conclude that there is an association between one specific lung cancer cell type and radon progeny exposure.\nAccording to annual radon progeny exposure records from the Atomic Industrial Forum (AIF) and MSHA, it is technically feasible for the United States mining industry to meet a standard lower than the current annual exposure limit of 4 WLM. Recent engineering research suggests that it is technically feasible for mines to meet a standard as low as 1 WLM. Based upon qualitative analysis of these studies and public health policy, NIOSH recommends that the annual radon progeny permissible exposure limit (PEL) of 4 WLM be lowered. NIOSH wishes to withhold a recommendation for a specific PEL, until completion of a NIOSH quantitative risk assessment, which is now in progress.\n\n# II. INTRODUCTION\nThe National Institute for Occupational Safety and Health (NIOSH) submits this report in response to the Mine Safety and Health Administration's (MSHA) Advanced Notice of Proposed Rulemaking (ANPR) concerning radiation standards for metal and nonmetal mines. This report evaluates fifteen epidemiologic studies that examine the lung cancer mortality of underground miners exposed to radon progeny. The fifteen studies are divided into two groups: five primary studies and ten secondary studies. Overall, the ten secondary studies provide additional information about the association between lung cancer mortality and radon progeny exposure, yet have more limitations (in study design, study population size, radon exposure records, thoroughness of follow-up, etc.) than the five primary studies. Recommendations for the medical surveillance of underground miners exposed to radon progeny are included. The United States mining industry's ability to meet a radon progeny exposure standard lower than the present four Working Level Months (WLM), based solely on technical feasibility, is also discussed.\nA working level (WL) is a standard measure of the alpha radiation energy in air. This energy can result from the radioactive decay of radon (Rn-222) and thoron (Rn-220) gases. A WL is defined as any combination of short-lived radon decay products (polonium-218, lead-214, bismuth-214, polonium-214) per liter of air that will result in the emission of 1.3 X 10^ million electron volts (MeV) of alpha energy .\nNIOSH defines a WLM as an exposure to 1 WL for 170 hours.\nFor the information of the reader, two appendices and a glossary are included. Appendix A contains data from the Atomic Industrial Forum (AIF) an organization representing the interests of the United States uranium mining industry, and MSHA on the numbers and radon progeny exposures of underground miners in the United States. Appendix B lists methods currently in use for controlling radon progeny exposures underground.\nFinally, there is a glossary containing epidemiologic and health physics terms.\n\n# III. EVALUATI ON OF EPI DEM IOLOGIC EVIDENCE\n\n# A. In tro d u ct ion\nThis report examines five primary and ten secondary epidemiologic studies of underground miners. It describes the important points, strengths, and limitations of each study. The five primary epidemiologic studies examined lung cancer mortality among uranium miners in the United States, Czechoslovakia, and Ontario; iron miners in Malmberget, Sweden; and fluorspar miners in Newfoundland.\nThe ten secondary epidemiologic studies examined mortality among iron ore miners in Grangesberg, Gallivare, and Kiruna, Sweden; zinc-lead miners in Sweden; metal and Navajo uranium miners in the United States; tin and iron ore miners in Great Britain; uranium miners in France; and tin miners in Yunnan, China.\nFinally, two recent studies analyze the interaction between radon progeny exposure and smoking. This report focuses on the lung cancer experience of these fifteen underground mining cohorts.\nIn general, the study cohorts did not show excess mortality due to cancers other than lung, except for four studies that reported excess stomach cancers and one report of excess skin cancer among underground miners.\nExcess stomach cancers were reported among underground tin miners in Cornwall, England (standardized mortality ratio (SMR) = 200, p value unspecified by the authors, however estimated at p<0.05, from the observed deaths and the Poisson frequency distribution) ; gold miners in Ontario (SMR=148, p<0.001) ; metal miners in the United States (SMR=149, p<0.01) ; and iron ore miners in Sweden (SMR=189, p<0.01) . Sevcova et al. (1978) reported excess skin cancers among underground uranium miners in Czechoslovakia (an observed skin cancer incidence of 28.6 versus an expected of 6.3 per 10,000 workers; p<0.05), that they attributed to external alpha radiation from radon progeny. Arsenic is present in the Czechoslovakian uranium mines (arsenic levels unidentified) and the association between arsenic and skin cancer is well documented . The excess mortality from stomach and skin cancers among these cohorts needs further study. In all five primary epidemiologic studies, the exposure records for the individual miners lack precision.\nFrequently, an individual miner's exposure was calculated from an annual average radon progeny exposure estimate for a particular mine or mine area, thus, an individual miner's true exposure could vary greatly from the estimated exposure. Of the five primary epidemiologic studies, the Czechoslovakian study has the best records for radon progeny exposure . The Swedish study has limited exposure records for their cohort (8 years of measurements for 44 years of follow-up), and the miners' mean exposures were about five WLM per year . The lower radon progeny concentrations found in Swedish mines indicate that the potential error due to excursions in concentration was less than in mines in the United States, Newfoundland, and Ontario, where higher concentrations were measured (Table III-2). Overall, the radon progeny exposure records from the United States, Ontario, and Newfoundland have similar limitations (detailed in sections B, D, and F). WL measurements made in uranium mines in the United States and fluorspar mines in Newfoundland fluctuated greatly, reaching unusually high radon progeny concentrations: in the fluorspar mines, a maximum of 200 WL , and in the uranium mines, 3 out of 1,700 mines averaged over 200 WL . NI0SH is currently investigating the variability and quality of the exposure records kept for uranium mines in the United States.\nExposure data quality, although important, does not solely determine a study's strength; one should also evaluate the epidemiologic and statistical methods used. This review reports both the attributable and relative risk estimates for lung cancer (see Glossary for definitions) when they are provided by the authors .\n\n# B. Uranium Miners in the U nited S tates\n\n# . Descr i p t i on\nThe United States Public Health Services (USPHS) conducted an epidemiologic study examining mortality among underground uranium miners from the Colorado Plateau Job turnover in the uranium mines was substantial; the majority of miners worked less than 10 years underground (not accounting for gaps in employment) . Nevertheless, approximately 33 percent of the cohort worked 10 or more years and 7 percent worked 20 or more years underground in uranium mines (not accounting for gaps in employment) . The number of months worked underground ranged from 1 to 370 (over 30 years), with a median of 48 months (4 years). Some miners worked underground in uranium or nonuranium mines before they entered the USPHS study, and before radon progeny levels were recorded. Among these miners, 13.7 percent started mining before 1947 . The cohort's early radon progeny exposures probably represented a small proportion of their total lifetime exposures; Lundin et al. (1971) noted that the study group accumulated only 16 percent of their total radon progeny exposure before 1950 .\nA bias toward overestimating exposure and a narrow sampling strategy were two major influences effecting the miners' exposure records. First, some of the USPHS exposure data records were biased by including disproportionately more measurements from mine areas with high radon progeny levels. Radon progeny samples taken during 1951-1960 were stated to be representative of the mine areas in which miners received exposures. Also, the U.S. Bureau of Mines (USBOM), the New Mexico State Health Department, and the Arizona mine inspector continued to take representative samples after 1960 . During 1960-68, however, additional radon progeny samples were collected for control purposes by mine inspectors from Colorado, Utah, and Wyoming .\nIn this case, inspectors sampled disproportionately more mines and mine sections that had high radon progeny levels. This sampling bias also tended to increase estimates for geographic areas of mining (locality, district, or state) . Thus, some average annual WL exposure records collected during 1960-68 overestimated the uranium miners' exposure.\nSecond, there is little exposure data available for some uranium mines, especially small mines.\nFor the entire period 1951-68, nearly 43,000 measurements were available to characterize about 2,500 uranium mines. More samples were usually taken in the larger mines that employed most of the miners.\nIn many mines, however, only one or two samples were ever taken .\nAt the present time, the USPHS exposure data set has 34,120 \"average\" (undefined by Lundin et al. 1971) annual WL exposure records from 1,706 surface and underground uranium mines, made over a 20-year period . These records consist of \"guesstimates\", \"estimates\", \"extrapolations\", and actual WL measurements (Table 111-1 (1981) used the formula for attributable risk to determine that about 80 percent of the deaths due to lung cancer in this cohort were attributable to uranium mining . As of 1971, statistically significant excess cancers were found in all radon progeny exposure categories above 120 WLM ; the exposure categories were: less than 120, 120-359, 360-839, 840-1799, 1800-3719, and 3720 and over, in WLM. NIOSH continues to monitor the mortality experience of this cohort, particularly those workers exposed at or below 120 WLM. The terms \"guesstimates,\" \"estimates,\" and \"extrapolations\" were defined in this manner by Lundin et al. (1971) ; NIOSH recognizes the limitations of these definitions, but uses them for consistency with published reports.\n\n# Strengths\nThis is a large, well traced, and analyzed study; the study cohort is clearly defined. It contains smoking histories and radon progeny exposure records for the same individuals. Although the radon progeny exposure data were measured by different persons, a standard sampling and counting technique was used and the technical quality of the measurements was good .\n\n# . L im ita tio n s\nThe major limitation in the exposure data quality are that there were few measurements for small mines, (although fewer miners worked in these mines) miners' work histories were self reported, and many exposures were overestimated during 1960-68 . Another limitation is that many miners fell into high radon progeny exposure categories; however 20 pe-rcent of the miners were assigned to the category below 120 WLM .\nSeveral reviewers have found that the USPHS study gives lower estimates of risk per WLM for radon progeny exposure than the other four major epidemiologic studies . This may be due to the overestimation of exposure by Lundin et al. (1971) or other factors.\n\n# C. Uranium Miners in\n\n# Strengths\nOne positive feature of this study is the large amount of exposure data available.\nRadon gas measurements started in 1948, with a minimum mean of 101+8 measurements per mine . Other strengths include the number of workers exposed to low radon progeny levels, a long period of follow-up (average of 26 years by 1975) , and the limited exposure to radon progeny from other underground mining (less than 2 percent of the study group members mined nonuranium ores) .\nIn addition, Sevc et al. (1984) investigated the hazards from other exposures, such as silica, arsenic, asbestos, chromium, nickel, and cobalt, and concluded that these were not causing the excess lung cancer risk of the uranium miners . Sevc (1970) reported maximum dust levels between 2.0-10.0 mg/m3 during 1952-56, and stated that the miners' risk of silicosis was relatively low . Chromium, nickel, and cobalt were present only in trace amounts in mine dusts. Although arsenic was present in these mines (concentration unspecified), there was no significant difference in lung cancer mortality between two mining areas with comparable radon progeny exposure levels, but fiftyfold differences in arsenic concentrations .\n\n# Limitations\nThe limitations of the Czechoslovakian study are that the exposure estimates made before 1960 were based on radon gas, rather than direct radon progeny measurements.\nA second limitation is that the cohort definition and the epidemiologic methods used by the Czechoslovakian researchers make it difficult to compare their findings with those from the other four primary studies.\nThe radon gas and progeny equilibrium ratio is necessary to estimate WL concentrations from radon gas measurements correctly. The authors provided insufficient detail about the equilibrium ratio in the Czechoslovakian uranium mines to allow evaluation of the data quality .\nIf Sevc et al. (1976) had equilibrium ratio records or a reliable way to estimate the equilibrium ratio, then using radon gas exposure measurements to estimate WL would not seriously bias their results.\nSevc, Kunz and associates defined their cohort as men who entered employment in the Czechoslovakian uranium mines in the years 1948-1953 (for Group A miners), and worked underground at least 4 years .\nIt is unclear from the published reports whether the Czechoslovakian miners accumulated their person-years at risk of dying (PYR) from the time they entered the cohort or from their time of first exposure. The cohorts' average 26 years of follow-up by 1975 , implies that the PYR were accumulated from a miner's time of first exposure .\nIn most epidemiologic studies, a miner's PYR accumulate after he enters the cohort. The Cze noslovakian method of accumulating PYR makes it difficult to directly compare their lifetable analysis and findings with those from other miner studies. Sevc et al. (1984) also neglected the effect of smoking in their data analysis, although they stated that this would not effect their results, because the percentage of cigarette smokers among miners (70 percent) was comparable to that among the general male population of Czechoslovakia .\n\n# D. Uranium\n\n# Strengths\nThis study's greatest strength lies in the miners' low mean cumulative exposures (40-90 WLM) to radon progeny, exposures much lower than those reported in the United States, Czechoslovakian, and Newfoundland studies (see Table III-2, at the end of this Chapter). Another good feature of this study is that the researchers carefully traced uranium miners' work experience in other hard rock mines.\nLarge numbers of uranium miners in Ontario (66 percent of the study cohort) had some hard rock mining experience.\n\n# . L im ita tio n s\nThis study has three disadvantages; first, the cohort is severely truncated, with only about 18 years (median value) of follow-up and a median attained age of 39 years by 1977 . A short follow-up on a young cohort creates problems because lung cancer is rarely manifested before age 40 . Second, thoron progeny and gamma radiation levels vary and can reach substantial levels In some Ontario uranium mines . For example, Cote and Townsend (1981) found that thoron progeny working levels were about half the radon progeny working levels in an Elliot Lake, Ontario uranium mine . The Kusnetz method is frequently used to measure radon progeny in mines and can discriminate between radon and thoron progeny. When used improperly, however, the Kusnetz method can mistakenly count thoron progeny as radon progeny, so that the true radon progeny exposure may be overestimated . From the limited information in the published reports , it is unclear whether measurement error was introduced by using the Kusnetz method improperly.\nThere are no epidemiologic data available to estimate the health risks due to thoron progeny. The Advisory Committee on Radiological Protection from the Canadian Atomic Energy Control Board (AECB) reviewed research on microdosimetry which indicated that the main contribution to the WLM from thoron progeny comes from the radioactive decay of long-lived Pb-212 (ThB, the half life=10.6 hours).\nIts half-life is long enough for the Pb-212 to translocate from the lungs into other tissue, where it emits much of its alpha energy. Radon progeny have shorter half-lives than Pb-212 and emit most of their alpha energy in the lung. Therefore, the AECB concluded that the risk of lung cancer induction by 1 WLM of thoron progeny is about one third of that for 1 WLM of radon progeny .\nFinally, Muller et al. (1985) published limited information about the smoking habits of these miners, and the researchers' present risk estimates are uncorrected for smoking . Out of a group of 57 uranium miners who died of lung cancer, only one was a nonsmoker and the rest smoked . Muller and associates plan to conduct a case-control study of the effects of smoking upon lung cancer risk in miners. Although they stated that correction for smoking will not substantially change their risk estimates , at low levels of radon progeny exposure, it is important to take into account the effect of smoking; thus, definitive conclusions regarding this study must await the smoking history analysis.\n\n# E. Iron Miners in\n\n# Strengths\nThe strengths of this study include the relatively low radon progeny exposures of the miners (mean of 4.8 WLM per year), the long follow-up period, and the stability of the work force. The ascertainment of vital status (99.5 percent), and the confirmation of diagnoses for causes of death was thorough (about 50 percent of all deaths in Sweden are followed by autopsy).\nIn addition, Radford and St. Clair Renard (1984) used case-control methods and environmental measurements to rule out health risks from diesel exhaust, iron ore dust, silica, arsenic, chromium, nickel, and asbestos in the mines .\n\n# . L im ita tio n s\nThe major limitations of the iron miners' study were the limited exposure data available for analysis and an unclear cohort definition; there was also a question about how the authors adjusted for lung cancer latency. Radon gas, in the Swedish iron mines, was first measured in 1968. That means that for the average 44 years of follow-up, there exist exposure estimates based on actual measurements for only 8 years. The researchers reconstructed past concentrations based on measurements made at each mine level and area during 1968-1972 and on knowledge of the natural and mechanical ventilation used previously.\nThey assumed that mine ventilation systems and radon progeny concentrations during 1968-72 were comparable with those in the past, by analogy with quartz dust levels measured in the mines since the 1930's .\nThe researchers calculated average yearly exposures in WLM for each decade from the average hours per month underground and radon progeny concentrations in each area, weighted by the number of man-hours worked underground . These crude calculations make tenuous the connection between a given individual miner and a particular radon progeny exposure level. Nonetheless, the iron miners as a group, probably received very low average exposures to radon progeny compared to uranium miners . Radford et a I., stated : \"...we consider that average exposures are probably accurate to + 30 percent\" ;\nthus, the true average exposure could be between 56 and 104 WLM.\nExactly how Radford and St. Clair Renard defined the cohort, and calculated or excluded the PYR, was unclear from the article.\nTo account for a 10-year lung cancer latency, they excluded PYR for lung cancer during the first 10 years after mining was begun . From their description, it is unclear when mining was begun and whether PYR were counted from the beginning of mining, January 1, 1951, or some other date.\nIt is assumed that most of the miners' PYR were excluded from the years prior to 1951, rather than the period 1951-1976 (years when the authors analyzed mortality), and that the mining population was stable. If one makes these assumptions (unstated by the authors), then adjusting for latency by excluding PYR during the first 10 years after the start of mining should produce unbiased SMR calculations. On the other hand, adjustments for latency that incorrectly exclude many PYR lower the expected number of deaths, thereby possibly overestimating the SMR and the risk due to radon progeny. Because of insufficient information, NIOSH is unable to completely evaluate the effect of the 10-year adjustment for latency on the SMR in this study, although it appears to be minor.\n\n# F. Fluorspar Miners in\n\n# Strengths\nOne strength of this study was the long follow-up period; workers were followed for an average of about 30 years of observation . Also, the researchers obtained smoking history data for 41 percent of the cohort .\n\n# . L im ita tio n s\nThere were three principle limitations in this study. First, there was limited exposure data available before 1968 (See above).\nSecond, the study failed to trace large numbers of workers; 591 workers who lacked adequate personal identifying information (name and year of birth) were dropped from the analysis.\nThird, this study lacks an adequate basis for estimating expected deaths.\nLung cancer rate comparisons between the mining population, with its many smokers, and the Newfoundland or Canadian national populations, would exaggerate excess deaths due to radon progeny exposure. Morrison et al. (1985) tried to avoid this problem by generating the expected number of deaths among underground workers from a comparison with mortality rates among surface workers (adjusted for age, time period, and disease specific mortality) . A problem with this study design is that the control group may be exposed to radon progeny. Some of the men classified as surface workers (controls) may have received some radiation exposure, by means of either misclassification or unrecorded short periods of working underground. Also, it is difficult to correctly adjust for age, time period, and disease specific mortality, when there are proportionately fewer workers in the control group (surface workers) than in the exposed group (as of 1971, underground workers accounted for 57 percent of the total person-years ). The lack of an adequate comparison group is a serious limitation, so risk estimates from this study must be viewed wi th caut ion.\n\n# G. Secondary Epidem iologic Studies\nThe ten epidemiologic studies reviewed herein examine mortality among miner populations in China, Sweden, the United States, Great Britain, France, and China.\nSeveral studies demonstrated elevated radon progeny levels and excess lung cancer deaths among underground miners, but lacked information about radon progeny exposure, or levels of other mine carcinogens.\nOther studies contained severe limitations or biases that also restricted their usefulness. Overall, the ten secondary studies provide additional information about the association between lung cancer mortality and radon progeny exposure, yet have more limitations (in study design, study population size, radon exposure records, thoroughness of followup, etc.) than the five primary studies. To be concise, the secondary studies are described in less detail than the primary studies.\nIron Ore Miners in Grangesberg, Sweden\n\n# Zinc-Lead M iners in Sweden\nThis case referent study examined lung cancer mortality during 1956-76 among residents from the parish of Hammar, Sweden, an area with two zinc-lead mines . Twenty-nine subjects who died of lung cancer, including 21 who were underground miners, were matched with three referents who died before or after each case. Some problems with the study were the smalI number of cases and a fai lure to match for age or smoking status. Axelson and Sundell (1978) reported a sixteenfold increase (p<0.0001) in lung cancer mortality among the miners versus nonminers. Although they lacked individual information on exposure, they estimated a radon progeny level of about 1 WL in the mines, based on measurements made in the 1970's . These results should be viewed with caution; since they demonstrated that age was a confounding factor, yet they did not match cases and referents for age.\n\n# . Iron Ore Miners in K iruna, Sweden\nThis study examined lung cancer mortality among residents of the Kiruna parish in Northern Sweden, an area containing two underground iron mines . One strength of this study is that migration in the Kiruna area was slight, therefore, nearly all former miners' deaths were registered in Kiruna. From 1950 to 1970 a total of 41 men (in Kiruna) between the ages of 30-74 years died of lung cancer. Thirteen of these were underground miners, and it is possible, although unclear in the report, that 18 were surface workers. One limitation of this study is that the the age distribution of underground miners was unrecorded, and therefore, proportional mortality was used instead of the lifetable method to calculate the expected mortality. Another limitation is that the expected mortality was not adjusted for smoking status, since information from family and fellow workers indicated that 12 of the 13 underground miners smoked (8 smoked cigarettes, 4 smoked pipes). Jorgensen (1973) compared the 13 deaths observed among underground miners with expected deaths of 4.47, based on local rates, and 4.21, based on Swedish national rates.\nIn both cases, he reported significantly elevated mortality (p<0.05) among the underground miners . Because this proportional mortality study involved few lung cancer cases, 13 for underground miners and 28 for all other men in Kiruna, the results should be viewed with caution. Radon progeny exposure records were unavailable for the underground miners, however, there were measurements of 10-100 pCi/l radon progeny (about 0.10-1.0 WL at 100 percent equilibrium).\nIro n Ore Miners in Kiruna and G a lliv a r e , Sweden\n\n# . Metal Miners in the U nited S tates\nThis cohort mortality study involved white male underground metal miners in the United States. The cohort was defined as miners who had completed, at a minimum, their fifteenth year of underground mining experience between January 1, 1937 and December 31,1948 For the period 1947-1955, there were no radon measurements available, however, a committee of experts estimated average monthly radon progeny exposures varied from 1-10 WLM.\n\n# T in M iners in C o rn w all, Great B r ita in\n\n# Uranium Miners in France\nIn 1956, 7,470 radon gas measurements were collected.\nFrom 1957 to 1970, about 20-30 radon gas measurements were collected per miner per year; from 1970 to the present, 57-70 per miner, per year. The only limitation of these records is that they are based on radon gas, rather than direct radon progeny measurements. At present, the mean factor of equilibrium in the French mines is 0.22. The miners' average annual radon progeny exposures varied from 2.5 to 4. There were many excess lung cancers at low radon progeny exposures, i.e., an SMR of 436 (p value unspecified by the authors, however estimated at p<0.05, from the number of observed deaths and the Poisson frequency distribution) at cumulative exposures below 140 WLM. Arsenic concentrations in ore samples were high, 1.50-3.53 percent . For the years 1950-59, it was estimated that a miner inhaled 1.99-7.43 mg arsenic per year . The authors suggested that the high arsenic content in the ore samples may cause lung cancer .\nThe strength of this study lies in the large number (12,243) of underground miners studied. One limitation is that the study cohort is ill-defined; the study design mixes aspects of a survey for incidence with a cohort study. Wang et al. (1984) fail to describe when the workers started mining and how many were lost to follow-up; also, whether the 12,243 miners worked between 1975-81 or constituted all tin miners who ever worked underground. The major limitation appears when comparing these studies with other mining research studies because Wang and associates handled radon progeny measurement techniques and epidemiologic methods in a different manner. For instance, they did not mention if their mortality statistics were adjusted for age or smoking status. Their comparison population, male residents in urban Shanghai municipality, has much higher lung cancer rates than males in rural Yunnan province . Therefore, the Shanghai comparison group was inappropriate and may have underestimated these miners' lung cancer r i sks.\nAnother limitation is that arsenic exposure has been associated with lung cancer among copper smelter and pesticide workers . This research may be most useful for studying the interaction of two carcinogens, arsenic and alpha radiation from radon progeny, rather than for studying radon progeny lung cancer risks alone.\n\n# H. Smoking\nThe two most thorough studies of the interaction between smoking and radon progeny exposure are those by Whittemore and McMillan (1983), using the U.S. white uranium miners data set , and by Radford and St. Clair Renard (1984) using the Swedish iron miners data set . The major flaw in other studies of the interaction between smoking and radon progeny exposure is an inadequate sample size of miners with both exposure records and smoking histories.\n\n# . Uranium Miners in th e U nited S tates\nWhittemore and McMillan (1983) examined lung cancer mortality among the white USPHS uranium miners cohort, based on a mortality follow-up through December 31, 1977.\nIn their analysis, they included nine additional miner lung cancer deaths which occurred after December 31, 1977, for a total of 194 lung cancer cases (see section III.B).\nFor each case, four control subjects were randomly selected from among those white miners born within 8 months of the case and known to survive him, yielding a total of 776 matched controls . A regression analysis of the radon progeny exposure and smoking data for cases and controls revealed that the data fit a multiplicative linear relative risk model , but showed \"significantly poor fit\" (p<0.01) for the additive linear relative risk model . The data demonstrated a synergistic effect, that is, the combined action of smoking and radon progeny was greater than the sum of the actions of each separately. .\n\n# Whittemore and McMillan, based on the multiplicative linear relative risk model , suggested that miners who have smoked 20 pack-years of cigarettes (excluding tobacco use within the past 10 years) experience radiat ion-induced lung cancer rates per WLM that are roughly five times those of nonsmoking miners\n(They estimated that B-j, the excess relative risk per unit of radon progeny, was 0.31X10~2 and B2 , the excess relative risk per unit of cigarette smoke exposure, was 0.51X103).\nIron Miners from Malmberget, Sweden\n\n# . Conclusions R elated to th e In te ra c tio n o f Radon Progeny Exposure and Smoking\nStudies of white uranium miners in the United States , and iron miners in Sweden , support different models of risk due to radon progeny and smoking; the first supports a multiplicative model, the second, an additive model. These two studies arrive at different conclusions which is not surprising, given the differences in statistical methods, cumulative exposure levels (the averages differed by a factor of 10), smoking histories, and method of calculating expected deaths between the studies. Based on the presently available information, it is impossible to conclude whether the additive or multiplicative model is the best. Nevertheless, present research indicates a higher risk from combined exposure; data from both radiation exposure and smoking histories are essential for an accurate estimation of radiogenic lung cancer risks.\n\n# I . Discussion and Conclusions R elated to the Epidem iologic E valu atio n 1. The Five Prim ary Epidem iologic S tudies\nThe five primary epidemiologic studies that examine lung cancer mortality among underground miners are the studies of uranium miners in the United States, Czechoslovakia, and Ontario, as well as iron miners in Sweden and fluorspar miners in Newfoundland.\nDespite the individual limitations of each study, the association of radon progeny exposure and lung cancer was shown to persist for all five studies, using different study populations and methodologies.\nThere was an elevated lung cancer SMR and a dose-response relationship for radon progeny exposure and lung cancer among the five underground miners' cohorts; the higher the estimated radon progeny exposure, the greater the number of excess deaths. Some studies adjusted their mortality figures for the estimated latency of radiogenic lung cancer, yet the association between lung cancer cases and radon progeny exposure remained.\nTable III-2 is a summary of the observed and expected deaths and the SMR's in the five studies. These studies handled adjustments for latency, lagging dose, smoking history, or age as detailed in the footnotes in Table III-2. As yet, there is no one standard method to adjust person-years, expected deaths, or SMR's, or even agreement that these parameters should be adjusted.\nA M five studies lacked adequate radon progeny exposure data for individuals because, in general, these data were originally collected for monitoring, and not research purposes.\nIn addition, some studies based the exposure assessment upon radon gas measurements, which must be converted to radon progeny estimates. five studies, rather than eliminate a particular study because of exposure data quality.\n\n# It is reasonable, however, to extract what information is available from these\nThe primary studies of iron miners in Sweden and uranium miners in Czechoslovakia searched for other exposures (i.e., mineral ores, radiation, diesel fumes) in the mining environment.\nThe Czechoslovakian uranium mines contained various amounts of arsenic, but only trace amounts of chromium, nickel, and arsenic . Researchers examined lung cancer mortality in two uranium mining localities that had similar radon progeny levels, but a fiftyfold difference in arsenic concentrations.\nThey failed to find a significant difference in mortality between the two groups of miners , concluding that arsenic was not affecting the lung cancer rates of underground miners in Czechoslovakia. Arsenic, chromium and nickel were essentially absent in the Swedish iron mines. There were occasional inclusions of serpentine, but no identifiable asbestos fibers in dust samples . The Swedish iron mines contained iron ore dust, but Stokinger (1984), after review of the literature from health reports involving underground iron ore miners, iron and steel workers, foundrymen, welders, workers in the magnetic tape industry, and others, concluded that these studies failed to clearly demonstrate the carcinogenicity of iron oxide dust .\nThe influence of other types of radiation present in the mines, such as long-lived alpha, beta, and gamma radiations, cannot be determined from these five studies. The miners do not show an excess mortality from leukemia, a disease linked to high gamma radiation exposures . Most of the studies provided insufficient information about diesel fume exposures in the mines, so that it is impossible to reach conclusions regarding the effect of diesel fume exposure upon lung cancer risk.\nIn the Swedish iron mines, 70 percent of miners with lung cancer left underground work or died before diesel equipment was introduced in the 1960's ; the remaining miners had brief diesel fume exposures immediately before death . Therefore, diesel fume exposure could not account for the excess mortality in the Swedish cohort . Cigarette smoke appears to be the most important carcinogen common to the five primary studies. The proportion of cigarette smokers among underground miners in the United States, Newfoundland and Sweden was greater than among the general male population in those countries . The influence of possible carcinogens in mines (in addition to radon progeny) upon lung cancer mortality needs further research.\n\n# . The Ten Secondary Epidem iologic Studies\nTen epidemiologic studies were identified by NIOSH as secondary studies, which strengthen the association between excess lung cancer mortality and radon progeny exposure, yet have more limitations (in study design, radon exposure records, follow-up, etc.) than the five primary studies. The ten epidemiologic studies examined lung cancer mortality among underground iron ore and zinc-lead miners in Sweden, metal and Navaho uranium miners in the United States, tin and iron ore miners in Great Britain, uranium miners in France, and tin miners in China. All ten studies have incomplete radon progeny exposure records. Nevertheless, all reported an elevated lung cancer mortality in underground miners and the presence of radon progeny in the mines. The studies of metal miners in the United States , and tin miners in China also found arsenic in the mines; Wang et al. (1984) suggested that the high arsenic content of the ore may be a cause of lung cancer . The study of tin miners in China found an exposure-response relationship between cumulative radon progeny exposure and excess lung cancer mortality, but at the lowest exposure level (less than 140 WLM), still found an unusually high SMR (436) . The arsenic exposures of these underground miners may contribute to the high lung cancer SMR; arsenic exposure is associated with lung cancer in copper smelter and arsenical pesticide workers .\nThe study of iron ore miners in Grangesberg, Sweden estimated an attributable risk of 30-40 cases per 10® PY-WLM for miners over the age of 50 . This attributable risk estimate is comparable to that reported by Radford and St. Clair Renard (1984) for miners in Malmberget, Sweden in the same age group .\n\n# The Lowest Cumulative Radon Progeny Exposures Associated w ith Excess Lung Cancer M o r ta lity\nThe five primary epidemiologic studies are far from completion, since the cohorts' follow-ups are truncated.\nFor example, the uranium miners in the United States were followed a mean of 19 years (by 1977), while the iron miners in Sweden were followed a mean of 44 years (the Swedish study has the longest follow-up period of the five primary studies). Lung cancer rarely is manifested before age 40, regardless of etiology .\nFrequently, the initial analyses performed on a cohort lack enough PYR and statistical power to show a statistically significant association between excess lung cancer mortality and low radon progeny exposure levels. Later analyses accumulate additional PYR for the entire cohort and specific subgroups, increasing the ability to detect an effect due to radon progeny. This point is important when determining the lowest radon progeny exposures associated with excess lung cancers. A longer follow-up period, resulting in more PYR and statistical power in a study, may reveal an association between excess lung cancer mortality and radon progeny at lower cumulative exposures. had an average of about 10 years of follow-up (by 1968) and found excess cancers above 120 WLM. The study of uranium miners in Czechoslovakia found excess mortality above 100 WLM . Two recent studies, of miners in Ontario and Sweden, reported excess cancers at cumulative radon progeny exposure levels of 40-90 WLM and 80 WLM, respectively . Thus, two epidemiologic studies found excess lung cancer mortality associated with radon progeny exposure levels below 100 WLM.\n\n# The study of uranium miners in the United States by Lundin et al . (1971)\nIn addition, studies suggest that both radon progeny exposure and smoking are involved in the lung cancer mortality of underground miners; however, the available information does not allow one to state whether radon progeny and smoking interact in an additive or multiplicative fashion . One estimate is that miners who smoked 20 pack-years of cigarettes have radiat ion-induced lung cancer rates per WLM that are roughly five times those of nonsmoking miners .\nFinally, the five primary and ten secondary mining epidemiologic studies all demonstrate excess lung cancer mortality among underground miners working in the presence of radon progeny.\n\n# IV . MEDICAL SCREENING AND SURVEILLANCE OF UNDERGROUND MINERS EXPOSED TO SHORT-LIVED ALPHA PARTICLES\n\n# A. Q u a litie s o f E ffe c tiv e Medical Screening and S u rv e illa n c e\n\n# B. Screening and Lung Cancer Prevention\nAlpha radiat ion-induced lung cancer may be preventable (by limiting exposures to radon and thoron progeny) but not treatable. By the time radiogenic lung cancer is detected among individuals in an exposed work force by routine periodic screening, the affected workers fail to benefit from any further preventive or therapeutic measures.\n\n# Available screening tests may detect radiat ion-induced, premalignant abnormalities in asymptomatic exposed workers years before disease appears. At the current state of knowledge, however, it is unknown whether medical removal of asymptomatic workers with these abnormalities will prevent progression to malignant disease. A recent study by NIOSH tested the within-reader reliability of an expert in sputum cytologic and histopathology. The reader reliably detected malignant changes, but frequently read early changes as \"premalignant\" on one occasion and as \"within normal limits\" on other occasions .\nTo date, there is no convincing evidence that routine periodic medical screening of workers exposed to pulmonary carcinogens is an effective means of prevention of mortality due to lung cancer in these workers.\nCoke oven workers are presently the only group of workers covered by a mandatory rule for periodic screening by sputum cytology and chest X-rays. Although the effectiveness of that regulation has not yet been evaluated, such studies are now underway.\nIn addition, NIOSH is currently collecting data on lung cancer rates and the results of sputum cytologic tests for some miners in the USPHS cohort . Also, frequent exposures of underground miners to chest X-rays for screening purposes are not recommended at present.\n\n# CRITERIA FOR DETERMINING THE SUITABILITY OF A CANCER SCREENING TEST FOR USE IN THE WORKPLACE\n\n# Coles and Morrison (1980) :\n1. The test should be \"effective\" in terms of its validity, reliability, sensitivity, specificity, and opera tional characteristics (such as predictive value).\nThe test should be \"acceptable\" to workers in terms of its cost, convenience, accessibility, lack of morbidity.\n\n# Halperin et al. (1984) :\nThe test should be \"effective\" in terms of its validity, relia bility, sensitivity, specificity, and operational characteristics (such as predictive value).\nThe test need not be uncompli cated or inexpensive, but its performance and interpretation must be done by competent profes sionals.\nThe test must be \"acceptable\" to workers in terms of its cost, convenience, accessibility, lack of morbidi t y .\nThe test results must be eval uated by comparison to a suitable population, not necessarily the general population.\n\n# Action levels and related medical decisions must be deter mined in advance of screening (based on #1 above).\n\n# Adapted from \nEffective treatment is avail able if asymptomatic disease is detected.\n\n# Detectable preclinical phase must be highly prevalent among screened population.\n\n# Halperin et al. (1984)\n1. The disease has important individual and public health consequences.\n2. Disease need not be treatable, but must be preventable.\n\n# A detectable preclinical phase (DPCP) must exist and a target population (exhibiting a high\nprevalence of DPCP) be identified.\nFollow-up care (diagnostic, treatment, and social services) must be avaiI able.\nNatural history of the disease determines the feasibility and frequency of testing.\n\n# Adapted from \nA review of studies reporting histopathologic associations with radon progeny exposures lacked sufficient information to conclude definitely that only one specific lung cancer cell type was associated with these exposures .\nIn addition, a case-control study using data from the Third National Cancer Survey found that cigarette smoking was significantly associated with all three histologic types of lung cancer ; the relationship with small-cell carcinoma was strongest overall (odds ratio = 5.1), whereas those with squamous and adenocarcinoma were approximately equivalent (odds ratio = 3.1). The issue of histopathologic associations with radon progeny exposures needs further research, especially considering that many underground miners smoked cigarettes.\n\n# Both cessation of smoking and reduction of the radon progeny exposures\n-f underground miners will lower their risks for lung cancer.\n\n# C. Recommendat i ons 1. Smoking\nSince it appears that inhaled radon progeny either add to or multiply the underlying high lung cancer risk in smokers, a smoking cessation program is recommended. The combined effects of a lower (more protective) Permissible Exposure Limit (PEL) and cessation of cigarette smoking would probably provide a significant reduction in lifetime risks.\n\n# Lung Function Tests\nA baseline chest X-ray and annual spirometrie lung function tests, performed and interpreted according to the criteria of NIOSH or the American Thoracic Society, would be appropriate for medical decision-making concerning job placement, medical removal protection, and disability compensation should work-related respiratory problems develop.at a later time.\n\n# . X -ra y Screening\nWhile chest X-ray screening is not an effective means of prevention of death due to occupational lung cancer, examination at 5-year intervals, and industry-wide analyses of the results of such tests may be an effective means of supplementing the primary prevention of other lung diseases, such as pneumoconioses.\n\n# . R a d ia tio n Exposure Records\nThe lifetime radiation exposure record of underground miners should include information about the dose and frequency of medical irradiation.\nIf radiation exposed workers are routinely screened for lung diseases by baseline and periodic follow-up chest X-rays, they will receive an average of about 0.025 rad per examination of external X-irradiation (where an \"examination\" consists of a postero-anterior and a lateral exposure) .\nIf examinations are conducted every 5 years, the average lung dose would be about 0.005 per year. Furthermore, because of the frequency of on-the-job accidents and injuries in underground mining , underground miners may receive considerably more medical X-irradiation over a working lifetime than workers exposed to other sources of ionizing radiation. For each of the following diagnostic examinations, the approximate X-ray dose to the lung is indicated in parentheses: thoracic spine (0.421 rad), ribs (0.324 rad), lumbar spine (0.133 rad), one shoulder (0.039 rad), lumbosacral spine (0.035 rad), and skull (0.002 rad) [\n\n# V. FEASIBILITY OF LOWERING THE STANDARD\nThis section examines the feasibility of lowering the current radon progeny exposure standard, including differences between current exposures and lower projected standards.\n\n# A. Comparison o f Current U.S. Underground Miner Radon Progeny Exposures with D iffe r e n t Standards\nThe uranium mining industry in the United States has recorded the annual exposures of underground miners, and the Atomic Industrial Forum (AIF) figures are displayed in Appendix Tables A-9 to A-11. There has been some discrepancy between MSHA records and AIF records . Overall, the industry has been successful in controlling exposures to 4 WLM. Furthermore, the percentage of miners exposed to 3 WLM or higher decreased between 1973 and 1982 (Tables A-9 to A-11, ).\nThere has been substantial mobility among the uranium miners, with many people working for short periods of time at different mines, so that the AIF separated the annual exposure data into two sets, \"all persons assigned to work underground\" and \"persons who worked underground 1,500 hours or more\" i.e., full time.\nIt appears that, for most underground uranium mine workers, the mining industry already can meet a radon progeny standard below the current level of 4 WLM annual exposure.\nIf the radon progeny exposure standard was set at 1 WLM, approximately one-third of all underground workers and less than two-thirds of the full-time underground workers would be exposed above a\n\n# In the case of nonuranium mines in the United States, it is clear they can meet a lower exposure standard, based on the limited data submitted by the mining companies to MSHA (Appendix Table A-5).\nOf those nonuranium mine workers whose exposures to radon progeny were recorded, the upper limits of exposure varied from 0.16 to 2.20 WL, depending upon the mining industry (Appendix Table A-1). Acknowledging the limitations on the way exposure data is collected (Appendix A, section A.2.a.), the mining companies submitted information to MSHA which suggests that no more than 450 individuals are occasionally exposed to substantial radon progeny levels (i.e., 0.3 WL and above) (Appendix Table A-5). During 1983, these radon progeny exposed employees were found in only 4 nonuranium mines, out of a total of about 574 U.S. nonuranium metal and nonmetal underground mines. Therefore, it should be feasible to control the radon progeny exposures encountered by these 450 (or fewer) miners.\n\n# B. The Technological C apacity to F u rth er Reduce Exposure\nSome of the highest radon progeny exposures are received by people working in the smallest uranium mines, those employing less than ten people . Probably, these small mines can improve their ventilation systems and reduce worker exposures. Currently, many of these small mines are not operating due to the depressed prices for uranium.\n\n# There are a variety of techniques besides ventilation that can reduce workers' radiation exposures (Appendix B).\nIn general, these techniques are more costly and less effective than ventilation. Nevertheless, these methods, in addition to ventilation, could be used to decrease the exposures of the relatively small number of uranium workers (46 during 1982) It should be technically feasible for the mining industry to control the radon progeny exposures of these relatively few workers receiving substantial exposures. Also, an engineering analysis (based on data from only two mines) suggested that it is technically feasible for uranium mines to meet a standard as low as 1 WLM, using control techniques such as ventilation, bulkheads, and backfilling.\n\n# VI. CONCLUSION\n\n# Each of the five primary epidemiologic studies contained strengths and limitations.\nAll of the studies rely on incomplete radon progeny exposure estimates to calculate the cumulative exposures of the underground miner cohorts. Nevertheless, they contain sufficient strength to demonstrate an excess lung cancer risk associated with radon progeny exposure. Also, an exposure-response relationship exists between cumulative radon progeny exposure and lung cancer mortality . Statistically significant SMR's above 400 were observed in three studies, where workers accumulated mean exposures above 100 WLM , Statistically significant SMR's between 140 and 390 were observed in two studies , where workers accumulated mean exposures below 100 WLM, and in preliminary findings from a third study by Tirmarche et al. (1985) where workers probably accumulated mean exposures below 100 WLM , NIOSH acknowledges the efforts of various groups to compare attributable and relative risk estimates across different epidemiologic studies. NIOSH can neither validate nor refute these findings.\nAt this point, without access to the raw data and more specific information about epidemiologic methods, NIOSH is unwilling to speculate or make comparisons between the attributable or relative risk estimates in the five primary studies.\nThere were several classifications for identifying a substance as a carcinogen. \"Potential occupational carcinogen\" means any substance, or combination or mixture of substances, which causes an increased incidence of benign and/or malignant neoplasms, or a substantial decrease in the latency period between exposure and onset of neoplasms in humans or in one or more experimental mammalian species as the result of any oral, respiratory or dermal exposure, or any other exposure which results in the induction of tumors at a site other than the site of administration.\n\n# Such classifications have been developed by the National\nThis definition also includes any substance which is metabolized into one or more potential occupational carcinogens by mammals.\nSince exposure to radon progeny has been shown to produce lung cancer in underground miners, it meets the OSHA criteria; thus, radon progeny should be considered an occupational carcinogen. Data on the current radon progeny exposures of uranium, metal, and nonmetal miners suggests that the mining industry, overall, is already capable of meeting a radon progeny standard below the current annual limit of 4 WLM. Recent limited research (based on data from only 2 mines) suggests that, using ventilation, bulkheads, and backfilling, it is technically feasible for mines to meet a standard as low as 1 WLM.\nAt the present time, there is no effective medical method to prevent or treat lung cancer to radon progeny exposure. Also, there is insufficient evidence to support an association between a specific lung cancer cell type and radon progeny exposure . Only exposure prevention measures are effective in lowering radon progeny induced lung cancer rates. These preventive measures include lowering the radon progeny exposures of underground uranium miners (and perhaps some underground metal and nonmetal miners), especially those that receive annual cumulative exposures near the present limit of 4 WLM. An additional measure is to encourage miners to stop smoking, because smoking and radon progeny exposure may act multiplicatively, or at least additively, to cause lung cancer.\nFinally, a lowering of exposure, especially for the workers currently exposed near 4 WLM, is recommended. Recent information suggests that it is technically feasible to control radon progeny exposures to levels as low as 1 WLM. NIOSH wishes to withhold a recommendation for a specific PEL, until completion of a quantitative risk assessment, which is now in progress.\nIn addition, the specific medical recommendations listed in Chapter IV should be implemented.\n\n# A. Current Work Force\n\n# Uranium Miners a. M iners in th e U nited S tates\nThe number of underground mine workers (including miners and service and support staff) dropped from approximately 5,037 in 1980 to 2,150 in 1982 (Table A-2). The number of underground miners, the group receiving the highest exposures, dropped from 2,760 to 1,275. This decrease was due to a recent fall in the price of uranium and reduced uranium demand.\nIn the mines in the United States there are numerous temporary, short-term workers; in 1978, out of all employees who worked underground, only 46 percent worked 1,500 or more hours underground (i.e., full-time).\n\n# b. M iners Outside th e U nited S tates\nCzechoslovakia, China, France, Italy, Australia, Canada, and Argentina have underground uranium mines (see Table A-3\n\n# Ill\n\n# B. C urrent Exposures in M ining\n\n# Stanley\nEquity Gold Inc.\n\n# Leadv i 1 1 e Un i t Asarco\n\n# Revenue -Vi rginius Ranchers\n-- -- -- Baryte 0.2 -- -- -- Coal 0.1 -- -- --\n\n# South Africa 1973\n-- In mines where production employees also perform maintenance, service and supervisory duties., such employees were classified as production workers. In cases where corporations had widely separated operations under different managers, each was considered a separate operation. cProduction includes production and development miners.\n\n# Exposure of U.S. underground uranium miners to radon daughters in 1979 as\nIn mines where production employees also perform maintenance, service and supervisory duties, such employees were classified as production workers. \"Maintenance includes mechanics and electricians.\nService includes motormen, haulage crews, drift repairmen, station tenders, skip tenders, etc. 'Salaried includes engineers, supervisors, geologists and ventilation personnel. uranium mines in the United States, this figure is somewhat misleading. These workers can receive high exposures, and because they only work for short periods of time, their annual average exposure is low. The average exposure for those miners working full time, that is over 1,500 hours underground, was higher; 1.45 WLM in 1978.\nUnderground mining exposure records were placed into four general job categories by the AIF, i.e., production, maintenance, service, and salaried. As a group, the production workers who worked more than 1,500 hours underground should have higher exposures than the remaining uranium mining work force.\nIn 1978, the average exposure of these workers was 1.74 WLM (see Table A-7) and in 1979 their average exposure was approximately 1.88 WLM .\nIn contrast, in 1979 and 1980, MSHA inspectors recorded average radon progeny WL concentrations for underground uranium mining production workers of 0.30 WL or higher, which means that some of these workers could receive 4 WLM or more per year. Cooper estimated that the average annual exposure of full-time underground production workers was about 2. 9 WLM during 1979 . The number of workers that receive these high exposure levels may be small; AIF reported that among full-time underground uranium miners in 1979, only 3 out of 1,711 production workers and 3 out of 488 maintenance workers received more than 4 WLM annually (see Tables A-10 and A-11).\nOverall, most uranium mine workers' (including those workers who spend only part of their time underground) exposure is well below the standard of 4 WLM and on the average may be about 1 WLM , (see Table A -7). A relatively small number of workers, primarily full-time underground production and maintenance workers, have exposures above the 4 WLM standard (see Tables A-9 through A-11). The most recent available data, for 1982, showed that only 2 underground employees (0.1 percent) received radon progeny exposures of 4.0-5.0 WLM and 44 employees (1.6 percent) received exposures of 3.0-4.0 WLM. .\nIt should be possible to lower radon progeny exposure levels for this relatively small number of miners.\n\n# b. Miners Outside the United States\nThe exposure of underground uranium miners depends on the quality of the uranium ore body and the ventilation rate.\nIn other countries, (excepting Canada) the uranium ore is frequently of a lower grade than the ore in the United States, so with good ventilation techniques, the foreign uranium miners should receive lower exposures than the miners in the United States. Recent figures for radiation exposure in underground uranium mines in Canada, France, India, Argentina, and China have been published in the literature (see Table A-3\nThe underground uranium miners of Canada had an average annual exposure to radon progeny of 0.74 WLM in 1978.\nIn 1980, the median exposure for miners in three underground mines in Saskatchewan was below 0.6 WLM and only about three workers in one mine were exposed to 3-4 WLM.\nIn addition, some of these miners had substantial gamma exposure.\nIn the Cluff mine, gamma exposures were as high as 3.5 rem and above, and in the Eldorado and Cluff mines many workers (approximately 60) were exposed to 1-3 rem .\nThe French uranium miners had average annual radon progeny exposures of 2.0 WLM and 1.4 WLM in 1978 and1979, respectively .\nIn 1975, the median radon progeny exposure was below 0.10 WL, yet as many as 5.35 percent of the workers were exposed to 0.30 to 0.80 WL, potentially receiving more than 4 WLM annually (see Table A-12) .\nIn 1975, there was also a record of gamma exposure in French underground uranium mines. The mean annual dose was 0.49 rem, but some miners received much higher doses; 9.16 percent received 1.0-1.5 rem, 5.3 percent received 1.5-2.5 rem and 0.65 percent received 2.5-3.0 rem .\nIn the underground uranium mines in France, gamma exposure may constitute a major part of the total radiation.\nThere is limited information available concerning typical radon progeny exposures in underground uranium mines in India, Argentina,and China . For the mines in India, figures for potential exposure are given by job category.\nIn 1979, the drilling crew received an estimate of 2.6 WLM of potential alpha energy exposure, the mucking crew about 2.1 WLM, and \"others\" about 1.7 WLM (see Table A -13) ,\nIn Argentina, the average annual radon progeny exposure was about 2.4 WLM during 1980.\n\n# Nonuranium Miners a. Hard Rock Miners in the United States\nSome of the highest radon progeny exposures are found in the iron, zinc, fluorspar, and bauxite mines (Table A-1).\nIn 1975, iron miners were exposed to 0.14-0.90 WL, zinc miners to 0.07-1.40 WL, fluorspar miners to 0.30-2.20 WL and bauxite miners to 0.07-1. 40 WL .\nIf these readings are typical, some hard rock miners in the United States, especially those in fluorspar mines, could have radon progeny exposures much higher than 4 WLM. However, recent data submitted by U.S. metal and non metal mining companies to MSHA suggests that no more than 450 individuals are occasionally exposed to 0.3 WL (Table A -5). During 1983, only 4 companies, 2 molybdenum, 1 phosphate and 1 tungsten, submitted individual exposure records for their employees to MSHA.\nIt is possible that the mining companies failed to report additional employees who received radon exposures, but this is the only data available. From this data, one concludes that, except for a few molybdeum, phosphate, and tungsten mines, radon progeny exposure is not a problem in U.S. hard rock mines. Thus, in general, hard rock mines should be able to meet an annual radon progeny standard below 4 WLM. , 1982, p. 199 .\n\n# b. Hard Rock Miners Outside the United States\nRadon progeny exposure levels have been measured in nonuranium mines in Finland, Italy, Norway, South Africa, Sweden, the United Kingdom and Poland (Tables A-14 to A-16) . The most recent figures for all of these countries show annual average radon progeny exposures of 2.6 WLM or less. However, in many of these countries the average potential alpha energy concentrations exceed 0.3 WL, suggesting that individual miners may be exposed to more than 4 WLM per year (if they work full time during the year). Nonuranium miners (especially iron, zinc, lead, copper, or gold miners) in Italy, Poland, South Africa, and Great Britain may be exposed to more than 4 WLM annually .\nIn the United Kingdom, 4 percent of the noncoal miners were exposed to 4 WLM or more, however, many of the miners did not work full 8-hour shifts.\nIf the underground noncoal miners in the United Kingdom worked full 8-hour shifts, as many as 20 percent of the workers could be exposed above 4 WLM/yr . Recent reports for five Chinese tin mines showed radon progeny levels of 0.67 to 1.73 WL during 1978 . 22 It may be most effective to combine some of these techniques, e.g., to use positive pressure ventilation in combination with procedures to decrease the volume of the mine air needing ventilation, such as bulkheads or backfilling. Bulkheads could be made more secure against radon gas leaks by maintaining a slight negative pressure behind the bulkhead and painting sealant on nearby exposed rock. Finally, most of the techniques described in Table B-1 and in this chapter will decrease inhalation exposure to alpha radiation from the decay products of radon and thoron gases, but won't affect gamma radiation levels.\n\n# Mechanical Ventilation\nMechanical ventilation is the primary and most successful technique currently in use for reducing exposure to radon decay products. In uranium mines in the United States, during the early 1950's before mechanical ventilation became prevalent, average measurements of 2-200 WL of radon decay products were common .\nIn contrast, during 1979 and 1980, the highest average working level for radon progeny recorded by MSHA was 0.46 WL (Table B-2). Thus, there has been a great decrease in exposure to radon decay products in uranium mines primarily due to improvement in ventilation.\nSweden has also successfully reduced radon progeny levels in nonuranium mines with mechanical ventilation.\nThe average annual exposure for the nonuranium miners of Sweden was 4.7 WLM in 1970, due to ventilation improvements, and decreased to 0.7 WLM in 1980 .\nIn the case of uranium miners in the United States, it is not clear whether there could be significant further decreases in exposures to radon decay products with ventilation improvements alone. These few mines may need to use other techniques, besides dilution ventilation, to reduce miners' exposure to radon progeny (Table B-1).\n\n# Other Dust Control Methods\nSpraying water and delaying blasting until the end of shifts are two other dust control methods currently in use in most underground uranium mines. Most mines use these methods to control silica dust, but in uranium mines these methods can help control uranium ore dust.\nDrilling and blasting are two mining activities that generate high levels of uranium ore dust. Exposure to uranium ore dust alone may be carcinogenic, and high dust or smoke levels may modify the respiratory tract distribution of a miner's exposure to radon progeny (by increasing the proportion of radon progeny attached to respirable and nonrespirable size dust particles).\nIn wet drilling, water sprays from the drill onto If a person approaches or exceeds the lifetime limit on exposure, they are trans ferred to another job at a lower exposure level with retention of pay, if available, or are removed from work at full pay if another job is not available. Advantages: Protects individual miners against high cumulative exposures. Disadvantages: Spreads exposure over a larger number of people. This system works best when used with a reliable bioassay for exposure, which is not available in the case of radon gas or progeny. Medical removal may not be effective if intense, short-term exposure to inhaled alpha radiation is more hazardous than cumulative radiation exposure.\n(Cont i nued) The drills are equipped with automatic water valves that turn the water and compressed air on simultaneously. (These techniques have been used in mines since the 1930's.) Advantages: The water cuts down on radioactive uranium ore dust. Disadvantages: Difficult to set up in areas where water is scarce. The miners us i ng the drill get w e t .\nDynamite blasting at the end of shift, instead of throughout the day, reduces exposure to dust and smoke. Also, radon gas levels tend to be high immediately after blasting .\nAdvantages: Most miners have less exposure to dust and smoke particles and thus less radiation exposure. Disadvantages: Extra production schedule planning is necessary.\nThis involves the use of fan maintenance, backup electrical systems, and spare fans to minimize fan shutdowns during working hours.\nPositive pressure at the rock surface is a barrier to radon flow. One drawback is that high positive pressure in one area may force the radon into nearby low pressure areas .\n(Cont inued) Exhaust ventilation removes radon, thoron and daughters, as well as diesel fumes, but it also increases the emission of radon from the surrounding rock by creating a negative pressure.\nPositive pressure ventilation is shut down during times when the mine is inactive, creating a temporary negative pressure. This results in energy savings during the shut down periods.\nThe best ventilation method to use depends on the mine topography and production schedule. Ventilation methods may be most effective when used in combination with techniques that cut down on the area needing ventilation, such as bulkheads and backfilling .\nThe filter respirator covers the miner's mouth and nose and filters the mine air through fiber filters .\nAdvantages: As a temporary short-term protective measure, the half-mask respirator affords approximately greater than 90 percent efficiency in reduction of miner's exposure to radon daughters attached to dusts, fumes, and mists. Disadvantages: The respirators may hinder vision, be warm to use under some working conditions, add significant resistance to the miner's breathing and require careful maintenance to assure their continued effectiveness. Filter respirators must be carefully fitted to each wearer, using quantitative respirator fit tests. Only MSHA/NIOSH-certified respirators shall be u s e d .\n(Cont inued) the rock while the drill operates, thus decreasing dust levels. Miners also wet down muck piles and the walls of some tunnels to control dust. Since the 1930's these two techniques have been used in some mines. Blasting increases uranium ore dust and radon gas levels remain high for about an hour afterwards . Delaying blasting until the end of the work-shift removes the miner from an area with high dust and radon gas levels, and allows the ventilation system to reduce these levels before the miner returns to work.\n\n# Additional Control Methods\nAir cleaning equipment, filter respirators, and separate air supplies are seldom used in the underground mining environment. An air cleaning apparatus can remove dust, but it is expensive compared to traditional ventilation methods and is most useful in circumscribed areas .\nFilter respirators and supplied-air respirators are difficult to use in the mining environment and their use should be limited to emergency conditions, such as temporary excursions of the radon progeny concentrations above 1 WL. Respirators tend to restrict movement and vision, may be too warm to wear, have significant breathing resistance, and require careful maintenance and fitting to assure their continued effectiveness. Only MSHA/NIOSH-certified respirators shall be used. Another radon progeny control method is robotics or increased automation. Techniques, such as robotics, that minimize the time the miner spends in the high exposure areas of the mine and in activities such as drilling, blasting, or loading ore, will decrease the miner's radiation exposure. Although, at present, robotics has a limited place in the mines, it may be possible in the future to further automate the uranium ore mining process.\n\n# B. A dm inistrative Controls\n\n# Medical Removal Protection\nOne type of administrative control is a medical removal protection (MRP) program. Under this program, when an individual's exposure approaches or exceeds a certain limit, the person is reassigned to an area with a lower exposure level. The MRP program has been very effective in reducing exposure in the (noncarcinogenic) lead industries . In this case, blood lead levels could be used as a method to biologically monitor a worker's lead exposure. However, MRP has certain drawbacks when used as an administrative control for exposure to a known human carcinogen such as radon progeny in underground uranium mines.\nFirst, according to our current knowledge of radiation carcinogenesis, it is prudent public health policy to presume that there is no threshold for radon-progeny-induced cancer, and thus no exposure can be assumed to be safe. Therefore, the high exposure individuals who are removed from the job are protected against further radon progeny risk, but the radon progeny exposure (and risk) is spread out over a larger population of workers. Second, at this time, there is no good biological monitoring method for radon progeny exposure because the primary health effect is a carcinogenic, rather than a toxicologic, response. Routine, periodic 132 sputum cytological examinations and chest X-rays are not effective screening tests for the detection of early reversible signs of lung cancer, and cancer itself may only appear after years of exposure. Finally, respirators (as they are presently designed) are very difficult to use in the underground mining environment.\n\n# Alarm Systems\nAnother type of administrative control involves the use of alarm systems. This method has been fairly effective in coal mines where continuous monitors for methane gas have been tied to alarm systems. Reliable continuous monitors for radon progeny are now technically feasible (see ) and could be connected to alarm systems, as well as the control center for the ventilation system. The person who controls the ventilation could increase air movement in mine areas with high radon progeny levels. Also, the continuous monitors might be useful for enforcement purposes, because the MSHA inspector would have a record of excessive radon progeny measurements levels since the last inspection. For recordkeeping and enforcement purposes, the use of data from continuous alarm-monitors would depend heavily on the reliability and validity of these devices, as well as their durability and security from tampering in the mine environment.\n\n# Contract Mining\nMany underground uranium miners, especially those that drill, blast, and move ore, are given incentive bonuses for the volume of ore removed. Such a system encourages high productivity from the workers, but any time they spend on safety measures means less time to spend mining ore. The contract mining system also encourages miners to work overtime, thus increasing their cumulative internal and external radiation exposures. In addition, some miners, especially before the reduced demand for uranium, went from mine to mine working uranium ore one month and gold the next, getting radon progeny exposures in both locations. This mobility of the work force makes it harder to monitor and track the miners' total radiation exposure, making it more likely that a miner could receive cumulative exposures in excess of current and future standards. One type of administrative control is to modify the contract mining system so that workers would have more incentive to protect their own health on the job. This issue needs further study and discussion, including input from the mining industries, unions, and contract miners.\n\n# GLOSSARY\nAbsorbed Do s e : The amount of energy absorbed by ionizing radiation per unit mass. Absorbed doses are expressed in units of rads or grays, or in prefixed forms of these units such as millirad (mrad, 10~3 rad), microrad (urad, 10-® rad), etc.- The gray (Gy) is equal to 1 joule per kilogram (1 J/kg). The £ad is equal to 6.24 x 10® MeV per gram, or 100 ergs per gram. One gray = 100 rad.\nAdditive Relative Risk Mod e l : The relative risk from the combined exposure to radon progeny and smoking equals the sum of the risks from each exposure considered separately. One example of an additive linear relative risk mode I is: Person-Years at Risk (PYR): In a lifetable analysis, the number of PY at risk of dying from disease, usually calculated from the time the miner enters the cohort until death or the end of follow-up. Some authors adjust the PYR for an assumed 10-year latent period for lung cancer by subtracting PYR accumulated during the first 10 years after a miner starts to work underground (see above, (Lagging)).\nR = 1+B,\nPotential Alpha Energy Concentration (PAEC): May cause biological damage during the radioactive decay of radon or thoron gases and their progeny, is measured in units called Working Levels (see below).\n\n# Proportional Mortality Ratio (PMR):\nThe ratio of two mortality proportions, expressed as a percentage, often adjusted for age or time differences between the two groups being compared.- Prospect ive: A study characteristic. Disease has not occurred in study groups at the start of a study. Units of Radioactivity: Curie and BecguereI 1 curie = 2.22 x 10^2 disintegrations/minute 1 becquerel (Bq) = 1 d/sec 1 picocurie (pCi) = 2.22 d/minute Radioactive Decay: Disintegration of the nucleus of an unstable nuclide by spontaneous emission of charged particles, photons, or both. Radon (Rn) or Radon and its Progeny: Specifically refers to the \"parent\" noble gas (Rn-222), and its short-lived alpha-radiation-emitting radioactive decay products (\"progeny\" or \"daughters\"). Radon is a gas, the radon progeny are radioactive solids. Rads and rems are comparable (i.e., the quality factor (QF) = 1) when dealing with beta particles and gamma photons. The QF for alpha particles from inhaled radon progeny are generally considered to be in the range of 10 to 20.\nRetrospective: A study characteristic. Disease has already occurred in study groups at the start of a study. Standardization: A procedure to reduce the biasing effect of a confounding variable. A feature of data analysis.\n\n# Standardized Mortality Ratio (SMR):\nThe ratio of mortality rates, expressed as percentage, usually adjusted for age or time differences between the two groups being compared. Synergism: The combined action of two factors which is greater than the sum of the actions of each of them.\nThoron: A radioactive gas (Rn-220), sometimes found in the presence of radon (Rn-222). Thoron progeny are the solid, short-lived, alpha radiation emitting decay products (progeny or daughters) of thoron gas.\nWorking Level (WL): A standard measure of the alpha radiation energy in air. This energy can come from the radioactive decay of radon (Rn-222) and thoron (Rn-220) gases. The working level is defined as any combination of short-lived radon decay products per liter of air that will result in the emission of 1.3 x 10^ million electron volts (MeV) of alpha energy.\nWorking Level Month (WLM): A person exposed to 1 WL for 170 hours is said to have acquired an exposure of one Working Level Month. The Mine Safety and Health Administration defines a Working Level Month as a person's exposure to 1 WL for 173 hours.\nTaken from Shapiro (1981) . Taken from Monson (1980) . + Taken from Thomas et a I., (1985) .\n\n# I. INTRODUCTION\nA report evaluating epidemiologic studies of lung cancer in underground miners was recently sent to the Mine Safety and Health Administration (MSHA) by the National Institute for Occupational Safety and Health (NIOSH).\nThat report concluded that prolonged exposure to radon progeny at the current standard of 4 WLM/year produced an elevated risk of death from lung cancer. It is the objective of this report to make quantitative risk estimates for various levels of cumulative exposure. In addition, other factors influencing the exposure-risk relationship will be identified and quantified whenever possible.\nThis report is based upon data collected from a cohort consisting of 3366 white underground uranium miners working in the Colorado Plateau (located within the states of Colorado, Utah, New Mexico and Arizona).\nThe actual risk estimates were computed from data on 3346 members of the cohort.\nTen original members were determined to have had no record of underground mining, four were non-white, and six had inadequate cigarette smoking i nformat ion.\nEntry into the cohort was defined by race, sex, working at least one month in underground uranium mines, volunteering for at least one medical survey between 1950 and 1960, and providing social and occupational data of sufficient detail .\nNIOSH has now updated the mortality experience of the cohort through December 31, 1982. Lung Cancer mortality was defined as anyone assigned an International Classification of Disease (ICD) code of 162 or 163 (same designation in Sixth through Ninth Revisions).\nPrevious analyses of this cohort reported by Waxwei ler et a l . and Whittemore and McMillan considered follow-up only through 1977. Table 1 presents a comparison of vital status of the cohort at the end of 1977 and 1982.\n\n# II. PROTOCOL FOR STATISTICAL ANALYSIS\nMuch of the epidemiologic work in the past regarding the analysis of mortality in occupational cohorts has involved modified life table analysis. This form of analysis has a strong appeal due to its familiarity and ease of interpretation.\nIt is mathematically straight forward since person-years at risk are simply divided into a number of strata and age-calendar year specific mortality rates from some reference population are applied to each.\nThe U.S. population is often used as the reference population in such life table analyses.\nThis expected mortality is then compared to the observed mortality via a ratio defined as:\n\n# A. Type of Analysis Used\n2 o SMR; = i i j 2 E ij i\nwhere SMR = standardized mortality ratio for cause j Ojj = the observed number of deaths for cause j in stratum i and Ejj = the expected number of deaths for cause j in stratum i from reference population rates If the total number of observed deaths in all of the strata of interest is large and if the reference population is the appropriate comparison group, this would be the method of choice. No modeling would be needed in such a situation.\nHowever, after stratification by age, race, sex, calendar year, other confounders, and finally the exposure of interest, there are seldom enough observed deaths to make rates in these strata reliable.\nAnother problem frequently encountered is a fundamental difference in certain etiologic characteristics between the study population and the reference population.\nFor example, the study group may smoke at substantially different rates than the reference population.\nOften the occupational study group is \"healthier\" than the reference population due to selection criteria for employment (Enterline ). This is usually referred to as the \"healthy worker effect.\"\nAn alternative to use of the modified life table approach is some form of statistical modeling. Modeling to estimate health risks is necessary when conclusions must be drawn about risk in regions of the exposure-response relationship for which data are too sparse to estimate risk directly.\nThe use of models also permits risk estimates to be simultaneously adjusted for confounders, such as age or co-carcinogenic exposures, as well as interactions between exposure and other risk factors.\nThis flexibility is particularly important in making risk estimates at relatively low cumulative exposures when using the Colorado Plateau data.\nMost miners in this cohort were exposed to high levels of radon progeny (mean exposure = 834 WLM).\nSince primary interest in risk estimates is below 120 WLM based on current exposures, some type of statistical model is essential.\nThere have been a number of types of models suggested for examination of cause-specific mortality as a function of various risk factors.\nThe two most popular types of models are the absolute risk model and the relative risk model. The absolute risk model can be written as: R(t ;z) = Rg(t) + R ( z , /?) where R9t;z) is the incidence at age t for someone with risk factors z, Rg(t) is the baseline or background incidence at age t and R(z, ) is the incremental incidence as a function of the risk factors z, and coefficients which are estimated from the data.\nThis form of risk model was not used in the risk assessment since it had been rejected due to poor fit to the U.S. uranium miner data by Lundin et al. .\nIn contrast, the relative risk model generally takes the form: R(t;z) = R0 (t) R(z,0). This model assumes that excess risk is proportional to background incidence rates.\nRelative risk models have become increasingly popular in recent years and were found to provide good fits to the data from earlier follow-ups of the U.S. uranium miners cohort by Lundin et al. and Whittemore and McMillan . This type of model has been selected as the basic analytical method for this report.\n\n# B. The Proportional Hazards Modei\nA relative risk model which is particularly well-suited to longitudinal mortality studies is one proposed by Cox .\nThis model is commonly referred to as the Cox proportional hazards model.\nA major advantage of this approach over the more common life table method is that it permits the use of internal comparison groups while controlling simultaneously for such confounders as cigarette smoking, age, and year of birth.\nIn addition, time-dependent covariates such as cumulative exposure may be incorporated into the model. This is essential in any longitudinal study where follow-up and the exposure period overlap.\nRelative risk estimates are based on rate ratios similar to those produced in the modified life table analysis.\nThat is, the Cox model operates in a dynamic framework by considering incidence rates over the entire period of follow-up.\nThe Cox model can be expressed mathematically as:\nX(t;z) = X 0 (t)exp(£z(t))\nwhere X(t;z) for this study is the age-specific lung cancer mortality rate for a miner with exposure and other risk factors represented by a covariate vector z.\nThe underlying age-specific lung cancer mortality rate for the unexposed is represented byAo(t).\nThe function exp(J3z) is generally used to model risk of death from the cause of interest which depends upon the risk factors z and the coefficients ^ which are estimated from the data.\n\n# C. Alternative Forms of the Risk Function\nAlthough the exponential or log-linear function exp(0z) is the usual choice of a model for risk, any positive function may be used as long as the risk function is equal to 1.0 when the coefficients are all equal to zero. The most common alternative risk functions are the linear (1 + 0z) and the power function (exp( /?1nz) = z^ ).\nAll three forms of risk functions were considered in modeling the U.S. uranium miners data.\n\n# D. Results of Model Development\n\n# Ident i f ic a t ion of Confounders and/or E ffe c t Mod i f iers\nCumulative exposure as measured by total WLM for each miner was the primary exposure variable. Since cigarette smoking is known to have a strong effect upon the risk of lung cancer, cumulative smoking history as measured in pack-years was also included in the model.\nAnother risk factor strongly associated with lung cancer mortality is age.\nThis was tightly controlled by using age as the time dimension t in the model A(t;z).\nThat is, the age at death of each lung cancer victim was recorded and all other miners alive and at risk were compared to him at that age.\nIn this way, the cumulative exposure to radon daughters and pack-years of cigarettes were incorporated as time-dependent covariates by calculating their values at each age of death from lung cancer. This assures that proper age-adjusted comparisons were made throughout the period of follow-up.\nA number of other variables were examined in developing the appropriate risk model.\nA list of all potential risk factors considered for inclusion in the model are provided in Table 2.\nThese variables were considered independently as potential confounders in a stepwise fashion (both backward and forward selection procedures) and also as potential effect modifiers by assessing their interaction with cumulative radon daughter exposure.\nAn attempt was made to compare the fit of each of the three models during the model development stage of the analysis.\nHowever, it soon became apparent that the linear model did not fit well over the full range of radon daughter exposures and cumulative smoking levels. In fact, the iterative solution to the likelihood equations would not converge when using the linear model when both cumulative exposure and pack-years of smoking were both entered simultaneously (either as linear or linear-quadratic forms).\nThe linear model could only be made to converge when the model was restricted to cumulative exposure below 600 WLM with no other covariates included.\nThe restricted linear model resulted in a non-significant result in this exposure range and was subsequently eliminated from consideration.\nOf the remaining two types of relative risk models (log-linear and power function), the covariates found to be most highly associated with lung cancer incidence rates were cumulative exposure (WLM), cumulative smoking (packs), and age at initial exposure (months). Table 3 illustrates the form and degree of fit as measured by the likelihood 1BGR -background radon exposure = 0.2 WLM/year BGS = background cigarette smoking = 0.005 packs/day ratio for these two models.\nThe log-linear model required the addition of quadratic terms in cumulative exposure and cigarette smoking to provide an adequate fit.\nThis was not necessary when developing the power function model.\nAs shown in Table 3, the power function model provided the best fit to the data and will be used hereafter in the risk assessment.\nSince the power function model involves the natural logarithms of cumulative exposure and cumulative cigarette smoking, zero values of these variables were not permitted.\nIn order to avoid this an estimate of cumulative background exposure was added to each miner's cumulative radon daughter and cigarette totals.\nBased upon estimates of the NCRP (Report No. 77, 1984), 0.2 WLM per year since birth were added to each miner's exposure totals. This is the estimated background exposure in the U.S. and is also the amount used by Whittemore and McMillan in an earlier analysis.\nIn a similar fashion 0.005 packs per day were added for each day since birth to the cumulative smoking totals based upon estimates of Hinds and First .\nOf particular interest is the joint effect of exposure to radon daughters and cigarette smoking.\nTherefore, the interaction of radon daughter exposure and cigarette smoking was included in the multiplicative power function model.\nThe results showed a negative, borderline significant result ( |3=0.087,p=0.058). When a similar analysis was run with mortality data complete only through 1977, there was no indication of a significant negative effect. Therefore, based on more complete follow-up through 1982, the joint effect of radon daughter exposure and cigarette smoking appears to be slightly less than multiplicative but greater than additive. This is similar to the finding of Thomas and McNeill in their grouped data analysis of the five major radon daughter cohorts.\nIt is still consistent with a synergistic effect of radon exposure and cigarette smoking which is usually defined as a joint effect exceeding the sum of the individual effects.\n\n# Weighting Exposure Over Time\nAn important consideration in fitting any of these models was the proper time-weighting of exposure.\nSince most forms of cancer, including lung cancer, have relatively long latency periods between exposure and manifestation of the disease, some weighting of exposure over time is appropriate.\nThe most common weighting scheme is commonly referred to as lagging.\nThis involves elimination of any exposure accumulated in a specified period of years before death from lung cancer.\nThis provides a way of considering only that exposure that had a reasonable chance of causing death from lung cancer.\nObviously exposures received in the few years immediately prior to lung cancer deaths are ineffective in the exposure-response relationship.\nIn order to investigate the appropriate number of years to lag exposure in this cohort, a series of lags ranging from 0 to 12 years was used. Figure 1 illustrates the results of these trials.\nIt is evident from the improved fit, as measured by the log-likelihood of the model, that a lag of 6 years for cumulative exposure is the best choice for this analysis.\nCumulative cigarette smoking was rather insensitive to the amount of lag in the range of 0 to 12 years. Therefore, for the purpose of consistency cumulative smoking was also lagged 6 years. This contrasts to the lag of 10 years chosen by Whittemore and McMillan for these data and also by Muller et al. for the Canadian data. Their choices were somewhat arbitrary and largely based on knowledge that most cancers involve relatively long latency periods. The implications of a shorter lag will be discussed in a later section of this report.\nAn issue related to lagging of cumulative exposure and cumulative cigarette smoking is the lack of information on these variables in recent years.\nRadon daughter exposure was last updated in 1969. However, the absence of current exposure information should have minimal impact upon this analysis since over 90% of the miners in the cohort had retired from uranium mining for more than one year by 1969.\nThose few who continued mining were exposed at levels considerably less than those experienced in earlier years.\nSince cigarette smoking status was also unknown after 1969, all miners still smoking at that time were assumed to continue at their last recorded smoking rate.\nNIOSH is currently conducting a survey of radon daughter exposure and cigarette smoking status subsequent to 1969, but this information will not be available for at least another year.\nThe aim of lagging exposure is the elimination of exposure which is not etiologically responsible for lung cancer mortality. An implicit assumption in the use of this technique is that exposure changes from completely effective to completely ineffective at one instant in time. The actual form of this weighting function is illustrated in Figure 2. Because of the biological implausibi Iity of such a situation, Land proposed that the effectiveness of cumulative exposure be linearly phased in over a period of several years.\nAn illustration of such a weighting function is provided in Figure 3.\nConsequently, we tried various combinations of lagging and linear partial weighting with the combination illustrated in Figure 3 providing the best fit, i.e. a lag of 4 years followed by linear partial weighting in the period 4-10 years prior to death from lung cancer.\nThis scheme provided a fit essentially the same as that of a simple lag of six years but was chosen over lagging because of its biological plausibility.\n\n# INFLUENCE OF TEMPORAL FACTORS\nPerhaps the most difficult aspect of producing a valid quantitative risk assessment is dealing with the effects of various time-related factors upon the exposure-risk relationship.\nOne very important temporal influence concerns the two components of cumulative exposure itself.\nIn most longitudinal studies the quantitative exposure index is some form of cumulative exposure.\nHowever, cumulative exposure is actually the product of duration of exposure and intensity or rate of exposure.\nWhen one uses cumulative exposure in assessing risk, the implicit assumption is that high exposure rates for short periods of time are equivalent etiologically to low exposures for long periods of time, all else being equal.\nA number of investigators have examined the effect of exposure rate in the U.S. uranium miner data. Whittemore and McMillan ) found no statistically significant effect of exposure rate.\nLundin et al . in the 1971 monograph concluded that there was no significant evidence of an exposure rate effect in the 120-360 WLM cumulative exposure range. These investigators apparently defined exposure rate as the ratio of total cumulative exposure and duration of employment (defined as the period of time between first and last employment in underground uranium mining work histories).\nFor most forms of employment, this is the accepted definition of average exposure rate.\nHowever, underground uranium mining is a very sporadic form of employment.\nThe actual time spent underground was often a relatively small fraction of the total employment history. Therefore, exposure rate as defined by cumulative exposure divided by the number of months actually spent underground is often a very different measure than that obtained by using duration of employment in the denominator.\nConsequently, the effect of exposure rate was re-examined using the actual average exposure rate experienced while underground, eliminating any gaps in employment.\nAlthough earlier analyses using total duration of employment produced negative but non-significant results, the refined definition showed a statistically significant negative exposure rate effect (p =-0.043, p<0.001) as shown in Table 4.\nThis implies that among groups of miners receiving equivalent cumulative exposures, those exposed to lower levels for longer periods of time are at greater risk of lung cancer.\nBecause the coefficient is relatively small, however, an appreciable effect upon risk of lung cancer would not be expected unless rates were different by an order of magnitude, i.e., a miner with exposure received at a rate ten times lower than a miner of the same age, smoking habits, and cumulative exposure would have (0.1)~-043= i i o 4 or 10.4% greater risk of lung cancer.\nBecause a negative exposure rate effect is very important and potentially controversial, it was examined in more depth.\nOf particular interest was the possibility that this effect was different at low versus high cumulative exposure levels.\nConsequently, the homogeneity of this effect across the full exposure range was examined by forming two sub-cohorts: one below the mean exposure (834 WLM) and one above the mean.\nThe interaction of the exposure rate effect with these two strata was then tested. Results showed a significant interaction ( P=0.157, P=0.019). The direction of the A. Exposure-Rate Effect Background for cumulative radon daughter exposure: BGR=0.4 WLM/year Background for cumulative cigarette smoking: BGS=0.005 packs/day interaction indicated that the exposure rate effect was stronger in the lower cumulative exposure range (0-834 WLM). Specifically, a miner who received total exposure below 834 WLM at rate one tenth as great as another miner of the same age, smoking status and cumulative exposure would have a 58 percent greater risk of lung cancer.\nHowever, the increased risk would only be 10 percent at the lower exposure rate for miners in the 834-10,000 WLM range.\nAlthough a statistically significant negative exposure-rate effect had not been found previously in this U.S. cohort, there is considerable evidence of such findings in animal studies of high LET radiation. Raabe et al . reported a strong low dose-rate effect in beagles exposed to internally deposited isotopes of radium and strontium.\nRisk of bone cancer was as much as ten times as great per unit dose for low rates as compared to the highest rates used. Cross et a l . found a negative dose-rate effect for risk of lung tumors in rats exposed to airborne radon daughters. Chameaud et al. found similar results in a French study of Sprague-Dawley rats exposed to inhalation of radon decay products.\nHill et a l . found reduced dose rates of fission-spectrum neutrons produced significantly higher neoplastic transformation rates per rad in cell cultures of C3H mouse embryos. Although all of these studies show low dose-rate effects, no study as yet, animal or human, has investigated such effects at the very low dose rates currently found in well-ventilated uranium mines.\n\n# B. Calendar Time\nIt is well-known that mortality patterns change over time.\nSuch exogenous risk factors as the prevalence of smoking and alcohol consumption, medical care, and various life style characteristics are all influenced by a changing society.\nTherefore, the effect of calendar time upon risk estimates, often called the cohort effect, must be controlled.\nThe analysis of the U.S. uranium miners cohort was stratified by decade of birth so that miners dying of lung cancer were compared only to those members of the cohort at the same age and who were born within 10 years of the case.\nThe usual assumption in a stratified analysis is that baseline mortality rates may be different from stratum to stratum but the relat i ve risk is the same across all strata for miners with comparable risk factors.\nIn order to check this assumption, the interaction of cumulative radon daughter exposure and birth decade was examined.\nResults indicated a statistically significant positive interaction ( P=0.173,P=0.002). This implies that miners born in later decades are at a greater risk of lung cancer per unit of exposure when compared to miners of the same age born earlier.\nSince miners born in later decades were exposed at lower exposure rates, this result could be associated with the negative exposure rate effect described ear Iier.\n\n# C. M ultistage Theory of Carcinogenesis\nOne of the most popular theories for explaining the temporal patterns in mortality studies of carcinogenesis is the multistage model. Originally proposed by Muller and Nordling and later refined by Armitage and Doll , the multistage theory predicts an increase in cancer incidence as a function of time since exposure to some carcinogen. In general, the theory proposes that a malignant tumor arises from a single cell which has undergone a series of heritable changes. The changes may be thought of as distinct stages in the carcinogenic process, each with a low probability of occurrence and a slow progression time in the absence of carcinogenic exposures.\nA carcinogen may act on any or all of the stages in this process.\nCarcinogens affecting the first stage are commonly referred to as initiators, while those affecting later stages are called promoters or progressors.\nInitiators are characterized by long latency periods between initial exposure and death, often exceeding 20 years.\nPromoters, on the other hand, usually have shorter latent periods since fewer stages must be transgressed before a malignant cell is produced.\nIt is impossible to prove whether or not the mathematical form of the multistage model actually holds in a given situation.\nHowever, a number of its predictions have been verified experimentally by Peto et al. .\nTherefore, if one subscribes to some form of the multistage model, it is possible to predict whether exposure acts at an early or late stage in the carcinogenic process by examining the temporal patterns in the data. Whittemore , Day and Brown , and Brown and Chu have all reported the effect on excess relative risk of age at initial exposure and time since cessation of exposure.\nBy examining these factors, we may better understand the underlying cancer mechanism operative in this cohort.\n\n# D. Age a t I n i t i a l Exposure\nWhittemore considered the multistage model using three exposure scenarios:\nsingle exposure at one point in time, continuous exposure at a constant rate, and exposure of varying intensity.\nWhen considering the latter category (the usual occupational situation) she found that excess relative risk was a decreasing function of age at initial exposure if an early stage was affected.\nWhen a late stage is affected by exposure, however, excess relative risk is an increasing function of age at initial exposure. Day and Brown predicted the functional relationship between excess relative risk and age at initial exposure for the first four stages of a five-stage process when duration was held constant. Figure 4 illustrates their findings which are in qualitative agreement with those of Whittemore. Results of the analysis in our data, as illustrated in Table 4, indicate a positive and statistically significant coefficient for age at initial exposure (P=0.0023, P=0.003). This implies that miners initially exposed at later ages are at greater risk of lung cancer than those exposed at younger ages, all else being equal.\nSpecifically, a miner with the same radon daughter exposure and smoking history who was initially exposed ten years (120 months) later in age than another miner, would have exp(0.0023x120)=1.32 or 32% higher risk of lung cancer.\nThis result is consistent with the effect of radon daughters occurring at a late stage in the carcinogenic process.\nA similar age effect was reported by Mancuso et al. in an analysis of cancer risk in the Hanford workers exposed to who I e-body radiation.\nAn analysis of age at start of smoking amona miners resulted in a negative but non-significant coefficient (3=0. 0016,p=0.22).\nThis would imply that cigarette smoking in this cohort acted at an early to intermediate stage. It could also be consistent with the hypothesis of Doll and Peto that smoking acts at both early and late stages, which would tend to obscure predictive ability of age at start of smoking.\nA plot of the effect of age at initial exposure for both radon daughters and cigarette smoking is given in Figure 5. Day and Brown predicted the effect upon relative risk of time since cessation of exposure when a multistage model is assumed.\n\n# E. Time Since Cessation of Exposure\nThey found that when exposure begins some time after infancy, excess relative risk increases, peaks, and then decreases with time since termination of exposure when the first stage is affected. When the penultimate (next to last) stage is affected, relative risk strictly decreases with time after last exposure.\nFigure 6 illustrates their predictions for the effect of time since cessation of exposure on the first four stages in a five stage model with duration of exposure fixed at five years.\nIn order to investigate the effect of cessation of exposure on this cohort, all miners were identified who had indicated retirement from uranium mining during the course of follow-up. Approximately 95% of the cohort had retired for more than one year prior to 1970.\nThe average time since last exposure was 18.0 years for those miners not dying of lung cancer and 9.9 years for lung cancer cases.\nThe time in months since last exposure was entered as a time-dependent covariable in the original model containing log of exposure, log of smoking, and age at initial exposure.\nThe estimated coefficient of this term was negative and highly significant ( P=-0.0056,p<0.001).\nThus a miner's chances of surviving lung cancer increase dramatically with each year outside the mines.\nSpecifically, the model predicts that the risk of lung cancer 10 years after mining uranium is exp(-0.0056x120)=0.511 relative to someone still mining with the same cumulative exposure, smoking history, and age.\nWhen a similar analysis of time since cessation of cigarette smoking was run, the results were inconclusive.\nThe coefficient was very small and non-significant (P=0.003,p=0.75). However, since a relatively small number of miners were ex-smokers (7.7%) there is little power for detection of such an effect even if it actually exists.\nFigure 7 illustrates the effect of time since last exposure for both radon daughters and cigarette smoking.\nThe implication of these results are essentially the same as that obtained by examination of age at initial exposure.\nThe strong negative effect of time since last exposure implies that radon daughters act at a late stage in the carcinogenic process.\nThe effect of stopping cigarette smoking, while based on a small amount of data, still indicates either an intermediate stage effect or a combination of early and late stage effects.\n\n# E F F E C T OF T IM E S IN C E L A S T E X PO SU R E ON E X C E S S R E L A T IV E R IS K T IM E S IN C E L A S T E X P O S U R E (Y E A R S !) LE G E N D . E X PO SU R E -------------RADON S M O K IN G\n\n# IV. ERRORS IN EXPOSURE DATA AND THEIR EFFECT UPON RISK ASSESSMENT\nIn animal carcinogenesis studies, exposures or doses are usually known with a high degree of accuracy and precision. However, the same cannot be said regarding epidemiologic quantitative risk studies.\nIn most epidemiologic studies, the actual dose to target organs can only be estimated by dosimetric modeling. This is seldom attempted in quantitative risk assessments.\nThe dosimetry of radon daughter exposure is very complex, involving such factors as respiration rates, particle size distribution, deposition in the lung, and radon/radon daughter equilibrium.\nMost risk assessments are modeled as functions of some exposure index, which is the method used in this report.\nIt is the purpose of this section to estimate the magnitude of exposure errors and their effect upon quantitative risk models.\nAccording to Lundin et a l . , exposures in a given mine and year were estimated in one of four ways:\n1. actual measurements 2.\ninterpolation or extrapolation in time 3. geographic area estimation 4. estimates prior to 1950 based upon knowledge of ore bodies, ventilation practices, and earliest measurements.\nThese methods will subsequently be called Methods 1,2,3,and 4. In assessing the error associated with individual exposure determinations, it is first necessary to consider the variability introduced by each of the four methods.\n\n# A. Magnitude of Error in Exposure Data\n\n# Method 1\nTable 5 provides a frequency count of white miners working underground from 1950-68 and the mean number of samples taken in each mine visited in those years. The Kusnetz procedure for measuring radon daughters was most often used during the period of study (Johnson and Schiager 1981). This is an area monitoring method based on alpha counts collected on a filter/pump apparatus.\nThe resulting data were generally thought to be of good quality (Lundin et al., 1971).\nData from mines in which 5 or more measurements were taken in a given year were analyzed.\nThese data followed a lognormal distribution with little change over the period 1951-1968. Prior to 1960 were taken largely by the U.S. Public Health Service, while post-1960 sampling was conducted by state mine inspectors.\nTherefore, data were separated into pre and post 1960 periods and estimates of the coefficient of variation (CV) were made for each period. Results indicated a slight but non-significant increase in CV's after 1960 (106.6% vs 118.3%).\nSince the measurements were grab samples taken at different times within each mine, the total pooled CV=112.5% over the period 1951-1968 is assumed to include sampling errors, counting errors, and environmental fluctuations over time. This estimate agrees well with the CV of 110% found in an independent study of U.S. mines in the period 1973-79 when exposure levels were much lower (Schiager et al. 1981).\nIn other studies, however, an average CV of 30% was reported for area samples in Canadian mines (Makepeace and Stocker 1980) while fluctuations of 20-30% around daily means were found for radon measurements in non-uranium Norwegian mines (Berteig and Stranden 1981).\n\n# Method 2\nIn order to assess the error in interpolating for gaps in sampling of 1 to 3 years, a simulation procedure was used.\nMines having the longest periods of continuous annual measurements were identified.\nThen the even years' averages wee omitted and the average of the two adjacent years was substituted.\nIn this way it was possible to compare the observed annual average with the expected average had that year been missing.\nThis strategy was repeated by imposing three year gaps in the data and again using the average of adjacent years to estimate the three intervening years.\nThe error variance attributable to Method 2 was then calculated by:\n0 2 , S dofliOj/E.»2 i N-1\nwhere 0j = actual measurements for intervening years Ej = interpolated values estimated by average of adjacent years.\nThe resulting CV was 120.8% for 1 year interpolation and 137.3% for 3 year interpolation. Since these results were not significantly different, they were pooled to yield a CV=131.9%.\n\n# Method 3\nThis method used annual mine averages in the same geographic locality to estimate radon daughter levels in mines for which Methods 1 and 2 could not be used.\nIn order to assess the error associated with this method, four of the uranium mining localities with the greatest number of annual measurements were selected. A simulation procedure similar to that used for Method 2 was employed.\nAnnual averages for selected mines in these localities were omitted for 1 to 4 years. The averages for mines in the nearest district were substituted as the expected radon level if the annual average actually had been missing.\nThe error variance was calculated in the same way as Method 2. The resulting CV was 148.6% for this method.\n\n# Method 4\nNo measurements were available in the period prior to 1950.\nTherefore, the estimates made using knowledge of ore bodies, ventilation, and earliest known measurements in these mines could not be verified. These estimates comprised less than 6% of the 34,120 annual averages used in exposure assessment.\nIn addition, since only 8 percent of the total underground exposure time for the cohort occurred prior to 1950, the influence of these measurements should be minimal. However, since the error for this method was probably the greatest of the methods used, we estimated the overall CV for Method 4 to be 25% greater than that for Method 3, i.e. CV=186%.\nTable 6 shows the number of annual averages for each of the four methods. Actual measurements comprised only about 10% of the data.\nIn order to obtain an overall estimate of the relative error, a weighted average of the CV's for each method was calculated based on the number of determinations for each method. The resulting overall CV=137%.\nThe error associated with each miner's cumulative exposure can then be calculated using our estimate of the error in each radon daughter level (WL). The total cumulative exposure (WLM) for each miner is obtained from: wlm = S ( « -¡jH u a io v , j where WL j j is the estimated exposure for mine i in year j and UGMONjj is the number of months spent underground in mine i during year j. The variance of WLM assuming independence of WL j j is then:\nVar(WLM) = X (UGMON..)2 var (WL..) i , j 1J 1J = 2 (UGMON..)2 (CV)2 (WL..)2 . . iJ ij ' -J 1 1\nwhere CV is the coefficient of variation for the estimated exposure WL j j .\nIf we substitute our estimate of the overall CV=137% and use total cumulative exposure divided by total months underground (WLM/TOTMON) as an estimate of WL j j for each individual miner, the average CV for cumulative exposure (WLM) is 0.97 or a relative standard deviation of 97% of the total WLM for each miner. Since radon daughter measurements were taken in different areas of each mine and often at different times of the day or week, we will assume that the variance in these measurements reflects the variance in exposure levels among individual miners, i.e.\n\n# Var(»LMij).\nwhere 0jj|< = variance in exposure measurement for miner k in mine i and year j .\n\n# B. E ffe c t on R ela tiv e Risk Estimation of Exposure Measurement Errors\nThere appears to be a general impression that errors in exposure measurements usually cause an underestimation of relative risk. Indeed, Bross originally demonstrated that if misclassification was equal in two comparison populations, one would tend to underestimate differences in proportions of diseased persons. Keys and Kihlberg qualified this concept by showing that relative risk is underestimated when misclassification errors are independent of disease and exposure relationships.\nIn general, it has been shown by Copeland et a l . among others, that relative risk estimates are biased too low in the presence of non differential misclassification (equal misclassification of disease in both exposed and unexposed groups).\nLittle work has been done concerning the effects of errors in continuous measures of exposure upon relative risk estimates obtained from statistical models.\nIt is this situation that is a potential problem to the analysis in this report. Prentice introduced a method for dealing with errors in individual exposure measures when using the Cox proportional hazards model.\nPrentice, and more recently Hornung , have shown that the direction of bias in relative risk estimation depends upon the error distribution and the shape of the exposure-response model.\nIn general, when the variability in individual exposure errors increases with the level of exposure and the relative risk model is supra-linear (curving upward), relative risk will actually be overestimated when exposure errors are ignored.\nThe popular log-1 inear or exponential risk function is an example of a model which may often overestimate relative risk in the presence of errors whose magnitude increases with increasing levels of cumulative exposure.\nAs was reported earlier, the log-linear model did not provide the best fit to the data.\nInstead, the power function model which involved the logarithms of cumulative exposure and cumulative cigarette smoking provided a better fit.\nThe effect upon risk estimates using this model was investigated when errors in exposure are lognormal as indicated in the previous section.\nWithout presenting the statistical details, it is sufficient to say that under these conditions (power function model and lognormal distribution of exposure errors) the effect upon relative risk estimates is negligible.\nIf the exposure measurements were generally higher than those actually experienced by the miners, as mentioned in the 1971 Monograph, relative risk per WLM would be underestimated regardless of the distribution of exposure measurement errors.\nIn summary, the degree of error in individual exposure measurements was quite high, an estimated CV of 97%. If, however, these individual errors were lognormally distributed about the annual average concentration in each mine, the degree of bias in relative risk estimates generated by the power function model would be minimal.\nRegardless of the form of the error distribution, the relative risks generated by the exposure-response model would be too low if the exposure measurements were systematically too high. Therefore, examination of the pattern of error in the exposure data would suggest that relative risks produced by the power function model are either unbiased or possibly a bit low.\n\n# V. QUANTITATIVE RISK ESTIMATES\nThe previous sections have outlined the protocol for the risk model development, the selection of an appropriate quantitative risk model, the temporal factors influencing risk estimation, and the magnitude and effect of exposure measurement errors.\nThese are factors requiring careful study before attempting to make valid quantitative risk estimates.\nIn most risk assessments, results are reported relative to some unexposed population.\nIn animal studies, a control group is generally used for this purpose.\nIn life table, analyses expected mortality is obtained from some standard population, often that of the U.S.\nThe problems inherent with the use of such external referents have been well documented . Although a subcohort of miners unexposed to radon daughters would be ideal for a referent group, there were no unexposed miners in the U.S. cohort. Since the proportional hazards model uses internal comparisons in generating risk estimates, risk projections relative to an unexposed population necessarily involve an extrapolation to zero exposure.\nIn the case of the power function model, a background exposure of 0.2 WLM/year of age was added to every miner's cumulative total.\nAll risk estimates are relative to someone exposed to these background rates. Therefore, quantitative relative risk estimates are somewhat sensitive to the choice of a background exposure rate.\nOne way of checking the appropriateness of the model is to divide cumulative exposure into discrete intervals and calculate lung cancer risks in each interval relative to risks experienced in the lowest interval.\nIn this way, relative risk estimates are free of any exposure-response function.\nIf the risk model then fits the risk estimates in the selected intervals, one would be assured that the model is appropriate for quantitative risk estimation.\nThe cumulative exposure intervals chosen for this analysis were: less than 20 WLM, 20-120, 120-240, 240-480, 480-960, 960-1920, 1920-3720, and greater than 3720 WLM.\nRisk estimates in each interval are calculated relative to the risk in the interval less than 20 WLM. and are plotted at the mean exposure in each interval: 66.6, 179, 351, 698, 1352, 2579, and 5416 WLM, respectively.\nFigure 8 illustrates how these interval estimates are uniformly lower than those produced by the risk model when using 0.2 WLM/year as a background rate of exposure. The shape of the risk model, however, shows remarkably good agreement with the pattern of relative risk estimates in the selected intervals.\nThis implies that the quantitative risk model is appropriate exclusive of the intercept.\nThis could be due to either an improper choice of baseline exposure rate or the fact that all interval estimates are relative to exposure in the lowest interval, 0-20 WLM.\nIf there is some level of excess risk in this interval relative to an actual unexposed population, the interval estimates would be too low.\nThe cumulative exposure of 0.2 WLM/year is an estimate is an estimate of the background exposure in the overall U.S. population , Exposures near ore-bearing lands are known to be considerably higher than average .\nTherefore, it is probable that background exposures in the Colorado Plateau area are higher than average U.S. levels.\n\n# DOTTED LINES AND VERTICAL BARS REPRESENT 95% CONFIDENCE LIMITS\nIn the interest of using a background more in line with exposures received by persons living in the Colorado Plateau, the background exposure was increased to 0.4 WLM/year. This produced a quantitative risk model that agreed very well with the interval estimates, as can be seen in Figure 9.\nUsing this model, relative risk estimates were calculated for cumulative radon daughter exposures in the range 30 to 120 WLM corresponding to exposure levels of from one to four WLM/year over a 30-year working lifetime.\nThese estimates range from a relative risk of 1.42 at 30 WLM to 2.07 at 120 WLM compared to someone of the same age and smoking habits with a cumulative lifetime background exposure of 24 WLM and a background exposure rate of 0.4 WLM/year.\nThese estimates (0.9 to 1.4 excess relative risk per 100 WLM) are slightly higher than those reported by Muller et al. for the Ontario miners, but somewhat less than the estimates of Radford and Renard for the Swedish iron miners.\nObviously, these estimates are subject to the usual caveats concerning extrapolation from higher cumulative exposures and exposure rates.\nBecause relatively few data are currently available in this cohort below 120 WLM (10 lung cancer deaths out of 709 miners), there may be some doubt that the model used actually is appropriate at these low levels.\nHowever, the pattern of relative risk estimates produced in each of the categorized exposure levels would suggest that this model fits the data well in range of 60 to 6000 WLM.\n\n# Magnitude and Effect of Errors in Exposure Measurements\nAnalyses of the errors associated with the four methods of estimating uranium mine exposure levels indicated a lognormal distribution of errors with the relative standard deviation or CV=97 percent.\nAlthough errors of this magnitude may cause overestimation of relative risk when using the log-linear risk model, the better-fitting power function model is generally insensitive to errors of this type.\nIn fact, if estimated exposure levels were systematically higher than those actually received by the miners , relative risks per unit WLM would be underestimated for this data.\n\n# Q u a n tita tiv e Risk Estimates\nPresent day radon daughter exposures are considerably less than those experienced in the past by uranium miners.\nThere is also current interest in low-level exposure to the general population from indoor radon and its decay products.\nConsequently, the primary cumulative exposure range of interest in risk assessment appears to be below 120 WLM. Although approximately 20 percent of the cumulative exposures in this study were below this level, there have been only 10 lung cancer deaths among this subgroup as of the end of 1982. Until this cohort is followed to extinction, epidemiologic models such as that produced in this report will be necessary to evaluate the risk of lung cancer mortality at these lower exposures.\nThe model developed for this report provides a very good fit to the data in the range 60 to 6000 WLM.\nIt seems reasonable that predictions based upon this model would be reliable at least for occupational exposure to adult white males.\nThere is little or no mortality data available regarding women and children.\nThe risk estimates provided in Table 7 are presented as an evaluation based upon careful consideration of all factors thought to influence such long-term mortality studies.\nAll of the caveats associated with such evaluations apply to some degree to these results. Exclusive of background exposure. 2Risks are calculated using exposure rate interaction model in Table 6 relative to miners of the same age and smoking habits with a cumulative lifetime background exposure of 24 WLM and background exposure rate of 0.4 WLM/year.\n\n# APPENDIX III\n\n# A. Introduction\nThis appendix contains examples of engineering control methods that can be used to reduce miners' exposure to radon progeny in underground uranium mines, although the same methods are applicable to other hard rock mines. Many of these control methods have been traditionally used in uranium mines, yet only recently have researchers (primarily from the Bureau of Mines) studied the efficacy of these methods .\n\n# B. Meehan i caI Vent i I a t i on\nMechanical ventilation is the primary and most successful technique for reducing exposure to radon progeny. Average measurements of 2 to 200 working levels (WL) of radon progeny were common in U.S. uranium mines during the early 1950's before mechanical ventilation became prevalent .\nIn contrast, during 1979 and 1980, the average concentrations of radon progeny recorded by MSHA ranged from 0.30 to 0.46 WL in the production areas of 61 underground uranium mines . Thus the concentration of radon progeny in U.S. uranium mines has been greatly decreased, mainly because of improved ventilation. Sweden has also successfully reduced radon progeny concentrations in mines with improved mechanical ventilation; the average annual exposure for nonuranium miners in Sweden decreased from 4.7 working level months (WLM) in 1970 to 0.7 WLM in 1980 .\n\n# General P rin c ip le s\nDilution ventilation in large mines consists of primary and secondary ventilation systems.\nIn the primary system, fresh air is brought into the mine either through separate air shafts or through mine entrances used for miner access and equipment transport. The air can be blown in by a fan located at the surface or drawn in by a fan located inside the mine. Once in the mine, the air is blown or drawn through the main active passageways and then is pushed or drawn out of the mine through special ventilation shafts or openings used to remove ore.\nThe secondary or auxiliary ventilation system provides fresh air to miners working in areas that include stopes and faces where access comes from a single shaft or drift and thus the work area is a dead end. For these areas, the air is often removed through the same shaft that was used to bring in the air. The source of fresh air for the secondary system is provided from the primary air system in the main passageway.\nTo prevent mixing fresh air and contaminated air in the shaft or drift leading to the dead end, the secondary system usually consists of ductwork with a fan to blow or exhaust fresh air from the main passageway to the face. The contaminated air then passively returns to ENGINEERING CONTROL METHODS the main passageway (because of a pressure gradient) through the shaft without contaminating the supply air. The contaminated air at the stope may also be brought back to the main passageway through a second duct and fan system. Once returned to the main passageway, the contaminated air joins the primary exhaust air stream which is then carried out of the mine.\n\n# Designing a Dilution Ventilation System\nVentilation requirements must be considered when planning and designing the mine. Adding mine ventilation as an afterthought once the mine has been designed or completed is usually more expensive and less efficient. Consideration should be given to the following when designing the ventilation plan for a mine :\n- Identify the outline of the ore body that will be mined;\n- Determine the rate of emanation of radon from the rock in which the ore occurs;\n- Place as much of the primary ventilation system as possible including entrances and passageways in barren ground (i.e., ground not containing ore);\n- Set up passageways so that a split or parallel system of ventilation can be used;\n- Set up the mine so that working faces ventilated in a series are minimized;\n- Design the mine so that air inlets are located on one side of the ore body and exhaust airways on the opposite side of the ore body;\n- Design the mine so that the distances ventilation air travels in the mine are minimized (reduce or eliminate reentrainment and short ci rcui ts);\n- Design the mine so that adequate volumes of air can be provided without having high pressure drops across air controls in haulage and production areas;\n- Design the ventilation system to account for increasing concentrations of radon gas, and therefore radon progeny, since as the mine ages there will be more surface area for gas exchange into the mine; and\n- Consider control devices, fans, push-pull systems, and minimizing leaks when designing the system. The primary ventilation system delivers fresh air for the secondary air system and removes contaminated air from the secondary air system. The design of the primary air system is discussed in the following paragraphs.\na. S p lit or P a ra lle l V e n tila tio n Systems A \"split\" or \"parallel\" ventilation system involves providing all or just a few working areas with fresh air that has not been previously used to ventilate other working areas. After the working areas are ventilated, the air is then pushed or drawn back into the primary system where it is moved out of the mine. By contrast, in a \"series\" ventilation system, all areas are ventilated by a single continuous air circuit.\nThe advantages of a split or parallel system include the reduction of both the residence time and cumulative air contamination . A series system, on the other hand, has several disadvantages.\nIn addition to its long residence air times and a cumulative build-up of air contaminants from one area to another, other disadvantages include the following:\n- High air velocities which are often required;\n- Higher power costs associated with moving air at high velocities because of increased static pressures, unless additional ventilation shafts are constructed ; and\n- The potential spread of toxic gases to all areas of the mine in the event of a fi re.\nHowever, to keep residence time down in a split or parallel ventilation system, the air velocities to the multiple drifts must be maintained. This will increase the fan and power requirements; additional ventilation shafts may also be necessary.\n\n# b. Control Devices\nSliding door regulators are used to prevent air from passing where miners and equipment need to pass through periodically. The problem with doors is that to be effective they must be closed after being used. Doors must also be well-constructed to remain secure with repeated usage; steel doors in substantial frames are most commonly used in Canada .\n\n# c. Pushing Versus P u llin g V e n tila tio n Systems\nThe pressure on the air intake side of a mine is always greater than on the exhaust side regardless of whether a pushing or pulling ventilation system is used. The difference is that the intake side\n\n# Primary Ventilation System\npressure is greater than atmospheric pressure for a pushing system, whereas in an exhaust or pulling system, the pressure on the intake side is below atmospheric pressure.\nExhausting (pulling) offers some advantages over a pushing system. For example, forcing air into haulageways and escape areas often requires air locks and other equipment. Exhaust systems draw air from these locations without the need for air locks and remove air from the mine through special airways to exhaust fans.\n\n# . Secondary ( A u x ilia r y ) V e n tila tio n System\nThe secondary (auxiliary) ventilation system brings sufficient fresh air to the working area from the primary air system without mixing it with the returning contaminated air from the face.\n\n# a .\nUse o f Ducts Another advantage of an air-blowing system is that it increases pressure. Measurements of radon gas content in air exhausted from mines have shown that the radon gas emitted into the atmosphere was 20% less with the air-blowing system than with an exhaust system . This indicates that less radon gas diffused into the ventilated areas when an air-blowing system was utilized than when an exhaust system was used.\n\n# c . Exhaust Duct System (P u ll System)\nIn the exhausting or pulling system, contaminated air is drawn from the working face by a duct that runs from the face to the main passageway in the primary air system through the access tunnel. Fresh air is then drawn into the access tunnel toward the work area by the pressure gradient created by removing air. Exhausting (pulling) air from the face instead of blowing (pushing) offers the fo 11ow i ng advan tages:\n- Fresh incoming air is maintained in the tunnel used by miners to access the active stope, and\n\n# d . Push-Pu11 System\nA push-pull system contains two ducts in the accessway, one for pushing clean air to the face and the other for exhausting air from the face back to the primary air system. This system has many of the advantages of both the push and the pull systems including the following:\n- The blowing of air that sweeps across and ventilates the active face, thus providing good dilution in work areas;\n- The efficient collection of contaminants near the work face; and\n- Reducing the contamination of air in the access tunnel.\nThe main disadvantages are the cost and that it occupies more drift area .\nThe amount of radon gas diffusing into mine spaces from interstitial rock is dependent on the pressure in the mine space. The lower the atmospheric pressure in the mine space as compared to the pressure in the interstitial rock, the more radon gas will pass from the rock to the mine space. Conversely, the greater the pressure in the mine space as compared to the rock, the less radon gas will seep into the mine space. Overpressurization and mine pumping are two control measures which take advantage of this principle to reduce concentrations of radon gas.\nIn overpressurization, more ventilation air is pushed into mine spaces than is removed. Although Edwards and Bates have stated \"nothing that we have found provides mining companies with sufficient guidelines for applying the overpressurized ventilation system effectively,\" they conducted a mathematical study of overpressurization and drew the following conclusion: overpressurization does decrease the radon flux. It was estimated that a 2% pressure differential in a sandstone matrix would result in a 50% reduction in radon flux with mine sink lengths of 100 meters or less. A mine sink is an area either in the mine itself or a naturally occurring space or lattice in the matrix where the interstitial air can flow.\nIf the distance between the sink and the mine space approaches 200 meters, the benefit of overpressurization is lost. Because of the dramatic increase in radon gas in the sink area during overpressurization of work areas, no miners should be allowed in those sinks without proper respiratory protection. However, many open spaces that can serve as sinks are filled in and cannot be occupied.\nThe Bureau of Mines is gathering information on the effects of overpressurization in mines. Data from the pressurization of an enclosed chamber in a mine indicated that the radon concentration was 99% lower than the concentration under static conditions and 92% lower than the concentration under controlled ventilation conditions ,\nIn a study by Schroeder et al . of mine areas that were pressurized by 10 mm of mercury, the radon flux decreased from 5 to 20 fold as compared to normal ventilation conditions.\nIn mine pumping, a negative pressure is created in the mine space by sealing air intake openings and permitting the exhaust fans to operate. This is done during an offshift when no miners are in the mine. Because of the negative pressure created in the mine with respect to the surrounding rock, radon is drawn into the mine space from the inter stitial rock at a rate higher than would occur under static conditions. The air intakes must be opened well before miners enter the mine to permit the ventilation system to remove the radon gas and radon progeny that have accumulated in the mine spaces. After this accumulation has been removed, the mine spaces should have lower concentrations of radon gas (and therefore radon progeny) when the miners reenter the mine. This is because much of the radon gas in the surrounding interstitial rock has been removed and is not available to diffuse into the mine working areas. However, monitoring of these areas would be required prior to allowing miners to enter. More studies are needed to determine the effectiveness of this control procedure .\n\n# Overpressurization and Mine Pumping\n\n# activities.\nSummers et al. tested the efficacy of this procedure and found that the amount of radon gas escaping through the surrounding rock was insufficient to warrant the uniform use of a wall sealant, provided that all cracks, fissures, and holes were sealed to prevent major leaks.\n\n# . Membrane S ealants Used on Bulkheads\n\n# . N egative A ir Pressure Behind a Bulkhead\nA slight negative pressure behind the bulkhead of about 0.03 cm water with respect to active areas will prevent radon gas leaks into fresh ventilation air [Thomas et al. 1981 (1) covering the backfill with one meter of clean sand, (2) sealing the surface of the tailings, (3) using a bulkhead to seal the backfilled stope and maintaining a negative pressure behind the bulkhead, and (4) using nonradioactive materials as backfill instead of mill tai Iings.\n\n# . E ffic ie n c y\nIn summary, backfilling with uranium tailings can be as effective as bulkheading in reducing radon progeny emissions, although it is more costly. Because high radon progeny concentrations are emitted from wet backfill and during the backfilling process, backfilling should not be used in active mine areas and miners should be protected from overexposure during backfilling operations.\n\n# E. S ealants Used on Mine W alls\nThis section describes sealants used as diffusion barriers against radon gas, including how the sealants are applied and the best materials used as sealants. Also, the effectiveness of sealants for reducing radon emanation and exposure will be discussed.\n\n# G. Automation\nAnother radon progeny control method is increased automation.\nTechniques such as robotics that minimize the time the miner spends in the high exposure areas of the mine and in activities such as drilling, blasting, or loading ore, will decrease the miner's radiation exposure. Although, at present, robotics has a limited place in the mines, it may be possible in the future to further automate the ore mining process.\n1. Two different sampling days are randomly selected from each 2-week block of t ime.\n2. The stations within a cluster are to be sampled on the same workdays and work shifts. All stations within a cluster are to be alternately sampled, seven times on each sampling day, each time in independent random order. During the work shift, the seven periods for sampling of the entire cluster shall be equally spaced in time. For example, the three stations A, B, and C could be considered a cluster and sampled as ABC, BCA, ACB, CBA, CAB, BAC, and ACB during seven successive intervals of approximately equal durations.\nIf it is not feasible to sample in this manner, then sampling can be conducted along the most efficient path but with a different, randomly determined starting point on each day (e.g., BCA, BCA,..., BCA during one sampling day and ABC, ABC,..., ABC or CAB, CAB,..., CAB during other sampling days).\n3. The estimated average work shift concentration (ftj) for each sampling day (i = 1,2,...12) is computed from an analysis of the seven grab samples taken on that day. Formulae for this computation are contained in section G. 4. Whenever a; for a particular station exceeds 0.14 WL, then that station shall be resampled the next workday.\n[Note:\nIn this case, f t ; = and sampling on the \"next workday\" (day B) is in addition to the two randomly selected sampling days required in a 2-week block of time.] a.\nI f oLq (the estimated average work shift concentration on the next workday) is < 0.14 WL, then exposure monitoring shall continue as described starting at section C,1. b. 'If also exceeds 0.14 WL, then:\n(1) steps shall be taken to reduce the radon progeny concentration in that work area by implementing work practices and engineering controls, (2) respiratory protection shall be required for all miners entering that work area, and (3) grab sampling as described in section C,2 shall be conducted on a consecutive daily basis.\nGrab sampling shall continue on a consecutive daily basis until the estimated average work shift concentrations on any two consecutive workdays (ft^ and are both < 0.10 WL. When and are both < 0.10 WL, then the requirements for respiratory protection are waived and exposure monitoring can revert to the schedule described starting at section C ,1. This criterion (as discussed in section H,2) serves to provide early confirmation that the corrective steps taken by the mine operator have been effective in limiting the average work shift concentration of radon progeny to a level not exceeding 1.5 times the recommended exposure limit (REL) of 1/12 WL.\n\n# G. Statistical Considerations and Data Analysis Formulae\nThe following are the statistical notations used in the sampling strategy: Cjj = measured concentration of radon progeny in the jth grab sample taken on the ith sampling day, where j = 1,2,...,7 for each day and i = 1,2,...,12 (2 workdays selected at random from each of six consecutive blocks of time).\n\n# c>\\j\n= measured concentration of radon progeny in the jth grab sample taken on day A, where j = 1,2,...,7.\n\n# CBj\n= measured concentration of radon progeny in the jth grab sample taken on the next workday following day A, where j = 1,2, ,7. than 0.14 WL on two consecutive workdays, substantial evidence exists that the long-term average work shift concentration exceeds 1/12 WL. Therefore, when aA and ftg both exceed 0.14 WL in a work area, NIOSH recommends that radon progeny concentrations be reduced in that work area by implementing work practices and engineering controls, and that the use of respiratory protection be required for all miners entering that work area. These recommendations are also made when the 95% lower confidence limit for the long-term average work shift concentration (LCL) exceeds 1/12 WL (see section D,4).\n\n# Return to Compliance with the REL\nThe NIOSH sampling strategy uses criteria with approximately 90% confidence for an initial determination that a work area is tentatively back to compliance with the REL. Specifically, estimated average work shift concentrations from two consecutive workdays (i.e., and ftg) in which both are < 0.10 WL was chosen as a criterion that demonstrates reasonable evidence that the average radon progeny concent rat ion is bei ng cont roI led to < 0.125 WL (i.e., 1.5 t imes the REL). Given the levels of intraday and interday variabilities observed in the Johnson data set, a work area with an average work shift concentration of 0.125 WL (i.e., 50% above the REL of 1/12 WL) has 0.90 probability to have one or both of a pair of consecutive estimated average work shift concentrations above 0.10 WL. This \"2-day\" decision rule limits the magnitude with which a work area's average work shift concentration may exceed 1/12 WL and be undetected. This rule also has the advantage of permitting an early return to normal operations after a period of corrective actions to reduce exposure concentrations, at the expense of having less than high confidence that the REL is not being exceeded by more than 50%. However, only a small proportion of time passes until the next sampling day (as specified in the sampling strategy relative to the year), so that the 2-day rule limits the contribution of a temporarily excessive exposure in a work area to a miner's cumulative annual exposure.\nAt a later time, the lower confidence limit criterion for noncompliance determined after 12 randomly selected sampling days (i.e., LCL > 1/12 WL) would be likely to detect a statistically significant increase above the REL if the long-term average work shift concentration were as high as 0.125 WL.\n\n# Less Frequent Exposure Monitoring\nThe upper confidence limit criterion (i.e., UCL < 1/12 WL) gives 95% confidence that the long-term average work shift concentration is not above 1/12 WL, under the assumption that aj's exhibit log-normally distributed random variations.\nThe additional requirement that &j and &j+i do not exceed 0.14 WL is meant to detect a temporarily or periodically high average work shift concentration (i.e., high aj's that are not sustained for the full block of time from which 12 sampling days were selected). When both of these requirements are met, only 2 randomly selected sampling days are then required per 26-week block of t ime.\n2 0 1 UCL< 0.063 WL gives greater than 95% confidence that the long-term average work shift concentration (a,) is < 0.063 WL (i.e., a. is no larger than 75% of the REL), under the assumption that ftj's exhibit log-normally distributed random variations. Under the additional assumption that geometric standard deviations (GSDs) for intraday and interday (log-normal) variability are similar to those reported in Johnson , the criterion that &12 (the estimated average work shift concentration on the last of the 12 sampling days) be < 0.033 WL gives 95% confidence that a projected future reference period would have a long-term average work shift concentration < 0.063 WL.\n\n# Cessation of Exposure Monitoring\n2 0 2 reported . However, several recent studies suggest that this is not a practical concern, at least not in healthy individuals .\nTheoretically, the increased fluctuations in thoracic pressure caused by breathing with a respirator might constitute an increased risk to subjects with a history of spontaneous pneumothorax.\nFew data are available in this area. While an individual is using a negative-pressure respirator with relatively high resistance during very heavy exercise, the usual maximal-peak negative oral pressure during inhalation is about 15-17 cm of water . Similarly, the usual maximal-peak positive oral pressure during exhalation is about 15-17 cm of water, which might occur with a respirator in a positive-pressure mode, again during very heavy exercise . By comparison, maximal positive pressures such as those during a vigorous cough can generate 200 cm of water pressure . The normal maximal negative pleural pressure at full inspiration is -40 cm of water , and normal subjects can generate -80 to -160 cm of negative water pressure . Thus while vigorous exercise with a respirator does alter pleural pressures, the risk of barotrauma would seem to be substantially less than that of coughing.\nIn some asthmatics, an asthmatic attack may be exacerbated or induced by a variety of factors including exercise, cold air, and stress, all of which may be associated with wearing a respirator. While most asthmatics who are able to control their condition should not have problems with respirators, a physician's judgment and a field trial may be needed in selected cases.\n\n# Cardiac E ffe c ts\nThe added work of breathing from respirators is small and could not be detected in several studies . A typical respirator might double the work of breathing (from 3% to 6% of the total oxygen consumption), but this is probably not of clinical significance .\nIn concordance with this view, several other studies indicated that at the same workloads heart rate does not change with the wearing of a respirator .\nIn contrast, the added cardiac stress due to the weight of a heavy respirator may be considerable.\nA self-contained breathing apparatus (SCBA) may weigh up to 35 pounds.\nHeavier respirators can reduce maximum external workloads by 20% and similarly increase heart rate at a given submaximal workload .\nIn addition, it should be noted that many uses of SCBA (e.g., for firefighting and hazardous waste site work) also necessitate the wearing of 10-25 pounds of protective clothing.\n\n# Miscellaneous Health Effects\nIn addition to the health effects (described above) associated with wearing respirators, specific groups of respirator wearers may be affected by the following factors: (1) Corneal Irritation or Abrasion Corneal irritation or abrasion might occur with the exposure. This would, of course, be a problem primarily with quarter-and half-face masks, especially with particulate exposures. However, exposures could occur with full-face respirators because of leaks or inadvisable removal of the respirator for any reason. While corneal irritation or abrasion might also occur without contact lenses, their presence is known to substantially increase this risk.\n\n# .(2) Loss or Misplacement of a Contact Lens\nThe loss or misplacement of a contact lens by an individual wearing a respirator might prompt the wearer to remove the respirator, thereby resulting in exposure to the hazard as well as to the potential problems noted above.\n\n# (3) Eye Irritation from Respirator Airflow\nThe constant airflow of some respirators, such as powered air-purifying respirators (PAPR's) or continuous flow air-line respirators, might irritate the eyes of a contact lens wearer.\n\n# B. Suggested Medical E valu atio n and C r i t e r i a f o r R e s p ira to r Use\nThe following NIOSH recommendations allow latitude for the physician in determining a medical evaluation for a specific situation. More specific guidelines may become available as knowledge increases regarding human stresses from the complex interactions of worker health status, respirator usage, and job tasks. While some of the following recommendations should be part of any medical evaluation of workers who wear respirators, others are applicable for specific situations.\n- A physician should determine fitness to wear a respirator by considering the worker's health, the type of respirator, and the conditions of respirator use.\nThe recommendation above leaves the final decision of an individual's fitness to wear a respirator to the person who is best qualified to evaluate the multiple clinical and other variables. Much of the clinical and other data could be gathered by other personnel.\nIt should be emphasized that the clinical examination alone is only one part of the fitness determination. Collaboration with foremen, industrial hygienists, and others may often be needed to better assess the work conditions and other factors that affect an individual's fitness to wear a respirator.\n- A medical history and at least a limited physical examination are recommended.\nThe medical history and physical examination should emphasize the evaluation of the cardiopulmonary system and should elicit any history of respirator use. The history is an important tool in medical diagnosis and can be used to detect most problems that might require further evaluation. Objectives of the physical examination should be to confirm the clinical impression based on the history and to detect important medical conditions (such as hypertension) that may be essentially asymptomatic.\n- While chest X-ray and/or spirometry may be medically indicated in some fitness determinations, these should not be routinely performed.\nIn most cases, the hazardous situations requiring the wearing of respirators will also mandate periodic chest X-rays and/or spirometry for exposed workers. When such information is available, it should be used in the determination of fitness to wear respirators.\nData from routine chest X-rays and spirometry are not recommended solely for determining if a respirator should be worn. In most cases, with an essentially normal clinical examination (history and physical) these data are unlikely to influence the respirator fitness determination; additionally, the X-ray would be an unnecessary source of radiation exposure to the worker. Chest X-rays in general do not accurately reflect a person's cardiopulmonary physiologic status, and limited studies suggest that mild to moderate impairment detected by spirometry would not preclude the wearing of respirators in most cases. Thus it is recommended that chest X-rays and/or spirometry be done only when clinically indicated.\n- The recommended periodicity of medical fitness determinations varies according to several factors but could be as infrequent as every 5 years.\nFederal or other applicable regulations shall be followed regarding the frequency of respirator fitness determinations. The guidelines for most work conditions for which respirators are required are shown in - The respirator wearer should be observed during a trial period to evaluate potential physiological problems.\nIn addition to considering the physical effects of wearing respirators, the physician should determine if wearing a given respirator would cause extreme anxiety or claustrophobic reaction in the individual. This could be done during training while the worker is wearing the respirator and is engaged in some exercise that approximates the actual work situation.\nPresent OSHA regulations state that a worker should be provided the opportunity to wear the respirator \"in normal air for a long familiarity period...\" .- This trial period should also be used to evaluate the ability and tolerance of the worker to wear the respirator . This trial period need not be associated with respirator fit testing and should not compromise the effectiveness of the vital fit testing procedure. CFR = Code of Federal Regulations. See CFR in references.\n- Examining physicians should realize that the main stress of heavy exercise while using a respirator is usually on the cardiovascular system and that heavy respirators (e.g., SCBA) can substantially increase this stress. Accordingly, physicians may want to consider exercise stress tests with electrocardiographic monitoring when heavy respirators are used, when cardiovascular risk factors are present, or when extremely stressful conditions are expected.\nSome respirators may weigh up to 35 pounds and may increase workloads by 20 percent. Although a lower activity level could compensate for this added stress , a lower activity level might not always be possible. Physicians should also be aware of other added stresses, such as heavy protective clothing and intense ambient heat, that would increase the worker's cardiac demand. As an extreme example, firefighters who use a SCBA inside burning buildings may work at maximal exercise levels under life-threatening conditions.\nIn such cases, the detection of occult cardiac disease, which might manifest itself during heavy stress, may be important. Some authors have either recommended stress testing or at least its consideration in the fitness determination . Kilbom has recommended stress testing at 5-year intervals for firefighters below age 40 who use SCBA and at 2-year intervals for those aged 40-50. He further suggested that firemen over age 50 not be allowed to wear SCBA. Exercise stress testing has not been recommended for medical screening for coronary artery disease in the general population .\nIt has an estimated sensitivity and specificity of 78% and 69%, respectively, when the disease is defined by coronary angiography ,\nIn a recent 6-year prospective study, stress testing to determine the potential for heart attacks indicated a positive predictive value of 27% when the prevalence of disease was 3.5% . While stress testing has limited effectiveness in medical screening, it could detect individuals who may not be able to complete the heavy exercise required in some jobs.\nA definitive recommendation regarding exercise stress testing cannot be made at this time. Further research may determine whether this is a useful tool in selected circumstances.\n- An important concept is that \"general work limitations and restrictions identified for other work activities also shall apply for respirator use\" .\nIn many cases, if a worker is physically able to do an assigned job while not wearing a respirator, the worker will in most situations not be at increased risk when performing the same job while wearing a respirator.\n- Because of the variability in the types of respirators, work conditions, and workers' health status, many employers may wish to designate categories of fitness to wear respirators, thereby excluding some workers from strenuous work situations involving the wearing of respirators.\nDepending on the various circumstances, several permissible categories of respirator usage are possible. One conceivable scheme would consist of three overall categories: full respirator use, no respirator use, and limited respirator use including \"escape only\" respirators. The latter category excludes heavy respirators and strenuous work conditions. Before identifying the conditions that would be used to classify workers into various categories, it is critical that the physician be aware that these conditions have not been validated and are presented only for consideration. The physician should modify the use of these conditions based on actual experience, further research, and individual worker sensitivities.\nHe may also wish to consider the following conditions in selecting or permitting the use of respirators:\n-History of spontaneous pneumothorax; -CIaus t rophob i a/anxi ety reac t i on; -Use of contact lenses (for some respirators); -Moderate or severe pulmonary disease; -Angina pectoris, significant arrhythmias, recent myocardial infarction; -Symptomatic or uncontrolled hypertension; and -Advanced age.\nWearing a respirator would probably not play a significant role in causing lung damage such as pneumothorax.\nHowever, without good evidence that wearing a respirator would not cause such lung damage, the physician would be prudent to prohibit the individual with a history of spontaneous pneumothorax from wearing a respirator.\nModerate lung disease is defined by the Intermountain Thoracic Society as being present when the following conditions exist-a forced expiratory volume in one second (FEV-|) divided by the forced vital capacity (FVC) (i.e., FEV-|/FVC) of 0.45 to 0.60, or an FVC of 51% to 65% of the predicted FVC value. Similar arbitrary limits could be set for age and hypertension.\nIt would seem more reasonable, however, to combine several risk factors into an overall estimate of fitness to wear respirators under certain conditions. Here the judgment and clinical experience of the physician are needed. Many impaired workers would even be able to work safely while wearing respirators if they could control their own work pace, including having sufficient time to rest.\n\n# C. Cone Ius ion\nIndividual judgment is needed to determine the factors affecting an individual's fitness to wear a respirator. While many of the preceding guidelines are based on limited evidence, they should provide a useful starting point for a respirator fitness screening program.\nFurther research is needed to validate these and other recommendations currently in use. Of particular interest would be laboratory studies involving physiologically impaired individuals and field studies conducted under actual day-to-day work condi t ions.\n\n# C E N T E R S F O R D IS E A S E C O N T R O L N A T IO N A L IN S T IT U T E F O R O C C U P A T IO N A L S A F E T Y A N D H E A L T H R O B E R T A . T A F T L A B O R\n\n# APPENDICES\n\n# APPENDIX I\n\n# EVALUATION OF EPIDEMIOLOGIC STUDIES EXAMINING THE LUNG CANCER MORTALITY OF UNDERGROUND MINERS\nConfounding Bias: A potential attribute of data.\nIn measuring an association between an exposure and a disease, a confounding factor is one that is associated with the exposure and independently is a cause of the disease. Confounding bias can be controlled if information on the confounding factor is present.\nCoulomb: The charge flowing past a point of a circuit in one second, when there is a current of one ampere in the circuit; also, the aggregate charge carried by 6 x 10^ electrons.\nElectron Vo 11: The change in potential energy of a particle having a charge equal to the electronic charge (1.60 x 10-^ coulombs), moving through a potential difference of 1 volt.\nHalf-Li fe: The time required for a radioactive substance to decay to one half of its initial activity.\nFollow-up Period: The length of time between a person entering an epidemiological study cohort and the present report (or the end of the study).\nIncidence Ra t e : The number of new cases of disease per unit of population per unit of time, e.g., 3/1000/year. Interaction: The association of one factor (occupation) with disease modified by the effect of another factor (smoking). The measure of association can be the rate or odds ratio. This follows a nonmult ip Iicative model (may be additive).\nIonizing Radi at ion: Any electromagnetic or particulate radiation capable of producing ions, directly or indirectly, in its passage through matter.\nLagging Exposures: Lagging of the cumulative exposure assigned to a miner. Some authors consider that radon progeny exposures are \"redundant\" if they occur after lung cancer is induced. Some authors believe that cumulative exposures should be lagged by a certain number of years (5 or 10), to exclude redundant exposures occurring during these years. For example, Radford and St. Clair Renard discounted the last 5 years of exposures from the cumulative total WLM assigned to each case of lung cancer in their analysi s . Biologic Latent Period: The time between an increment of exposure and the increase in risk attributable to it.+ Epidemiologic Latent Period: The time between first exposure and death in those developing the disease during the study interval.\nLinear Hypothesis: The hypothesis that excess risk is proportional to dose.\n\n# FIGURE 4\n\n# EFFECT OF ACE AT INITIAL EXPOSURE ON A MU LT IS TA GE MODEL\n\n# A G E A T INITIAL E X P O S U R E\n\n# VI. SUMMARY AND CONCLUSIONS\nA valid quantitative risk assessment is much more than simply fitting an exposure-response curve to mortality data. This is especially true when considering an epidemiologic risk assessment.\nThere are a great variety of risk factors and temporal effects that may alter the interpretation of the data analysis.\nThis report is an attempt to address such modifying influences in an effort to better understand the underlying cancer mechanisms operative in the cohort of U.S. uranium mi daughters.\nThere were a number of findings which are important in lung cancer in the U.S. cohort.\nInfluence of C ig a re tte Smoking\nThe joint effect of cumulative cigarette smoking daughter exposure was found to be intermediate multiplicative.\nThis would imply a synergistic usual definition as an effect exceeding the sum risks.\n\n# Exposure-Rate E ffe c t\nAnalysis of this data revealed that modeling cumulative exposure alone may not adequately predict the relative risk of lung cancer from chronic exposure to radon daughters.\nMiners receiving a given amount of cumulative exposure at lower rates for longer periods of time were at greater risk relative to those with the same cumulative exposure received at higher rates for shorter periods of time.\nThis This implies that results extrapolated from historical exposures at high rates may yield conservative results at current lower rates.\nIndeed, it is possible that lower risk estimates in the U.S. study, when compared to the four other major radon studies, as reported by Thomas et al. may be due to the higher exposure rates received by U.S. miners.\n\n# Late-Stage Carcinogenic E ffect\nCareful examination of temporal effects implies that exposure to radon daughters acts at a late stage in the carcinogenic process.\nAll temporal factors agreed in this respect.\nThe appropriate lag to remove redundant exposure was a relatively short six years.\nOlder miners at initial exposure were at greater risk than those exposed at younger ages.\nThe relative risk of lung cancer decreases with the length of time after cessation of exposure.\nWhether or not the mathematical form of the multistage theory of carcinogenesis applies to this cohort, the temporal patterns are worth noting.\n\n# C. BuIkheads\n\n# D e s c rip tio n\nThe second most important control measure used in underground mines today is the construction of bulkheads across inactive stopes or drifts . Bulkheads isolate inactive stopes, prevent the mixture of contaminated air from these stopes with fresh air, and help control the direction of air flow to working areas.\nMaintaining a negative air pressure behind a bulkhead will prevent leaks ; this is important because radon progeny concentrations can exceed 1,000 WL behind a bulkhead .\nIn addition, bulkheads must be strong and flexible enough to maintain an airtight seal during typical mining conditions, such as the ground movement and air shocks from blasting and the impact from accidental contact with mining equipment.\n\n# A bulkhead consists of three functional parts:\n(1) the primary structure, (2) the seal between the primary structure and the rock, and (3) a surface seal on the rock within one meter from the plane of the bulkhead [Summers et al. 1982\nThe primary bulkhead structure fills most of the opening in the stope and provides resistance to shocks from blasting or contact with machinery.\nThe primary structure consists of timber or an expanded metal lath covered with a continuous non-porous membrane. The membrane may be attached to, or sprayed upon, the timber in the primary structure. The membrane must not crack or develop holes or leaks during mining activities .\nThe second part of the bulkhead, the seal between the primary structure and the surrounding rock, must resist running water and the air shocks and rock movements due to blasting.\nThe third part of the bulkhead, the seal on the surface of the rock within one meter from the plane of the bulkhead, must be made of a material that adheres to damp rock surfaces and can withstand mining 6. Fan Operation estimate that 100 bulkheads sealing 12.5 stopes would reduce the overall radon gas emissions into mine air by 2.25 Ci/day, a reduction of 25%.\nIn summary, bulkheads are very effective in reducing radon gas (and thus radon progeny) in mine air. Especially promising are the new bulkheads designed by Summers et al. and further tested by Bloomster et al.\n. These bulkheads may eventually replace the leakier and more flammable polyurethane bulkheads presently being used underground.\n\n# D. Backf i11in q\nIn the uranium mining process, large quantities of ore are brought to the surface, leaving voids which may collapse if they are not stabilized.\nThe tailings remaining after the uranium is extracted are often used as backfill.\nThere are three benefits of backfilling stopes:\n(1) ground stabilization, ( 2 Next, the coarse tailings \"sand' ' is mixed with water to form a slurry and pumped into worked-out stopes.\nSometimes the slurry is mixed with cement before pumping. After the water in the slurry percolates away, the stope is left filled with densely packed sand or cement.\nThe radon progeny hazard can be increased, at least temporarily, by backfilling. Although the sand has considerably less radium than the ore or host rock, the finely divided sand has a larger surface area and many fine interstices between the grains through which radon gas can move. Therefore, the radon gas emanation rate of the sand is much higher than the ore or host rock . During backfilling, agitation of the slurry releases high concentrations of radon gas . Also, high concentrations of radon gas can collect above the sand in the newly filled stope (possibly reaching 65,000-75,000 pCi/l). Thus the advantage of decreasing the ventilation volume with the backfill must be weighed against the increased emanation rate of the backfill . Mixing the slurry with cement will not prevent this increase in emanation rate because the radon gas can also travel freely through fine pores in the cement, especially water-filled pores.\nIndeed, radon gas emanates from porous cement, sand, or ore at a higher rate when it is wet than when it is dry unless the dry material is overlain with a thick During experiments in a mine, Franklin et al. found that backfilling 90% of a stope reduced the total radon progeny emissions from the stope by 85%. A feasibility study estimated that backfilling can be as effective as problem unless there were several thousand visible pinholes per square meter of sealant.\n\n# E ffe c tiv e n e s s o f S ealants in Reducing Radon Emanation Rates\nThe effectiveness of sealants depends, in part, upon the porosity of the rock walls. Sealants produce the greatest decrease in radon emanation when applied to sandstone or other porous rock; sealants applied to granite will appear to be less effective because granite provides a natural barrier to radon emanation . Thus results from the tests for the effectiveness of sealants vary greatly depending on the porosity of the rock walls along with the mine ventilation rate, the grade of the uranium ore, and other factors. estimated that the overall decrease in radon emissions would be 56% if the same sealant coating was applied to 80% of the mine surfaces. Although sealants were less effective and more costly than bulkheads, the use of sealants is less disruptive to the mining process than the use of bulkheads .\nIn summary, there are at least seven materials available that make effective mine sealants. These materials can reduce radon emanation from mine walls by 50-75%.\n\n# F. C o n tro llin g R ad io active Water Underground\n\n# APPENDIX IV\n\n# GRAB SAMPLING STRATEGY REQUIREMENTS FOR DETERMINATION OF RADON PROGENY EXPOSURES\nA.\n\n# Introduct ion\nAirborne concentrations of radon progeny must be monitored regularly to provide the basis for their control. Miners' exposures must be limited to no more than 1.0 WLM per year and the average concentration of radon progeny in any work area must not exceed 1/12 WL during any work shift. The sampling strategy described here was developed after an evaluation of mine sampling data and the typical variability of radon progeny concentrations in underground mines. This strategy will allow the collection of timely and reliable environmental data that can be used as the basis for control of cumulative exposures.\nThis sampling strategy allows for the determination of the arithmetic average of time-varying concentrations of radon progeny during a work shift in a given work area. The determination is based on an unbiased estimate made from grab samples taken at random intervals through out the work shift. Random sampling of work shifts during a reference period is also included for determination of a long-term arithmetic average work shift concentration.\nThe formulae needed to calculate the statistical quantities used in this sampling strategy are contained in section G of this appendix. The rationale for the critical decision points used in the sampling strategy are contained in section H.\n\n# B. Definition of Terms and Notations\nSTATION: A sampling location within a work area that represents the radon progeny concentration to which miners are exposed. CLUSTER: Two or more stations at which sampling will be conducted during any work shift. The stations in a cluster should be located at different work areas but must be in close proximity to each other so that alternating grab samples could be taken during the same work shi ft.\n\n# BLOCK OF TIME:\nA period in which two different sampling days are randomly selected.\n\n# AVERAGE WORK SHIFT CONCENTRATION: The average concentration of radon progeny in working levels (WL) during a work shift at a given station.\n\n# AVERAGE: The arithmetic mean.\nThe same term can be used for the average of several sample results or for the arithmetic mean of a distribution of concentrations that vary during a continuous period of time.\nIn the latter case, the terms \"average,\" \"arithmetic average,\" and \"time-weighted average\" are synonymous.\n\n# otj :\nAverage work shift concentration for day i, where i = 1,2,...,12 and day i is the ittl day in a time-ordered sequence of the 12 days that were randomly selected from the reference period.\n\n# LCL:\n95% one-sided lower confidence limit for a.\n\n# UCL:\n95% one-sided upper confidence limit for a.\nIf is < 0.14 WL, then: (a) continue collecting seven grab samples on each of the two randomly selected sampling days in each 2-week block of time, and (b) continue using the criteria given in section C. After 12 weeks of sampling in which no two consecutive sampling days ( f t ; and &j+i) were in excess of 0.14 WL, use the criteria given in section D for assurance, based on 12 days of sampling, that the average work shift concentration of radon progeny is in compliance with the REL, which, if verified, will result in less frequent exposure monitoring requirements.\n\n# D. Criteria for Less Frequent Exposure Monitoring\nTo determine if less frequent exposure monitoring can be conducted at a specific work area, the following statistical decision criteria must be used 1. Compute a. (the estimated average work shift concentration using seven grab samples per sampling day) for a work area during the reference period in which 12 samples were taken and no two consecutive sampling days ($j and &j+-|) were in excess of 0.14 WL. Formulae for this computation are contained in section G.\n2. Compute LCL and UCL, the 95% one-sided lower and 95% one-sided upper confidence limits, respectively, for the average work shift concentration during the reference period from which the 12 sampling days were taken. Formulae for these computations are contained in section G; o i . from section D,1 is a quantity used in the formulae for LCL and UCL.\n\n# The block length can be increased\nIf LCL exceeds 1/12 WL, then: (a) steps shall be taken to reduce the radon progeny concentration in that work area by implementing work practices and engineering controls, (b) respiratory protection shall be required for all miners entering that work area, and (c) grab sampling as described in section C,2 shall be conducted on a consecutive daily bas i s .\nGrab sampling shall continue on a consecutive daily basis until the estimated average work shift concentrations on any two consecutive workdays (&^ and o^) are both < 0.10 WL. When ^ and ag are both < 0.10 WL, then the requirements for respiratory protection are waived and exposure monitoring can revert to the schedule described starting at section C , 1. \n\n# E . Criteria for Continuation of Less Frequent Exposure Monitoring\nAfter completion of two additional sampling days during the subsequent 26-week period, the data from the last 12 days sampled must be used to compute a new UCL for the period in which the 12 sampling days occurred.\n1. Sampling may continue under the less frequent sampling schedule (i.e., 2 days per 26-week block of time) if both of the following results occur at a station:\n(a) UCL for the reference period from which the last 12 sampling days were taken is < 1/12 WL, and (b) the estimated average work shift concentrations on the last two of the 12 sampling days (&11 and &12) were both < 0.14 WL.\nIn this case, an updated UCL shall be recomputed after completion of sampling in each subsequent 26-week block of time to determine if less frequent sampling (i.e., on two days during a 26-week period) should be continued according to the criteria of this part.\nIf ei ther of these conditions are not met, then LCL must be computed from data obtained from the last 12 days sampled (see section E,2 which follows).\nIf LCL for the reference period from which the 12 sampling days were taken at a station exceeds 1/12 WL, then:\n(a) steps shall be taken to reduce the radon progeny concentration in that work area by implementing work practices and engineering controls, (b) respiratory protection shall be required for all miners entering that work area, and (c) grab sampling as described in section C,2 shall be conducted on a consecutive dai ly basis.\nGrab sampling shall continue on a consecutive daily basis until the estimated average work shift concentrations on any two consecutive workdays and ftg) are both < 0.10 WL. When and are both < 0.10 WL, then the requirements for respiratory protection are waived and exposure monitoring can revert to the schedule described starting at section C,1.\nIf LCL for the reference period from which the 12 sampling days were randomly taken is < 1/12 WL, but the estimated average work shift concentration determined for either of the last two of the 12 sampling days (&11 or &12) exceeds 0.14 WL, then monitoring at that station shall return to the more frequent sampling schedule (2 days per 2-week block of time).\nIn this case, &11 or &12 becomes ^ and sampling is required on the next workday to obtain ag, as described starting at section C,4,a.\n\n# F . Criteria for Cessation of Exposure Monitoring\nSampling can be discontinued at a station if both of the following results occur at that station:\n(1) UCL for the reference period from which 12 sampling days were taken is < 0.063 WL, and (2) the estimated average work shift concentration for the last of the 12 sampling days (&12) is < 0.033 WL. However, sampling should return to the regular schedule, as described starting at section C,1 if an environmental change or a change in mining operations occurs that may alter radon progeny concentrations in that work area.\n\n# APPENDIX V\nIn recommending medical evaluation criteria for respirator use, one should apply rigorous decision-making principles ; tests used should be chosen for operating characteristics such as sensitivity, specificity, and predictive value. Unfortunately, many knowledge gaps exist in this area. The problem is complicated by the large variety of respirators, their conditions of use, and individual differences in the physiologic and psychologic responses to them. For these reasons, the following guidelines are to be considered as informed suggestions rather than established NIOSH policy recommendations.\nThey are intended primarily to assist the physician in developing medical evaluation criteria for respi rator use.\n\n# A. Background Info rm ation\n\n# Pulmonary E ffe c ts\nIn general, the added inspiratory and expiratory resistances and dead space of most respirators cause an increase in tidal volume and a decrease in respiratory rate and ventilation (including a small decrease in alveolar ventilation). These respirator effects have usually been small both among healthy individuals and, in limited studies, among individuals with impaired lung function . This generalization is applicable to most respirators when resistances (particularly expiratory resistance) are low . While most studies report minimal physiologic effects during submaximal exercise, the resistances commonly lead to reduced endurance and reduced maximal exercise performance . The dead space of a respirator (reflecting the amount of expired air that must be rebreathed before fresh air is obtained) tends to cause increased ventilation. At least one study has shown substantially increased ventilation with a full-face respirator, a type that can have a large effective dead space . However, the net effect of a respirator's added resistances and dead space is usually a small decrease in ventilation .\nThe potential for adverse effects, particularly decreased cardiac output, from the positive pressure feature of some respirators has been Raven et al. found statistically significant higher systolic and/or diastolic blood pressures during exercise for persons wearing respirators. Arborelius et al. did not find significant differences for persons wearing respirators during exercise.\n\n# Body Temperature E ffe c ts\nProper regulation of body temperature is primarily of concern with the closed circuit SCBA that produces oxygen via an exothermic chemical reaction.\nInspired air within these respirators may reach 120°F (49°C), thus depriving the wearer of a minor cooling mechanism and causing discomfort. Obviously this can be more of a problem with heavy exercise and when ambient conditions and/or protective clothing further reduce the body's ability to lose heat. The increase in heart rate because of increasing temperature represents an additional cardiac stress.\nClosed-circuit breathing units of any type have the potential for causing heat stress since warm expired gases (after exothermic carbon dioxide removal with or without oxygen addition) are rebreathed. Respirators with large dead spaces also have this potential problem, again because of partial rebreathing of warmed expired air ,\n\n# . Sensory E ffe c ts\nRespirators may reduce visual fields, decrease voice clarity and loudness, and decrease hearing ability. Besides the potential for reduced productivity, these effects may result in reduced industrial safety. These factors may also contribute to a general feeling of stress .\n\n# Psychologic E ffe c ts\nThis important topic is discussed in recent reviews by Morgan [Morgan 1983a[Morgan , 1983b. There is little doubt that virtually everyone suffers some discomfort when wearing a respirator. The large variability and the subjective nature of the psycho-physiologic aspects of wearing a respirator, however, make studies and specific recommendations difficult.\nFit testing obviously serves an important additional function by providing a trial to determine if the wearer can psychologically tolerate the respirator. The great majority of workers can tolerate respirators, and experience in wearing them aids in this tolerance . However, some individuals are likely to remain psychologically unfit for wearing respirators.\n\n# . Local I r r i t a t i o n E ffe c ts\nAllergic skin reactions may occur occasionally from wearing a respirator, and skin occlusion may cause irritation or exacerbation of preexisting conditions such as pseudofolliculitis barbae. Facial discomfort from the pressure of the mask may occur, particularly when the fit is unsatisfactory."},"raw_text":{"kind":"string","value":"for their support in typing and preparing the document for pub I¡cation. Table 1-1.-Respirator recommendations Average work shift concentration gf radon progeny (WL) Respirator recommendations 0 to 0.083 (1/12) No respirator required >0.083 to < 0.42 Any disposable respirator equipped with a HEPA § filter Any more protective respirator >0.42 to i 0.83 Any air-purifying half-mask respirator equipped with a HEPA filter Any SAR** equipped with a half mask and operated in a demand (negative-pressure) mode Any more protective respirator >0.83 to < 2.08 Any powered PAPRtt equipped with a hood or helmet and a HEPA filter Any SAR equipped with a hood or helmet and operated in a continuous flow mode Any more protective respirator See footnotes at end of table. for radon progeny Credit factor for respirator use 65% utilization 90% utilization NA+ NA 2.1 3.6 # # 2.4 5.3 2.4 5.3 # # 2.7 7.4 2.7 7.4 Table 1-1 (Continued).-Respirator recommendations for radon progeny Average work shift concentration gf radon progeny Respirator recommendations Credit factor ________ for respirator use_______ 65% utilization 90% utilization >2.08 to < 4.15 Any air-purifying, full face-2.8 8.5 piece respirator equipped with a HEPA filter Any PAPR equipped with a tight-2.8 8.5 fitting facepiece and a HEPA filter Any SAR equipped with a full 2.8 8.5 facepiece and operated in a demand (negative-pressure) mode Any SAR equipped with a tight-2.8 8.5 fitting facepiece and operated in a continuous-flow mode Any self-contained breathing 2.8 8.5 apparatus (SCBA) equipped with a full facepiece and operated in a demand (negative-pressure) mode Any more protective respirator ^ > 4.15 to <. 83.0 Any SAR equipped with a half-2.9 9.9 mask and operated in a pressuredemand or other positive-pressure mode Any more protective respirator ^ Ŝ ee footnotes at end of table. Table 1-1 (Continued).-Respirator recommendations for radon progeny Average work shift concentration gf radon progeny Credit factor for resDi rator use Respirator recommendations 65% utilization 90% utilization >83.0 to < 166.0 Any SAR equipped with a full facepiece and operated in a pressure demand or other positive pressure mode 2.9 10.0 Any more protective respirator # # >166.0 or unknown concentration or emergency entry Any SCBA equipped with a full facepiece and operated in a pressure demand or other positive pressure mode 2.9 10.0 Any SAR equipped with a full facepiece operated in a pressure demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in a pressure demand or other positive pressure mode 2.9 10.0 Emergency escape Any self-contained self-rescuer (SCSR) NA NA As estimated using the sampling techniques described in Appendix IV. jNA=Not applicable. §HEPA = high-efficiency particulate air. \" S e e appropriated credit factors below. SAR = supplied-air respirator. 'TPAPR = powered air-purifying respirator. *Adapted from Schiager et a l . 1981. 'Used in an instant working level monitor. English 28 13.27 2.11 These studies contain limitations in study design, radon progeny exposure records, smoking history information, followup, etc. Comparisons between these studies, especially for the purposes of risk assessment. 'p<0.05 (some p-values were estimated from the observed lung cancer deaths and the Poisson frequency distribution); rate ratios depend on lung cancer mortality in the comparison population and are sensitive to error in rates that are based on a small number of expected deaths. §The expected number of deaths was estimated from the rate ratios provided by the authors. *Not applicable. The 95% confidence limits of the rate ratios range from 14.4 to infinity. 13. Edling C, Axelson 0. Quantitative aspects of radon daughter exposure and lung cancer in underground miners. Br J Ind Med 1983;40:182-7. 14. Whittemore AS, McMillan A. Lung cancer mortality among U.S. uranium miners: A reappraisal.# FOREWORD\nAs Director of the National Institute for Occupational Safety and Health (NIOSH), I am accustomed to making decisions on difficult issues, but few issues have presented the legislative, scientific, and public health dilemmas that accompany recommending criteria to control the exposure of workers to radon progeny in underground mines.\nThe development of this criteria document is subject to the provisions of two legislative mandates. First, the Occupational Safety and Health Act of 1970 [Public Law (PL) 91-596, which established NIOSH] requires safe and healthful working conditions for every working person. The Act further requires NIOSH to preserve our human resources by providing medical and other criteria that will ensure, insofar as practicable, that no worker will suffer diminished health, functional capacity, or life expectancy as a result of work experience [PL 91-596, Sections 6(b) (5)]. The Act also authorizes NIOSH to recommend new criteria to further improve working conditions Sections 22(c) and (d)].\nIn addition, the Federal Coal Mine Health and Safety Act of 1969 and the Federal Mine Safety and Health Amendments Act of 1977 require NIOSH to develop and revise recommended occupational safety and health standards for mine workers. Specifically, the Secretary of Health, Education, and Welfare (now the Secretary of Health and Human Services) is required to consider, \"in addition to the attainment of the highest degree of health protection for the miner . . . the latest available scientific data in the field, the technical feasibility of the standards, and experience gained under this and other health statutes\" Title 1,Section 101(d)]. These mandates have required NIOSH to weigh its obligation to assure the highest degree of health protection for miners against the technical feasibility of the recommended standard in the development of recommendations for controlling radon progeny exposure in underground mines.\nThe control of exposure to radon progeny presents an unprecedented problem because of the ubiquitous yet variable nature of their presence in mines and the ambient environment. To complicate this matter further, recent reports indicate that an exposure-related health risk may exist at background exposure levels.\nThe full ramifications of this dilemma can easily be appreciated by considering two points. The first is that dilution ventilation (the primary engineering approach to reducing the concentration of radon progeny in mines) is accomplished by the exchange of mine air with air from the outside environment. Obviously, this approach is not a viable option for the total elimination of radon progeny in underground mines because the outside air is also contaminated with radon progeny.\nIn addition, this approach would not be a prudent community environmental public health measure in some situations because it involves releasing an additional burden of radon progeny to the ambient environment and thereby contributing to the background level in the immediate area of the mine. Thus ventilation cannot be used to totally eliminate exposure to radon progeny in mines.\nThe second point to consider in this dilemma is that the variable nature of radon progeny exposure in the ambient environment precludes recommending an annual cumulative exposure limit that includes both occupational and ambient contributions. Because ambient exposure varies, such a recommendation would result in an occupational exposure limit and associated risk that would vary with the locale. This approach is obviously undesirable, for it would lead to a nightmare of confusion and complicated enforcement requirements and would probably result in unequal protection of miners.\nData from both human and animal studies clearly demonstrate a direct link between lung cancer and radon exposure. Specific epidemiological studies provide a basis for quantitatively estimating human risk at various exposure levels. Such analyses clearly show that a radon exposure of 4 WLM (4 working level months) per year over a 30-year working lifetime (the current Mine Safety and Health Administration [MSHA] standard) poses a significant and unacceptable risk of lung cancer. This risk must be substantially reduced.\nIn recommending an exposure limit for radon progeny, NIOSH considered not only the results of its own risk assessment and the technical feasibility of the recommended standard, but also the uncertainty of the data available on risk. Uncertainties are inherent in both the risk assessment methods and the scientific data on which the risk assessment is based. This fact must be understood and acknowledged. Some of the factors involved in these uncertainties include the choice of risk assessment method and model, the measurement methods used for data collection, and risk estimates derived from data that are heavily weighted with higher exposures.\nThe first of these factors in risk uncertainty involves the choice of a risk assessment method and/or model (such as the Cox proportional hazards model used in the NIOSH risk assessment study). NIOSH has attempted to develop a mathematical model that best describes the lung cancer risk in miners exposed to radon progeny. The use of a risk assessment model is merely a practical way to work with a very complex problem. There are modeling approaches other than the one chosen for this study. Each choice would result in a somewhat different description of the relationship between radon progeny exposure and lung cancer risk. NIOSH has attempted to compare the alternatives that are available and applicable. NIOSH scientists have considered the differences that might arise through a review of the available scientific literature and discussions with other scientists who have evaluated this exposure-related lung cancer risk.\nAlthough alternative models might yield minimally different quantitative risk estimates, none of them would lead the Institute to a qualitatively different risk assessment (i.e., that exposures to radon progeny at the current standard are associated with excesses of lung cancer).\nThe second factor involved in risk uncertainty is the measurement method used for data collection. This study involves a follow-up period of more than 35 years, more than 3,000 miners, and thousands of measurements. The older data are subject to greater uncertainty than the more recent data because of improvements in the entire measurement process over the course of the study.\nThe third factor involved in risk uncertainty is the process of generating risk estimates at lower exposure levels. One consideration is that such risk estimates are derived from data heavily weighted by higher exposures (note that the annual cumulative exposures of most miners in this study are higher than either the current MSHA standard or the proposed NIOSH recommended exposure limit [REL]). Another consideration is the desirability of placing occupational risk in the context of background exposure risk. However, the latter has not been evaluated and would have to be estimated on the basis of occupational data. We therefore do not believe that it is currently possible to contrast these two types of risks. Nonetheless, EPA has generated some initial information on background exposure risk in A Citizen's Guide to Rad o n . This document indicates that action should be taken to lower radon progeny levels in homes with measured concentrations of 0.02 WL or greater. NIOSH estimates that this concentration would probably result in a cumulative exposure that is less than 1 WLM but within an order of magnitude of that value. New information is clearly needed on background exposure levels and the hazards associated with such exposure before occupational and nonoccupational risks can be reliably quantified and validly contrasted. Until these data are available, the final target exposure limits cannot be identified for control of this hazard in our total environment. The uncertainties in the data and a recent study commissioned by the Bureau of Mines on the feasibilities of controlling radon progeny levels in mines have been weighed along with the available evidence and the obligations of NIOSH. This process has resulted in an REL of 1 WLM per year. Our own quantitative risk assessment clearly shows that significant health risks are posed by an exposure level of 1 WLM per year over a 30-year working lifetime. NIOSH therefore regards this REL as an upper limit and further recommends that mine operators limit exposure to radon progeny to the lowest levels possible.\nIn addition, NIOSH wishes to emphasize that this recommended standard contains many important provisions in addition to the annual exposure limit. These include recommendations for limited work shift concentrations of radon progeny, sampling and analytical methods, recordkeeping, medical surveillance, posting of hazardous information, respiratory protection, worker education and notification, and sanitation. All of these recommendations help minimize risk.\nIn summary, NIOSH has the legislative, scientific, and public health responsibility to protect the health of miners by developing recommendations that eliminate or minimize occupational risks, recommended exposure limit of 1 WLM per year, I of the recommended standard fully satisfies the Although I am approving the do not feel that this part Institute's commitment to protect the health of all of the Nation's miners.\nFuture research may provide evidence of new and more effective methods for reducing occupational exposures to radon progeny, more reliable risk estimates at low exposure levels, and improved risk assessment methods.\nIf new information demonstrates that a lower exposure limit constitutes both prudent public health and a feasible engineering policy, NIOSH will revise its recommended standard. \n# I. RECOMMENDATIONS FOR A RADON PROGENY STANDARD\nThe National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to radon progeny in underground mines be controlled by compliance with this recommended standard, which is designed to protect the health of underground miners over a working lifetime of 30 years. Mine operators should regard the recommended exposure limit for radon progeny as the upper boundary for exposure; they should make every effort to limit radon progeny to the lowest possible concentrations. This recommended standard will be reviewed and revised as necessary.\nRadon progeny (also known as radon daughters) are the short-lived decay products of radon, an inert gas that is one of the natural decay products of uranium. The short-lived radon progeny (i.e., polonium-210, lead-214, bismuth-214, and polonium-214) are solids and exist in air as free ions or as ions attached to dust particles. The NIOSH recommended exposure limit (REL) is based on (1) evidence that a substantial risk of lung cancer is associated with an occupational exposure to radon progeny, and (2) the technical feasibility of reducing exposures.\nIn this document, NIOSH presents recommendations that will protect miners employed year-round at any mine work area for as long as 30 years (the period of time used by MSHA as a miner's working lifetime). The exposure limit contained in this recommended standard is measurable by techniques that are valid, reproducible, and available to industry and government agencies. NIOSH has concluded that current technology is sufficient to achieve compliance with the recommended standard.\nBecause knowledge of the carcinogenic process is incomplete and no data exist to demonstrate a safe level of exposure to carcinogens, NIOSH maintains that occupational exposure to carcinogens such as radon progeny should be reduced to the lowest level technically achievable. Compliance with this standard does not relieve mine operators from complying with other applicable standards.\n# S ection 1 -D e fin itio n s ( a ) Miner\nMiners include all mine personnel who are involved with any underground operation (e.g., drilling, blasting, haulage, and maintenance).\n# (b ) Working Level\nOne working level (WL) is any combination of short-lived radon progeny in 1 liter (L) of air that will ultimately release 1.3 x 10^ million electron volts (MeV) of alpha energy during decay to lead-210.\n# ( c ) Working Level Month\nA working level month (WLM) is the product of the radon progeny concentration in WL and the exposure duration in months. For example, if a miner is exposed at a concentration of 0.083 WL for 1 month 1 (170 hours [hr]),* then the cumulative exposure for the month is 0.083 WLM.\nIf the cumulative exposure of the same miner is 0.083 WLM for each of 12 consecutive months (2,040 hr), then the cumulative exposure for the year is 1 WLM.\n# (d ) Work Area\nA work area is any stope, drift heading, travelway, haulageway, shop, station, lunchroom, or any other underground location where miners work, travel, or congregate.\n# ( e ) Average Work S h if t C oncentration\nThe average work shift concentration is the average concentration of radon progeny present during a work shift in a given area. This concentration is used to represent the miner's breathing zone exposure to radon progeny.\n# Section 2 -Environment (Workplace A i r ) ( a ) Recommended Exposure L im it (REL)\nExposure to radon progeny in underground mines shall not exceed 1 WLM per year, and the average work shift concentration shall not exceed 1/12 of 1 WL (or 0.083 WL). The REL of 1 WLM per year is an upper limit of cumulative exposure, and every effort shall be made to reduce exposures to the lowest levels possible.\n# (b ) Sampling and A nalysis\nGrab samples for radon progeny in the workplace shall be taken and analyzed using working level monitors, the Kusnetz method, or any other method at least equivalent in accuracy, precision, and sensitivity. Sampling and analytical methods are described in Chapter II. Details of the recommended sampling strategy are contained in Appendix IV. The recommended sampling strategy allows the use of grab samples for estimating the average work shift concentration of radon progeny.\n# Section 3 -M onitoring and Recording Exposures ( a )\nExposure M onitoring All operators of underground mines shall perform environmental evaluations in all work areas to determine exposures to radon progeny.\n(1) An initial environmental evaluation shall be conducted in each work area to determine the average work shift concentration of radon progeny.\n*Note that Mine Safety and Health Administration (MSHA) regulations are based on 173 hr per month.\n(2) Periodic environmental evaluations shall be conducted at intervals (as described in Appendix IV) in each work area. An alternative sampling strategy may be used if the mine operator can demonstrate that it effectively monitors exposure to radon progeny.\n(3) If environmental monitoring in a work area indicates that the average work shift concentration of radon progeny exceeds 1/12 WL (as described in Appendix IV), the mine operator shall prepare an action plan describing the types of engineering controls and work practices that will be implemented to reduce the average work shift concentration in that area.\n# (b ) Exposure M onitoring Records\nThe mine operator shall determine and record the exposure to radon progeny.\nEach miner's exposure shall be calculated using monitoring data obtained for the areas in which the miner worked. These records shall include (1) locations, dates, and times of measurements, (2) sampling and analytical methods used, (3) the number, duration, and results of the samples taken, and (4) all items required by Sections 3(b) (2) and (3). All records shall be retained at the mine site or nearest mine office as described in Section 10.\n( 1 ) C a lc u la tin g the M in e r's D a ily Exposure\nThe average work shift concentration of radon progeny for each work area shall be used to calculate each miner's daily exposure.\nIf no monitoring has been conducted in a work area on a particular day, the daily average work shift concentration for that area shall be determined by averaging the results obtained on the last day of monitoring with the results from the next day that monitoring is conducted.\nA miner's exposure (in WLM) for a given area is calculated as foI lows:\nWLM = WL x T 170 hr\nwhere WL is the average work shift concentration of radon progeny, T is the total time (hours) spent in the area, and 170 is the number of hours worked per month.\nA miner's total cumulative exposure for the year is the sum of the daily exposures (as calculated above) for all work areas in which time was spent during the work shift.\n(\n# ) Uranium Mines\nExposure to radon progeny shall be recorded daily for each uranium miner. These records shall include the miner's name, social security number, the time spent in each work area, estimated exposure to radon progeny for each work area as determined in Section 3(b) (3), and (if applicable) the type of respiratory protection and duration of its use.\n(3) Nonuranium Mines Exposure to radon progeny shall be recorded daily for all miners assigned to work in areas where environmental monitoring for radon progeny is required as described in Appendix IV. These exposure monitoring records shall include the miner's name, social security number, time the miner has spent in each work area, estimated exposure to radon progeny for each work area as determined in Section 3(b) (3), and (if applicable) the type of respiratory protection used and the duration of its use.\n(4) Respirator Credit\nThe type of respirator worn and the credit given for wearing it (see Section 7) shall be recorded for each miner. Mine operators shall record both the average work shift concentration of radon progeny and the adjusted exposure concentration calculated by using the respirator credit. The adjusted exposure concentration shall be used to determine the miner's cumulative exposure for compliance with the REL of 1.0 WLM/year. Section 4 -Medical Surveillance (a) General (1) The mine operator shall institute a medical surveillance program for all miners.\n(2) The mine operator shall ensure that all medical examinations and procedures are performed by or under the direction of a Iicensed physician.\n(3) The mine operator shall provide the required medical surveillance at a reasonable time and place without loss of pay or cost to the miners.\n(4) The mine operator shall provide the following information to the physician performing or responsible for the medical surveillance program: a copy of the radon progeny standard, the miner's duration of employment, the miner's cumulative exposure to radon progeny (or an estimate of potential exposure to radon progeny if the miner is a new employee), a description of the miner's duties as they relate to his exposure, and a description of any protective equipment the miner has used or may be required to use.\n(5) The mine operator or physician shall counsel tobacco-smoking miners about their increased risk of developing lung cancer from the combined exposure to tobacco smoke and radon progeny. The mine operator or physician shall encourage the miner to participate in a smoking cessation program. The mine operator shall enforce a policy prohibiting smoking at the mine site. (6) The physician shall provide the mine operator and the miner with a written statement describing any medical conditions found during the preplacement or periodic medical examinations that may increase the miner's health risk when exposed to radon progeny. This written statement shall not reveal specific findings, but shall include any recommended limitations on the miner's exposure to radon progeny or ability to use respirators and other personal protective equipment.\n# (b ) Preplacement Medical Examination\nThe preplacement medical examination of each miner shall include the foI lowing:\n(1) A comprehensive medical and work history (including smoking history) that emphasizes the identification of existing medical conditions and attempts to elicit information about previous occupational exposure to radon progeny.\n(2) A thorough examination of the miner's respiratory system, including pulmonary function tests. The initial and subsequent pulmonary function tests shall include determination of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV-j) using the current American Thoracic Society (ATS) recommendations on instrumentation, technician training, and interpretation. A prospective miner with symptomatic, spirometric, or radiographic evidence of pulmonary impairment should be counseled about the risks of continued exposure.\n(3) A posterio-anterior chest X-ray using the current ATS recommendations on instrumentation, technician training, and interpretat ion.\n(4) Other tests deemed appropriate by the physician.\n# ( c ) P e rio d ic Medical Examination\nThe periodic medical examination for each miner shall include the fotlowing:\n(1) An annual update of medical and work histories (including smoking history).\n(2) An evaluation of the miner's respiratory system. Because of the potential for chronic respiratory disease, this evaluation shall include spirometry at intervals determined by the physician.\nMiners that have spirometric or radiographic evidence or symptoms of pulmonary impairment should be counseled by the physician regarding the risks of continued exposure.\n(3) A posterio-anter¡or chest X-ray at intervals determined by the physician using the current ATS recommendations on instrumentation, technician training, and interpretation. Periodic chest X-rays are recommended for monitoring miners exposed to fibrogenic respiratory hazards (e.g., quartz). Ordinarily, chest X-rays may be obtained every 5 years for the first 15 years of employment and every 2 years thereafter, depending on the nature and intensity of exposures and their related health risks. A recent X-ray obtained for other purposes (e.g., upon hospitalization) may be substituted for the periodic X-ray if it is of acceptable quality.\n(4) Other tests deemed appropriate by the physician.\n# Section 5 -Posting\nAll warning signs shall be printed in both English and the predominant language of non-Eng Iish-reading miners. Miners unable to read the posted signs shall be informed verbally about the hazardous areas of the mine and the instructions printed on the signs.\n(a) Readily visible signs containing the following information shall be posted at mine entrances or in work areas that require environmental monitoring for radon progeny as described in Appendix IV:\n# AUTHORIZED PERSONNEL ONLY DANGER! POTENTIAL RADIATION HAZARD RADON PROGENY\n(b) If respiratory protection is required, the following statement shall be added in large letters to the sign required in Section 5(a):\n# RESPIRATORY PROTECTION REQUIRED IN THIS AREA Section 6 -Work P ra c tic e s and Engineering C ontrols\nEffective work practices and engineering controls shall be instituted by the mine operator to reduce the concentration of radon progeny to the lowest technically achievable limit. Since there is no typical mine and each operation has some unique features, the work practices and engineering controls in this section may need to be adapted for use in particular si tuat ions. Examples of effective ore extraction and handling procedures include the following: minimizing the number of ore faces simultaneously exposed, performing retreat mining toward intake air, limiting the underground storage and handling of ore, locating ore transfer points away from ventilation intakes, removing dust spilled from ore cars, minimizing ore spillage by maintaining roadways and carefully loading haulage vehicles, and covering ore until it is moved to the surface.\n( 2 ) B la s tin g\nBlasting should be performed at the end of the work shift whenever possible. Miners shall be evacuated from exhaust drifts until environmental sampling confirms that the average work shift concentration of radon progeny does not exceed 1/12 WL. Refer to Section 7 if respiratory protection is required for subsequent reentry.\n( 3 ) Worker R o tatio n\nThe mine operator shall not use the planned rotation of miners to maintain an individual's exposure below the REL of 1.0 WLM per year. NIOSH acknowledges, however, that some miners may inadvert ently be exposed to short-term high concentrations of radon progeny. For example, such exposures may occur when engineering controls fail. To ensure that the miners' cumulative exposure remains below the REL in such circumstances, it may be necessary to transfer them to other jobs or work areas that have lower concentra tions of radon progeny. Miners transferred under these circum stances shall retain their pay as prescribed for coal miners under Section 203(b) of the Federal Coal Mine Safety and Health Act of 1977.\n# (b ) Engineering C o ntrols\nMechanical exhaust ventilation used alone or in combination with other engineering controls and work practices can effectively reduce exposures to radon progeny. Ventilation systems discharging outside the mine shall conform with applicable local, State, and Federal [40 CFR*61,Subpart B] air pollution regulations and shall not constitute a hazard to miners or to the general population.\n(1) Ductwork shall be kept in good repair to maintain designed airflows. The effectiveness of mechanical ventilation systems shall be determined periodically and as soon as possible after any significant changes have been made in production or control. A log shall be kept showing designed airflow and the results of all airflow measurements.\n(2) Fans shall be operated continuously in the work areas of an active mine and before the opening of a previously inactive mine or inactive section until environmental sampling confirms that the average work shift concentrations of radon progeny do not exceed 1/12 WL. Refer to Section 7 if respiratory protection is required.\n*Code of Federal Regulations. See CFR in references.\n(3) Fresh air shall be provided to miners in dead end areas near the working faces.\n(4) Bulkheads, backfill, and sealants shall be used to control exposures as appropriate.\nAppendix III provides a general discussion of engineering control methods.\nS ection 7 -R e s p ira to r S e le c tio n and C re d it fo r R e s p ira to r Use ( a ) General C onsiderations NIOSH has determined that a radon progeny exposure limit of 1.0 WLM per year is technically achievable in mines through the use of effective work practices and engineering controls. Over a 30-year working lifetime, this exposure limit will reduce but not eliminate the risk of lung cancer associated with exposure to radon progeny. NIOSH considers respirators to be one of the last options for worker protection. Work practices and engineering controls are more effective means for limiting exposures and providing a safe environment for all workers. Respirator use in underground mines is not always practical for a number of reasons, including the additional physiological burden and safety hazards they pose. NIOSH therefore recommends that engineering controls and work practices be used where technically achievable to control the exposure of miners to radon progeny.\nCompliance with an exposure limit of 1.0 WLM per year requires an average exposure of 1/12 WL throughout the year to ensure that the miner can work for an entire year (i.e., 2,040 hr). For average work shift concentrations above 1/12 WL, NIOSH recommends mandatory respirator use as well as the implementation of engineering controls and work practices to reduce exposure to radon progeny.\nOccupational exposure to radon progeny above background concentrations has been associated with excess lung cancer risk. Therefore, regardless of the exposure concentration, NIOSH advises the use of respirators to further reduce exposure and decrease the risk of lung cancer.\nRespiratory protection shall be used by miners (1) when work practices and engineering controls are not adequate to limit average work shift concentrations of radon progeny to 1/12 WL, (2) when entering a mine area where concentrations of radon progeny are unknown, or (3) during emergencies. Use only those respirators approved by NIOSH or the Mine Safety and Health Administration (MSHA).\n# (b ) R e s p ira to r P ro te c tio n Program\nWhenever respirators are used, a complete respiratory protection program shall be instituted. This program must follow the recommendations contained in ANSI Z88. (published by the American National Standards Institute) and the respirator-use criteria in 30 CFR 57.5005.\nThe respiratory protection program described in ANSI Z88.2-1969 requires the following:\n(1) A written program for respiratory protection that contains standard operating procedures governing the selection and use of respi rators.\n(2) Periodic worker training in the proper use and limitations of respi rators.\n(3) Evaluation of working conditions in the mine.\n(4) An estimate of anticipated exposure.\n(5) An estimate of the physical stress that will be placed on the miner. A detailed medical examination of each miner shall be conducted according to the guidelines set forth in Appendix V. (6) Routine inspection, maintenance, disinfection, proper storage, and evaluation of respirators. (7) Information concerning the manufacturers' instructions for respirator fit-testing and proper use.\n# ( c ) R e s p ira to r S e le c tio n\nNIOSH makes the following recommendations for respirator selection:\n(1) A respirator is not required for exposure to average work shift concentrations less than or equal to 1/12 WL.\n(2) For exposure to average work shift concentrations greater than 1/12 WL, NIOSH recommends those respirators listed in Table 1-1. (3) For entry into areas where radon progeny concentrations are unknown or exceed 166 WL, or for emergency entry, NIOSH recommends only the most protective respirators (any full-facepiece, positive-pressure, self-contained breathing apparatus [SCBA] or full-facepiece, positive-pressure, supplied-air respirator and SCBA combinat ion).\nThese recommendations are based on the fact that radon progeny exist as particulates and that miners are not exposed to hazardous concentrations of nonparticulate contaminants.\nIf protection against nonparticulate contaminants is required, different types of respirators must be selected.\n# (d ) C re d it fo r R e s p ira to r Use\nWhen respirators are worn properly, the miner's average work shift exposure can be reduced by a factor that depends on the class of respirator worn. Table 1-1 provides the credit factors for the various classes of respirators. For example, if a miner wears a helmet-type, powered, air-purifying respirator (PAPR) for 65% of the work shift and the radon progeny concentration in the work area is 0.3 WL, then the miner's exposure can be adjusted by dividing 0.3 WL by 2.7, the credit factor for this class of respirator. This results in an adjusted exposure of 0.11 WL for that miner. Respirator credit is discused in detaiI in Chapter 11.\n# S ection 8 -Inform ing Workers o f the Hazards o f Radon Progeny ( a ) N o tific a t io n o f Hazards\nThe mine operator shall provide all miners with information about workplace hazards before job assignment and at least annually thereafter.\n( b ) T ra in in g (1) The mine operator shall institute a continuing education program conducted by persons with expertise in occupational safety and health. The purpose of this program is to ensure that all miners have current knowledge of workplace hazards, effective work practices, engineering controls, and the proper use of respirators and other personal protective equipment. This program shall also include a description of the general nature of the environmental and medical surveillance programs and the advantages of participating in them. This information shall be kept on file and be readily available to miners for examination and copying. The mine operator shall maintain a written plan of these training and surveillance programs.\n(2) Miners shall be instructed about their responsibilities for following proper work practices and sanitation procedures necessary to protect their health and safety.\n# S ection 9 -S a n ita tio n ( a ) E ating and D rinking\nThe preparation, storage, dispensing (including vending machines), or consumption of food shall be prohibited in any area where a toxic material is present. The mine operator shall provide facilities so that miners can wash their hands and faces thoroughly with soap or mild detergent and water before eating or drinking.\n# (b ) Smoki ng\nSmoking shall be prohibited in underground work areas.\n# ( c ) To i I e t Fac i I i t i es\nThe mine operator shall provide an adequate number of toilet facilities and encourage the miners to wash their hands thoroughly with soap or mild detergent and water before and after using these facilities.\n# (d ) Change Rooms\n(1) The mine operator shall provide clean change rooms for the miners.\n(2) The mine operator shall provide storage facilities such as lockers to permit the miners to store street clothing and personal i terns.\n# ( e ) Showers\nThe mine operator shall provide showers and encourage the miners to shower at the end of the work shift.\n# ( f ) Laundering\n(1) The mine operator shall provide for the cleaning, laundering, or disposal of contaminated work clothing and equipment.\n(2) The mine operator shall ensure that contaminated work clothing or equipment that is to be cleaned, laundered, or disposed of is placed in a closed container to prevent dispersion of dust.\n(3) Any person who cleans or launders this contaminated work clothing or equipment must be informed by the operator that it may be contaminated with radioactive materials.\n# S ection 10 -Recordkeeping Requirements\n( a ) Record R etention (1) The mine operator shall retain all records of the monitoring required in Section 3(b).\n(2) All monitoring records shall be retained for at least 40 years after termination of employment.\n(3) The mine operator shall retain the medical records required by Section 4. These records shall be retained for at least 40 years after termination of employment.\n# (b ) A v a il a b i l it y o f Records\nThe miner shall have access to his medical records and be permitted to obtain copies of them. Records shall also be made available to former miners, or their representative and to the designated representatives of the Secretary of Labor and the Secretary of Health and Human Services.\n# ( c ) T ran s fer o f Records\n(1) Upon termination of employment, the mine operator shall provide the miner with a copy of his records specified in Section 10(a).\n(2) Whenever the mine operator transfers ownership of the mine, all records described in this section shall be transferred to the new operator, who shall maintain them as required by this standard.\n(3) Whenever a mine operator ceases to do business and there is no successor, the mine operator shall notify the miners of their rights of access to those records at least 3 months before cessation of business.\n(4) The Director of NIOSH shall be notified in writing before (a) a mine operator ceases to do business and there is no successor to maintain records, and (b) the mine operator intends to dispose of those records.\n(5) No records shall be destroyed until the Director of NIOSH responds in writing to the mine operator.\nII.\n# INTRODUCTION\n\n# A. Scope\nRadon is a gas that diffuses continuously from surrounding rock and broken ore into the air of underground mines, where it may accumulate; radon may also be carried into mines through groundwater containing dissolved radon [Snihs 1981]. Radon gas may be inhaled and immediately exhaled without appreciably affecting the respiratory tissues. However, when attached or unattached radon progeny are inhaled, they may be deposited on the epithe lial tissues of the tracheobronchial airways. Alpha radiation may subse quently be emitted into those tissues from polonium-218 and polonium-214, thus posing a cancer risk to miners who inhale radon progeny.\nThis document presents the criteria and recommendations for an exposure standard that is intended to decrease the risk of lung cancer in miners occupationally exposed to short-lived, alpha-emitting decay products of radon (radon progeny) in underground mines. The REL for radon progeny applies only to the workplace and is not designed to protect the population at large. The REL is intended to ( 1) protect miners from the development of lung cancer, (2) be measurable by techniques that are valid, reproducible, and available to industry and government agencies, and (3) be technically ach i evabIe.\n# B. Current Standard\nMSHA has established radiation protection standards for workers in underground metal and nonmetal mines [30 CFR 57.5037 through 57.5047]. This standard limits a miner's radon progeny exposure to a concentration of 1.0 WL and an annual cumulative exposure of 4 WLM. Each WLM is determined as a 173-hr cumulative, time-weighted exposure [30 CFR 57.5040(6)]. Smoking is prohibited in all areas of a mine where radon progeny exposures must be determined; respiratory protection is required in areas where the concen tration of radon progeny exceeds 1.0 WL.\nAccording to current MSHA regulations, the exhaust air of underground mines must be sampled to determine the concentration of radon progeny.\n# Uran i um M ines\nIf the concentration of radon progeny in the exhaust air of a uranium mine exceeds 0.1 WL, samples representative of a miner's breathing zone must be taken at random times every 2 weeks in each work area (i.e., stopes, drift headings, travelways, haulageways, shops, stations, lunchrooms, or any other place where miners work, travel, or congregate).\nIf concentrations of radon progeny exceed 0.3 WL in a work area, sampling must be done weekly until the concentration has been reduced to 0.3 WL or less for 5 consecutive weeks. Uranium mine operators must calculate, record, and report to MSHA the radon progeny exposure of each underground miner. The records must include the miner's time in each work area and the radon progeny concentration measured in each of those areas.\n# Nonuranium Mines\nIf the concentration of radon progeny in the exhaust air of nonuranium mines exceeds 0.1 WL, and if concentrations are between 0.1 and 0.3 WL in an active working area, samples representative of a worker's breathing zone must be taken at least every 3 months at random times until the concentrations of radon progeny are less than 0.1 WL in that area. Samples must be taken annually thereafter.\nIf the concentration of radon progeny exceeds 0.3 WL in a working area, samples must be taken at least weekly until the concentration has been reduced to 0.3 WL or less for 5 consecutive weeks. Operators of nonuranium mines must calculate, record, and report to MSHA the radon progeny exposures of miners assigned to areas with concentrations of radon progeny exceeding 0.3 WL. The records must include the miner's time in each work area and the radon progeny concentration measured in each of those areas.\n# C. Uranium Decay S e ries\nFigure 11-1 shows the sequence by which the most abundant isotope of uranium (238u) decays to a radioactively stable isotope of lead (206pb). Radon (222Rn) is an inert gas with a radiologic half-life of 3.8 days; it is a product of the natural decay of radium (226Ra ). When radon decays, alpha particles and gamma radiation are emitted, and an isotope of polonium (218p0 ) ¡s formed. Polonium-218 (218p0 ) anc| j ts decay productslead-214 (214pb), bismuth-214 (214b ' i ), and polonium-214 (214p0 )-are commonly referred to as short-lived radon progeny because they have half-lives of 27 minutes or less (see . Both polonium-218 and polonium-214 emit alpha particles as they decay. The short-lived progeny are solids and exist in air as free ions (unattached progeny) or as ions adsorbed to dust particles (attached progeny).\nBecause it is a gas, radon diffuses through rock or soil and into the air of underground mines, where it may accumulate; radon may also be carried into mines through groundwater containing dissolved radon [Snihs 1981]. Radon may be inhaled and immediately exhaled without appreciably affecting the respiratory tissues. However, when the radon progeny (either attached or unattached) are inhaled, they may be deposited in the epithelial tissues of the tracheobronchial airways, where alpha radiation from polonium-218 and polonium-214 may be subsequently emitted. The quantity of mucus in those airways and the efficiency of its clearance (retrograde ciliary action) into the esophagus are important factors that affect the total radiation absorbed at a specific site within the respiratory tract.\nAlpha particles are energetic helium nuclei. As they pass through tissue, they dissipate energy by the excitation and ionization of atoms in the tissue; it is this process that damages cells. Because alpha particles travel less than 100 micrometers in tissue, intense ionization occurs close to the site of deposition of the inhaled alpha-emitting radon progeny. Beta particles (electrons) and gamma radiation (shortwave electromagnetic radiation) can also cause ionization in tissues, but they travel farther through tissues and dissipate less energy per unit path length than do alpha particles [Casarett 1968;Wang et a l . 1975;Shapiro 1981]. The beta parti cles and gamma radiation emitted by radon progeny make a negligible contri bution to the radiation dose in the lung [Evans 1969].\n# D-U n its o f Measure\nThe common unit of radioactivity is the curie (Ci), which is the rate at which the atoms of a radioactive substance decay; 1 Ci equals 3.7 x 10^® disintegrations per second (dps). The picocurie (pCi) corresponds to 3.7 x 10~2 dps. The International System of Units (SI) unit of radio activity is the becquerel (Bq), which is equivalent to 1 dps. Therefore, 1 pCi is equivalent to 0.037 Bq.\nWhen radon gas and radon progeny are inhaled, the radiation exposure is primarily caused by the short-lived radon progeny (polonium-218, lead-214, bismuth-214, and polonium-214, which are deposited in the lung) rather than by the radon gas. Because it was not feasible to routinely measure the individual radon progeny, the U.S. Public Health Service introduced the concept of the working level, or WL [Holaday et al. 1957]. The WL unit represents the amount of alpha radiation emitted from the short-lived radon progeny. One WL is any combination of short-lived radon progeny in 1 liter (L) of air that will ultimately release 1.3 x 10^ million electron volts (MeV) of alpha energy during decay to lead-210. The SI unit of measure for potential alpha energy concentration is joules per cubic meter of air (J/m3 ); 1 WL is equal to 2.08 x 10\"5 J/m3 [ICRP 1981],\nThe equilibrium between radon gas and radon progeny must be known in order to convert units of radioactivity (Ci or Bq) to a potential alpha energy concentration (WL or J/m3 ). The equilibrium factor (F) is defined as the ratio of the equilibrium-equivalent concentration of the short-lived radon progeny to the actual concentration of radon in air [ICRP 1981]. When the equilibrium factor approaches 1.0, it means that the concentration of radon progeny is increasing relative to the concentration of radon. At complete radioactive equilibrium (F=1.0), the rate of radon progeny decay equals the rate at which the progeny are produced. Thus the radioactivity of the decay products equals the radioactivity of the radon [Shapiro 1981].\nIn under ground mines, the equilibrium factor mainly depends on the ventilation rate and the aerosol concentration [Urban et al. 1985]. Values of F ranging from 0.08 to 0.65 are typical in underground mines [Breslin et al. 1969]. Radioactivity and potential alpha energy concentration values at various equilibria are presented in Table 11-1. The common unit of measure for human exposure to radon progeny is the working level month (WLM). One WLM is defined as the exposure of a worker to radon progeny at a concentration of 1.0 WL for a working period of 1 month (170 hr).* The SI unit for WLM is joule-hour per cubic meter of air (J-h/m3 ); 1 WLM is equal to 3.6 x 10-3 J-h/m3 . *Note that MSHA regulations are based on 173 hr per month. *F is defined as the quotient of the equilibrium-equivalent radon progeny activity divided by the radon activity.\nThe rad (radiation absorbed dose) is the unit of measure for the absorbed dose of ionizing radiation. One rad corresponds to the energy transfer of 6.24 x 107 MeV per gram of any absorbing material [Shapiro 1981]. The rem (roentgen equivalent man) is the unit of measure for the dose equivalent of any ionizing radiation in man. One rem is equivalent to one rad multiplied by a radiation quality factor (QF). The radiation QF expresses the relative effectiveness of radiation with differing Iinear-energy-transfer (LET) values to produce a given biological effect. The radiation QFs for beta particles and gamma radiation are each approximately 1; the radiation QF for alpha radiation varies from 10 to 20 [NGRP 1975;ICRP 1977;NCRP 1984a].\nFor equal doses of absorbed radiation (rads), the dose equivalent (rems) attributed to alpha particles is 10 to 20 times greater than the dose equiva lent attributed to high-energy beta particles or gamma radiation. The SI unit of measure for the dose equivalent is the sievert (Sv). One rem is equal to 0.01 Sv [Shapiro 1981].\n# E. Worker Exposure\nIn 1986, 22,499 workers were employed in 427 metal and nonmetal mines in the United States.\nIn the past few years, the number of underground uranium mines operating in the United States has decreased dramatically from 300 in 1980 [Federal Register 1986] to 16 in 198416 in [MSHA 1986]. Accordingly, the number of miners employed in these mines has also decreased from 9,076 in 19799,076 in [Cooper 1981, to 1,405 in 1984[AIF 1984], and to 448 in 1986[MSHA 1986].\nTable II-2 shows the range in concentrations of airborne radon progeny measured in U.S. underground metal and nonmetal mines from 1976 through 1985 [MSHA 1986]. As illustrated in 38 of the 254 operating underground nonuranium mines sampled during fiscal year 1985 contained concentrations of airborne radon progeny equal to or greater than 0.1 WL in [MSHA 1986]. With an estimated average of 55 workers per mine, approximately 2,090 nonuranium miners were at risk of exposure to radon progeny concentrations equal to or greater than 0. 1 WL in 1985[MSHA 1986. presents the annual cumulative radon progeny exposures of miners in 20 U.S. underground uranium mines in 1984; these data are presented by job category. Of the 1,405 underground uranium miners working in 1984, 400 (28%) had annual cumulative exposures to radon progeny greater than 1.0 WLM [AIF 1986]. The gamma radiation exposures of U.S. uranium miners are generally regarded to be less than the whole-body occupational exposure limit of 5 rem (50 mSv) per year [Breslin et al. 1969;Schiager et a l . 1981].\n# F. Measurement Methods fo r A irborne Radon Progeny\n\n# D escrip tio n o f Measurement Methods\n\n# a . Grab Samp I i ng Methods\nGrab sampling methods for measuring airborne radon progeny involve drawing a known volume of air through a filter and counting the alpha or beta radioactivity on the filter during or after sampling. Grab sampling methods used in underground mines are listed in Table II-5.\nIn one-count grab sampling methods such as those used with instant working-level monitors, the radioactivity is determined over a single counting period using a scintillation counter.\nIn two-count methods, the radioactivity is determined over two counting periods, and the ratio of these two measurements is used to calculate the radon progeny concentrations.\nIn a three-count method, radon progeny concentrations are derived from the relative changes in the measurements taken at three 30-minute intervals.\nCritically important factors are the proper calibration of radiation detectors and pumps, filters that precisely fit the equipment, and accurate maintenance of the flow rate during the sampling period. It is also important to prevent the accumulation of radionuclides to avoid contamination of the pump, counting equipment, and filters [Schiager et al. 1981]. \n# --\nStatistical uncertainties associated with the various grab sampling methods for radon progeny are presented in Data indi cate that the relative precision of the methods is the same. The major differences are the total time period required for sampling and analysis, the capability of determining exposure concentrations at the work site, and the amount of routine maintenance and cali bration required of the instrumentation.\n# b. Continuous M onitoring Methods\nIn continuous monitoring methods, air is sampled continuously, and (as with other methods) the alpha or beta radioactivities are determined over the length of the collection period. Continuous monitoring devices and systems have been described elsewhere [Haider and Jacobi 1973;Holmgren 1974;Droullard and Holub 1977;Kawaji et al. 1981;Bigu and Kaldenbach 1984;Sheeran and Franklin 1984;Bigu and Kaldenbach 1985;Droullard and Holub 1985]. The characteristics and statistical uncertainties for some continuous monitoring methods are presented in Table II-7.\nThe U.S. Bureau of Mines has designed an automated continuous monitoring system in which up to 768 detector stations can be linked to a central control unit. The system was designed to trigger an alarm when airborne radon progeny exceed a specified concentration [Sheeran and Franklin 1984]. Although continuous monitoring methods can provide a rapid estimate of exposure concentrations, placement of the instrumentation in active work areas is difficult and may not always be representative of the exposure in the miner's breathing z o n e .\n# c . Personal Dosimeters\nPersonal dosimeters for radon progeny are intended to automatically record a miner's cumulative exposure regardless of fluctuations in radon progeny concentrations. Thus these devices eliminate the need to document work area location and occupancy time. Although several personal dosimeters have been tested in U.S. uranium mines, none are in routine use in this country because of problems in calibration and lack of precision [Schiager et al. 1981].\n# . Pass i ve Dos i meters\nPassive dosimeters rely on the natural migration of attached and unattached radon progeny to the detection area of the device without the use of an air pump. Thin plastic foils sensitive to alpha particles are used as detectors. Although passive dosimeters using track etch foi Is have been studied in under ground mines [Domanski et a l . 1982], such devices are still in the developmental stage [Schiager et al. 1981]. \n# Act i ve Dos i meters\nActive dosimeters use a mechanical pump to draw a known volume of air through a filter. The alpha radiation emitted by the radon progeny collected on the filter is counted and recorded automatically. The following dosimeter detectors have been tested for use under mining conditions: thermoluminescent detectors [McCurdy et al. 1969;White 1971;Phillips et al. 1979;Southwest Research Institute 1980;Grealy et al. 1982], electronic detectors [Durkin 1977], and track etch detectors [Auxier et al. 1971;Zettwoog 1981;Bernhard et a l . 1984]. Active track etch dosimeters are used for radiation monitoring in all underground mines in France [Schiager et a l . 1981;Bernhard et a l . 1984].\n# d. Factors to Consider When S e le c tin g Measurement Methods\nConcentrations of radon progeny have been reported to vary among the different uranium mines and work areas within each mine [Schiager et a l . 1981]. These variations have been attributed to the type of mining process, the grade of ore mined, and the effectiveness of the ventila tion to control exposures. Historically, radon progeny exposures in work areas were measured by grab sampling techniques that used the Kusnetz count method or by the instant working-level monitor. More recently, other methods such as continuous monitors and personal dosimeters have also been used in mines. Personal dosimeter methods are clearly more desirable, but they have not been rigorously tested in U.S. mines, and they have been reported to be unreliable for determining exposures over an 8-to 10-hr work shift [Schiager et al. 1981]. Continuous monitoring methods can rapidly detect changes in radon progeny concentrations and can be equipped with an alarm system that will be activated at preset concentrations. These monitors are often stationed at fixed locations within travelways, haulageways, shops, etc. because of the difficulty of moving and restationing them within active mine areas. Although these monitors do not usually provide adequate data for determining worker exposures, they can signal the occurrence of problems in the ventilation system and identify exposure sources.\nNIOSH believes that the use of instant working-level monitors or the Kusnetz count method will provide reliable estimates of exposure to radon progeny. Other methods at least equivalent in accuracy, precision, and sensitivity can be used (see Table II -6). Any method chosen must be capable of meeting the sampling strategy requirements described in Appendix IV.\n# G. R e s p ira to r S e le c tio n and C re d it fo r R e s p ira to r Use\n\n# . R e s p ira to r S e le c tio n\nHistorically, NIOSH has recommended the use of the most protective respirators* when workers are exposed to potential occupational carcinogens [NIOSH 1987]. Although cumulative exposure to radon progeny may result in cancer, the use of the most protective respirators may not always be technically feasible or safe in routine underground mining operations. Supplied-air respirators (SARs) that are NIOSH/MSHAcertified provide breathing air from compressors or a cascade system of air-supply tanks and are approved only for use with air lines less than 300 ft long. However, the use of SARs may not be practical in under ground mining operations. The reasons are that it is difficult to provide sufficient quantities of breathing air through air lines over long distances and that the air lines are susceptible to crimping and severing from the movement of mining vehicles and haulage cars on tracks. Furthermore, many underground work areas and passageways in mines are too small and cramped with equipment to accommodate air compressors or large air-supply tanks.\nIn addition to being cumbersome in underground mines because of their size, self-contained breathing apparatuses (SCBAs) weigh as much as 35 lb, and SARs weigh approximately 6 lb. Thus when SCBAs or SARs are worn for extended periods, their additional weight can also cause increased physiological burden in the form of heat stress [White andRonk 1984a, 1984b;White and Hodous 1987;White et a l . 1987].\nFinally, NIOSH believes that the routine use of SCBAs and SARs may result in increased injuries in underground mining operations. NIOSH is not aware of any studies specifically dealing with injuries or other safety hazards associated with the use of SARs and SCBAs in mines. However, several studies have shown that obstacles introduced into the workplace result in a significantly increased risk of injury from tripping, slipping, or falling [National Safety Council 1981;Szymusiak andRyan 1982a, 1982b]. Because mining is currently one of the most dangerous industries in the United States with regard to occupational deaths and injuries (MMWR 1987, BLS 1987, NIOSH believes that this problem would be exacerbated by the routine use of SCBAs and SARs.\nNIOSH believes that there is sufficient safety and health evidence to recommend against the routine use of SARs and SCBAs for reducing exposure to radon progeny during underground mining operations. Table 1-1 lists the respirators that NIOSH recommends for use against exposure to radon progeny. For average work shift concentrations of radon progeny that exceed 1/12 WL, the recommended respirators include air-purifying respirators with high-efficiency particulate air (HEPA) filters. The HEPA filter media are recommended by NIOSH for use with the air-purifying classes of respirators. These filters are the most *E i ther (1) any self-contained breathing apparatus (SCBA) equipped with a full facepiece and operated in a pressure-demand or other positive-pressure mode, or (2) any supplied-air respirator (SAR) equipped with a full face piece and operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary SCBA operated in a pressure-demand or other positive-pressure mode.\nefficient type of particulate filter available, and they are less susceptible than others to performance degradation resulting from humid storage and use conditions [Stevens and Moyer 1987].\n# . C re d it fo r R e s p ira to r Use\nA miner's exposure to radon progeny may be less than the average work shift concentration in an area, depending on the class of respirator worn and the percentage of time the respirator is worn properly. This reduced exposure for miners who wear respirators can be calculated by dividing the average work shift concentration of radon progeny by the credit factor (CF) for that class of respirator (see Table 1 -1).\nThe credit factors in Table 1-1 were determined by the following equat ion:\nP* = 1/CF = Pw x tw + Pn x tn\nwhere Pf = the total penetration of radon progeny into the respirator facepiece.\nAPF = the assigned protection factor (a complete listing of the APFs for all classes of respirators can be found in the NIOSH Respirator Decision Logic [NIOSH 1987]).\n# CF = the credi t factor\nPw = the penetration of radon progeny while wearing the respirator (i.e., 1/APF) tw = the proportion of time during the work shift that the miner wears the respirator properly Pn = the penetration of radon progeny while not wearing a respirator properly (i.e., 100% or 1.0) tn = the proportion of time during the work shift that the miner does not wear the respirator properly (i.e., 1.0 -tw )\nAn unpublished Canadian study evaluated the proportion of time during the work shift that a group of underground uranium miners properly wore their helmet-type, powered, air-purifying respirators [Linauskas and Kalos 1984;Kalos 1986] If a m i n e operator can verify to MSHA that respirator utilization is greater than 65%, NI0SH recommends a recalculation of the CFs using this higher utilization rate. However, the highest utilization rate that NIOSH recommends is 90%. The CFs for these extremes of utilization rates are listed in Table 1-1.\n# III. BASIS FOR THE RECOMMENDED STANDARD\n\n# A. Assessment o f E ffe c ts 1 . Human Studies a . A ssociation o f Radon Exposure w ith Lung Cancer M o r ta lity\nAppendix I contains the report prepared by NIOSH and submitted to MSHA on May 31, 1985, entitled Evaluation of Epidemiologic Studies Examining the Lung Cancer Mortality of Underground Miners. Several of the epidemiologic studies evaluated in that report demonstrate an association between exposure to radon progeny and lung cancer mor tality in underground uranium miners [Lundin et al. 1971;Sevc et a l . 1976;Kunz et a l . 1978;Waxweiler et al. 1981;Placek et al. 1983;Samet et a l . 1984;Muller et a l . 1985;Tirmarche et a l . 1985]. The relationship between exposure to radon progeny and lung cancer mortality has also been observed in workers in underground metal mines [Wagoner et a l . 1963], iron ore mines [Boyd et al. 1970;Jorgensen 1973Jorgensen (updated in 1984; Damber and Larsson 1982;Ed ling and Axe I son 1983;Radford and Renard 1984], tin mines [Fox et al. 1981;Jingyuan et a l . 1981;Wang et a l . 1984], fluorspar mines [Morrison et al. 1985], gold mines [Muller et a l . 1985], and zinc/lead mines [Axe I son and Sundell 1978].\nIn addition, some of these studies demonstrate a direct exposure-response relationship between lifetime cumulative exposure to radon progeny and lung cancer mortality [Lundin et al. 1971;Sevc et a l . 1976;Kunz et al. 1978;Morrison et al. 1985;Muller et al. 1985].\nStatistically significant standardized mortality ratios (SMRs)* above 400% were observed in three studies in which workers accumulated mean lifetime exposures above 100 WLM [Sevc et al. 1976;Kunz et a l . 1978;Waxweiler et a l . 1981;Morrison et al. 1985]. Statistically significant SMRs between 140% and 390% were observed in two other studies in which workers accumulated mean lifetime exposures below 100 WLM [Radford and Renard 1984;Muller et a l . 1985] and in preliminary findings of a third study in which workers accumulated estimated mean lifetime exposures below 100 WLM [Tirmarche et a l . 1985].\n# b. S y n e rg is tic E ffe c ts o f Other Substances\nAlthough the literature consistently demonstrates an association between lung cancer incidence and exposure to radon progeny, it is possible that some of the miners studied were exposed to other substances as well. These substances may have acted synergistically *The standardized mortality ratio (SMR) is the ratio of the mortality rates of two groups being compared. This ratio is expressed as a percentage and is usually adjusted for age or time differences between the two groups.\nwith radon progeny to potentiate the effects of the radon exposure.\n[ Doull et al. 1980]. Substances with synergistic potential include arsenic [NIOSH 1975a;Wang et a l . 1984;Sevc et a l . 1984], hexavalent chromium, nickel, cobalt [NIOSH 1975b;NIOSH 1977;Sevc et a l . 1984]; serpentine [Radford and Renard 1984]; iron ore dust [Boyd et al. 1970;Jorgensen 1973Jorgensen , 1984Damber and Larsson 1982;Ed ling and Axe I son 1983;Pham et al. 1983;Radford and Renard 1984], and diesel exhaust [Wagoner et a l . 1963;Boyd et a l . 1970;Waxwei ler et al. 1981;Fox et a l . 1981;Damber and Larsson 1982;Ediing and Axelson 1983;Jorgensen 1984;Sevc et al. 1984;Muller et al. 1985;Morrison et al. 1985;Tirmarche et al. 1985].\nRisk analyses were performed on data from epidemiologic studies of U.S. uranium miners [Whittemore and McMillan 1983; Appendix II] and Swedish iron ore mine workers [Radford and Renard 1984]. These analyses indicate that the risk of mortality from lung cancer among miners who are exposed to radon progeny is greater among those who smoke cigarettes than those who do not smoke.\n# c. R e la tio n o f Lung Cancer Risk to Cumulative Radon Exposure\nSince completion of the NIOSH report (Appendix I), Howe et a l .\n[1986] published a study of surface and underground mine workers who had worked in Canada in the Eldorado Lodge Uranium Mine between 1948 and 1980. That cohort included 8,487 workers. Based on these stratified categories the risk of death from lung cancer increased linearly with increasing exposure. For the exposure categories of 5 to 24, 25 to 49, and 50 to 99 WLM, the relative risk was elevated, but the difference from the expected risk for an unexposed population was not statistically significant. For all exposure categories above 100 WLM, the relative risk was significantly elevated (p<0.05); note, however, that the first 10 years of followup were excluded from this calculation. For the total cohort, the relative risk coefficient was 3.28% per WLM, and the absolute risk coefficient was 20.8 per 10® person-years per WLM (any excess mortality within the 10 years following initial exposure was excluded from this calculation).\nTwo additional epidemiologic studies that were not included in the 1985 NIOSH report (Appendix I) have also been reported. Pham et a l .\n[1983] studied 1,173 iron mine workers in France who were aged 35 to 55 and who had normal chest X-rays at the beginning of the study period in 1975. Thirteen mine workers who had worked underground for a mean of 25.2 years died of lung cancer between 1975 and 1980; only 3.7 deaths were expected from an age-standardized comparison with French males for this same period (SMR = 351; p<0.05). Although exposure records were not available, the authors estimated that some workers may have received lifetime cumulative exposures to radon progeny in the range of 100 to 150 WLM.\nSo 11i et al. [1985] observed 318 niobium mine workers in Norway from 1953 through 1981; 77 of these miners were underground workers. This cohort experienced a total of 12 lung cancer deaths, though only 2.96 deaths were expected on the basis of age-specific rates for Norwegian males (SMR = 405; p<0.001). The underground workers experienced 9 lung cancer deaths whereas only 0.81 were expected on the basis of age-specific rates for Norwegian males (SMR = 1,111; p<0.001). From estimates of total exposure to alpha radiation (based on limited measurements of radon and thoron progeny taken in 1959), the authors determined that the risk of lung cancer increased significantly (p<0.05) with increasing alpha radiation for the exposure categories of 1 to 19, 20 to 79, 80 to 119, and greater than or equal to 120 WLM. The excess absolute risk for those exposed workers was reported to be 50 per 10® person-years per WLM.\nThe epidemiologic studies of lung cancer mortality in mine workers exposed to radon progeny (including those studies discussed in Appendix I) are summarized in Tables III-2 and III-3.\n# An i maI Stud i es\na . E ffe c ts o f Exposure to Radon Progeny Chameaud et al. [1984a] studied the effects of exposure to radon progeny in specific pathogen-free (SPF) Sprague-Dawley rats. A total of 1,800 rats were exposed to radon progeny for 1 to 3 hr per day for 14 to 82 days, yielding an accumulated exposure of 20 to 50 WLM. An additional 600 rats were unexposed. The lung cancer incidence in rats was reported to be directly proportional to their lifetime cumulative exposure to radon progeny. The authors con cluded that the amount of radiation needed to double the natural incidence of lung cancer in these rats was 20 WLM. Reduced life spans were not observed for rats in any of the exposure groups.\nb. R e la tio n o f Lung Cancer Incidence to Radon Progeny Exposure Chameaud et al. [1981;1984a] determined that the lifetime risk coefficient (uncorrected for life span shortening) for the induction of lung cancers in rats was approximately 140 to 850 x 10~® per WLM for exposures ranging from 20 to 4,500 WLM (Table III -4). This is consistent with the lifetime risk coefficient for lung cancer in humans (150 to 450 x 10\"® per WLM) estimated by the International Commission on Radiological Protection (ICRP) [ICRP 1981]. As shown in Table MI-4, lung cancer incidence in rats increased as cumulative exposure to radon progeny increased. In contrast, the lifetime risk of lung cancer per unit of exposure (WLM) decreased with increasing exposure. These findings agree with those of the NI0SH risk assessment (Appendix II), in which the lifetime cumulative risk of lung cancer per unit of exposure decreased as cumulative exposure increased in underground uranium mine workers.\n# c . S y n e rg is tic E ffe c ts o f C ig a r e tte Smoke\nChameaud et a l . [1980,1982] studied the ability of radon progeny to initiate lung cancer in groups of 50 SPF Sprague-Dawley rats that were subsequently exposed to cigarette smoke. The chamber concentrations of alpha radiation were 0, 300, and 3,000 WL; these concentrations yielded cumulative dose levels of 0, 100, 500, and 4,000 WLM, respectively, over a 2-month period for those groups of animals. Treatment groups were exposed to a total of 352 hr of cigarette smoke (9 cigarettes/500 L of air for 10 to 15 min per day, 4 days per week for 1 year. Exposure to radon progeny alone demonstrated a directly proportional dose-effect relationship for induction of cancer (500 and 4,000 WLM). However, when a similar period of radon exposure was followed by exposure to cigarette smoke, a dose-related, twofold to fourfold increase occurred in lung cancer incidence. The authors stated that the groups receiving high and medium doses of radon and cigarettes had cancers that were not only larger but were more invasive and metastatic compared with the groups exposed to radon alone. Conversely, neither the cigarette smoke alone nor the low-dose radon progeny exposure (100 WLM) alone induced lung cancer.\nIn a parallel lifetime study, Chameaud et a l . [1981] related the sequence of exposure to radon progeny and cigarette smoke to the incidence of lung tumors (cancer incidence was not specified) in groups of 50 SPF Sprague-Dawley rats. One group of rats was exposed to radon progeny only (a cumulative exposure of 4,000 WLM); a second group was exposed first to cigarette smoke and then to radon progeny (4,000 WLM); a third group was exposed to radon progeny (4,000 WLM) and then to cigarette smoke; and a fourth group was exposed to cigarette smoke only. Similar incidences of tumors were observed among the rats exposed to radon progeny only (10 tumors) and those exposed first to cigarette smoke and then to radon progeny (8 tumors).\nIn contrast, when the exposure to radon progeny preceded the exposure to cigarette smoke, the effect was potentiated-that is, 32 rats developed tumors. As stated previously, none of the rats exposed to cigarette smoke only developed lung cancer. No statistical analyses were performed on the results of this study.\n# d. S ig n ific a n c e o f Animal Studies\nLife span experiments in animals exposed to radon progeny alone have demonstrated that increasing exposures produce increasing incidences of lung cancer. This finding is similar to those of the epidemio logic studies cited in the preceding section (III, A, 1). Because epidemiologic data are available, these animal data contribute relatively little to the final assessment of risk in humans or to the determination of an REL for exposure to radon progeny. Thus this document discusses only selected animal studies of the carcin ogenic potential of radon progeny. Other studies have examined the sequential or concomitant exposures of rats, dogs, and hamsters to substances other than radon progeny (e.g., uranium ore dust, thorium, and tobacco smoke). Several additional studies (critiqued but not described in this document) confirm the adverse health effects of radon progeny on exposed animals [Chameaud et al. 1974[Chameaud et al. , 1984bFilipy et al. 1977aFilipy et al. , 1977bGaven et al . 1977;PNL 1978;Cross et a l . 1981Cross et a l . , 1982aCross et a l . , 1982bCross et a l . , 1983Cross et a l . , 1984Cross 1984]. These animal studies generally confirm the risk of lung cancer reported among workers exposed to radon progeny.\n# B. Risk Assessment\nNIOSH studied the lung cancer risk of uranium miners by using data from a U.S. Public Health Service (USPHS) study [Lundin et a l . 1971] of white male uranium mine workers from the Colorado Plateau area (Colorado, Arizona, New Mexico, and Utah).\nThat NIOSH risk assessment is described in a report entitled Quantitative Risk Assessment of Lung Cancer in U.S. Uranium Miners, which is reproduced in Appendix II. Appendix I contains a detailed discussion of the USPHS data.\nIn the NIOSH risk assessment, data were analyzed for 3,346 workers who had been followed from 1950 through 1982. By 1982, 1,215 workers had died; 256 of these deaths (21.1%) were due to lung cancer. A generalized version of the Cox proportional hazards model was used to estimate the relative risk of death resulting from lung cancer over a 30-year working lifetime at several cumulative exposure values.\n(The 30-year working lifetime was selected to maintain consistency with the working lifetime commonly described by MSHA.) Relative risk is defined as the ratio of lung cancer mortality in a selected exposed group to lung cancer mortality in a comparison group. The quantitative risk assessment model presented in Appendix II did not include the length of time since the end of the mining exposure, which is a significant predictor of relative risk. This term was subsequently added to the generalized Cox model, and new parameter estimates were computed. The estimates in Tables 111-5 and 111-6 are based on this model. The major difference between the two quantitative risk assessment models is that under the new model, the relative risk estimates increase more rapidly during exposure and decrease more rapidly after exposure.\nThe risk of death resulting from lung cancer increased with increasing lifetime cumulative exposure to radon progeny (Table MI -5); this finding is consistent with Appendix II. This direct relationship has been observed in previous epidemiologic studies [Lundin et a l . 1971;Sevc et al. 1976;Kunz et a 1. 1978;Morrison et a l . 1985;Muller et a 1. 1985]. As shown in Table MI-5, the relative risk of 1.57 at 30 WLM corresponds to an average exposure of 1 WLM per year for a working lifetime of 30 years. *Estimates are based on a log-relative risk model fitted to age at initial exposure, time since cessation of exposure, and the natural logarithms of the following variables: cumulative mining and background exposure to radon progeny; cumulative cigarette smoking and background smoking; and rate of exposure to radon progeny. +The approximate 95% confidence limits were calculated by applying the parameters from the quantitative risk assessment model together with their variances and covariances to the lung cancer mortality rates in the Colorado Plateau using an actuarial approach.\nIn addition to receiving workplace exposures to radon progeny, workers were assumed to have received average environmental exposures of 0.4 WLM/year. This is the value derived in the NIOSH risk assessment that led to the best fit of the model to the data. This assumed value is consistent with estimates of exposure to radon progeny for persons living near ore-bearing lands in the United States [NCRP 1975;Brookins 1986]. The average nonoccupational exposure to radon progeny from natural geologic sources for persons in the United States is approximately 0.2 WLM/year [NCRP 1984b].\nRelative risk modeling is common in the epidemiologic literature (especially in studies with lengthy followup) because the dramatic changes that occur in mortality rates with age and calendar year make absolute risk models extremely complicated. Most relative risk models assume that mortality rates in exposed populations are roughly proportional to the rates in unexposed populations at all ages and calendar periods. Because this assumption often approximates reality over a broad range of ages and calendar periods, the relative risk model can be expressed in a less complex form than absolute risk models (i.e., the relative risk model can be expressed without terms involving age and calendar year).\nExcess lifetime risk estimates for lung cancer mortality have been generated (Table III-6) by applying the relative risk estimates in Table III-5 (see also Appendix II) to the lung cancer and all-causes mortality rates for white males in the Colorado Plateau States. Excess risk is defined as the arithmetic difference between the risk of lung cancer mortality in a selected exposed group and the risk of lung cancer mortality in an unexposed comparison group.\nThe estimated excess lung cancer deaths (i.e., excess lifetime risk) in Table 111-6 were computed by approximating the average of the exposuredetermined relative risk function over 5-year age intervals spanning an entire lifetime. These average relative risks and the corresponding mortality rates for lung cancer and for all causes of death among white males in the Colorado Plateau were used to compute the probability of lung cancer mortality during a lifetime using the National Academy of Sciences actuarial method [NAS 1987].\nIt is important to understand the limitations of these risk estimates when examining the values in Table III-6. These limitations include the foIlowi n g :\n• A relatively small portion of the cohort had the observed lower levels of cumulative occupational exposure, and the ability to generate precise point-risk estimates at the lower range of occupational exposure is not as strong. Only 7% of the workers in the cohort had lifetime cumulative exposures below 30 WLM, and only 7 of the 256 lung cancer deaths occurred among workers with lower cumulative exposures.\n• The reliability of these excess lifetime risk estimates depends on (1) the accuracy of the original relative risk estimates and (2) the appropriateness of using lung cancer rates for the general white male population in the Colorado Plateau as an estimate of the background lung cancer rate (i.e., that which would occur in populations exposed only to background levels of radon progeny). This cohort contained no unexposed mine workers from which to estimate background lung cancer rates. Although certain limitations exist in using this type of rate [Monson 1980], background lung cancer mortality rates from the general U.S. white male population were used to estimate the background rates for the cohort.\n• The background lung cancer rates were not corrected for cigarette smoking. However, the relative risk estimates used to calculate the lifetime risk estimates were adjusted for smoking. This implies that the lifetime risk estimates are only appropriate for a population with a pattern of smoking similar to that of the white male population of the Colorado Plateau.\nIn developing its recommendations, NIOSH has attempted to compare the risk of occupational exposure to radon progeny with the risk of background exposure in homes (i.e., exposure accruing outside the mining environment).\nThe estimated average background exposure to radon progeny is approximately 0. Given this value for background lung cancer risk, another question that must be considered is to what level it would be reasonable to control occupational risk.\nIn its benzene decision, the U.S. Supreme Court gave the following example as the basis for evaluating the occupational risk of chemically induced leukemia: An exposure associated with 1 excess death per million exposed persons might pose an acceptable risk, whereas an exposure associated with 1 excess death per 1,000 exposed persons would pose a significant risk that should be reduced. This example is useful, but it cannot be strictly applied in all cases because it was offered as an illustration and not a fixed rule.\nIn the specific case of lung cancer risk associated with radon progeny exposure, the example cannot be strictly applied because the background risk of lung cancer is much greater than the risk of leukemia at background exposure levels and because cigarette smoking is known to create a confounding effect that greatly increases risk. An excess of 1 lung cancer death per 1,000 would probably not be detectable in a general population if data were subject to considerable uncertainty, since it would necessitate differentiating between 46 and 45 deaths per 1,000.\nAnother important consideration is the technical feasibility of a given exposure limit. As stated earlier, NIOSH has determined that a cumulative exposure limit of 1 WLM per year is achievable (though some argue that it is not feasible on the basis of economics or current technology). NIOSH has found no evidence that any cumulative exposure lower than 1 WLM per year is feasible. As shown in Table III-6, the occupational exposure limit required to reduce expected lifetime risk to 1 excess lung cancer death per 1,000 miners is approximately 0.1 WLM per year. This cumulative exposure would require an occupational exposure concentration that is less than the concentration associated with a cumulative background exposure of 0.4 WLM per year, assuming background expoure is acquired outside the occupational environment. An occupational exposure limit of 0.1 WLM per year would therefore require average mine concentrations lower than the estimated background exposure concentrations.\nIn view of the preceding factors, the level of uncertainty in available data, and the apparent unfeasibility of limiting cumulative exposures to less than 1.0 WLM per year, it does not seem reasonable to recommend exposure limits that would yield only 1 excess lung cancer death per 1,000 miners.. NIOSH has determined that an exposure limit of 1 WLM is feasible in some mines and that such an exposure limit would substantially reduce risks from those associated with the current MSHA standard. An REL of 1 WLM per year is therefore recommended to substantially reduce risk and to stimulate the implementation and development of engineering and mining techniques to reduce exposure. The enforcement of this recommendation combined with additional health and developmental research may facilitate future exposure reductions and thereby reduce lung cancer risk.\n# C. Techn i caI Feas i b i I i ty\nIn a report to the U.S. Bureau of Mines, Bloomster et a l . [1984a] analyzed the technical feasibility of reducing the airborne concentrations of radon progeny in underground uranium mines. The study included data from 14 underground uranium mines operating during the study period (September 1981to May 1984. The authors concluded that some mines could operate at an annual exposure standard of 2 WLM by using dilution ventilation alone if it was introduced early in the development of the mine and if no contamination of inlet air was present. An extensive engineering analysis of 2 of the 14 mines indicated that it might be feasible to meet an operating standard of 1 WLM by using dilution ventilation in combination with other control methods such as bulkheading, air filtration, and use of sealants. The authors expressed doubt about the technical feasibility of operating these uranium mines at a standard of 0.5 WLM. Appendix III provides descriptions of engineering control methods that may be useful in underground mines.\n# D. Recommendati ons\nSeveral schemes exist for identifying and classifying a substance as a carcinogen. For example, the National Toxicology Program (NTP) [NTP 1984], the International Agency for Research on Cancer (IARC) [WHO 1979], and the Occupational Safety and Health Administration (OSHA) [29 CFR 1990, Identification, Classification, and Regulation of Potential Occupational Carcinogens (also known as \"The OSHA Cancer Policy\")] have all considered this problem. NIOSH considers the OSHA classification the most appropriate for use in identifying potential occupational carcinogens and supports the following definition:\nA \"potential occupational carcinogen\" is any substance, or combination or mixture of substances, which causes an increased incidence of benign and/or malignant neoplasms, or a substantial decrease in the latency period between exposure and onset of neoplasms in humans or in one or more experimental mammalian species as the result of any oral, respiratory, or dermal exposure, or any other exposure which results in the induction of tumors at a site other than the site of administration [29 CFR 1990.103].\nThis definition also includes any substance that mammals may potentially metabolize into one or more occupational carcinogens.\nThe epidemiologic data examined by NIOSH demonstrates that occupational exposure to radon progeny in underground mines has the potential for causing lung cancer in miners (see Appendix I) [Pham et al. 1983;So 11i et al. 1985;Howe et a l . 1986]. These human data are supported by a number of studies in which various animal species exposed to radon progeny also developed lung cancer [Chameaud et a l . 1974[Chameaud et a l . , 1980[Chameaud et a l . , 1981[Chameaud et a l . , 1982[Chameaud et a l . , 1984a[Chameaud et a l . , 1984bFilipy et al. 1977aFilipy et al. , 1977bGaven et al. 1977;PNL 1978;Cross et al. 1981Cross et al. , 1982aCross et al. , 1982bCross et al. , 1983Cross et al. , 1984Cross 1984]. Furthermore, the NIOSH risk assessment presented in Appendix II, which was based on the human studies, clearly demonstrates that a relationship exists between cumulative radon progeny exposure and the risk of developing lung cancer. The risk assessment shows that as cumulative exposure decreases, the risk of developing cancer decreases.\nIn arriving at an REL, NIOSH attempts to identify that exposure at which no worker will suffer material impairment of health or functional capacity.\nIn the case of radon progeny, this task is difficult because the NIOSH risk assessment shows that even with an exposure of 0.5 WLM per year (15 WLM for a 30-year cumulative exposure) or below, the risk of developing lung cancer increases (see Table III-4 and Appendix II).\nThese results indicate that NIOSH should recommend an annual cumulative exposure limit well below 0.5 WLM, but NIOSH must also consider the technical feasibility of the REL.\nIn previous NIOSH recommendations for the control of carcinogens, technical feasibility has often been interpreted as the ability to quantitate exposure; however, those recommendations were intended for use by nonmining industries where product substitution and engineering and process controls are generally more feasible.\nData from 1984 indicate that 94.4% of the workers in U.S. underground uranium mines accumulated annual radon progeny exposures of less than 2 WLM [AIF 1986].\nInformation obtained from the Bureau of Mines [Bloomster et al. 1984a] indicates that it is now technically feasible to achieve an annual radon progeny concentration of 1.0 WLM. NIOSH therefore recommends that cumulative exposure to radon progeny be limited to 1.0 WLM per year. This recommendation is intended to protect the health of America's underground miners, but it is tempered by the fact that currently it is not technically feasible to achieve annual exposures lower than 1.0 WLM using work practices and engineering controls.\nTo meet the NIOSH recommendation for an annual cumulative exposure of 1 WLM and to assure that mining is a viable year-long occupation, NIOSH believes that the daily average work shift concentration of radon progeny should not exceed 1/12 WL in any work area. Although adherence to the NIOSH REL will significantly reduce the risk of lung cancer in underground mine workers, it will not eliminate it.\nNo effective medical procedure currently exists to treat lung cancer caused by exposure to radon progeny. Furthermore, it has been demonstrated that exposure to both radon progeny and tobacco smoke result in a combined lung cancer risk that is greater than the risk posed by radon progeny or smoke alone. Thus it should be noted that the interaction between radon progeny and smoking is at a minimum additive, and more likely multiplicative. Cigarette smoking should therefore be emphasized as an even greater detriment to mine workers exposed to radon progeny than it is to the general public. The implementation of smoking cessation programs should reduce the incidence of lung cancer in underground mine workers.\nBecause radon progeny are ubiquitous, exposure cannot be totally eliminated. For U.S. residents, the average annual nonoccupational exposure to radon progeny from natural geologic sources is approximately 0.2 WLM, and annual occupational exposures may be considerably higher. The REL of 1 WLM per year is not designed for the population at large, and no extrapolation is warranted beyond occupational exposures in underground metal or nonmetal mines. The REL is designed only for the radon progeny exposures of underground metal and nonmetal mine workers as applicable \n# IV. RESEARCH NEEDS\nThe following research is needed to further reduce the risk of lung cancer development from occupational exposure to radon progeny.\n# A. Epidem iologic S tudies\nNeeds for epidemiological studies have been identified as follows:\n• A need exists for a followup study of the U.S. miner cohort from the original Public Health Service study to explore the risk of lung cancer among nonsmoking miners exposed to low concentrations of radon progeny. NIOSH is currently resurveying this cohort to update exposure histories and gather additional information on smoking behavior, dietary practices, and tumor cell types.\n• A study is needed to determine whether radon gas itself or other contaminants that might be found in uranium mines are associated with increased morbidity and mortality.\n• An epidemiologic study of injuries is needed in the mining industry to identify safety-related problems, since this industry has one of the highest injury rates in the United States. Particular emphasis should be given to whether or not respirator use is associated with an increased injury and health risk. This investigation should examine slips, trips, falls, and heart attacks.\n# B. Engineering C o ntrols and Work P ra c tic e s\nResearch should be conducted to develop more effective control technology methods for reducing exposure to radon progeny to less than 1 WLM. A control technology assessment of the uranium mining industry will assist in this effort by examining existing state-of-the-art technologies and work practices and by recommending new methods for controlling exposure to radon progeny.\n# C. R e sp ira to ry P ro te c tio n\nThe following two types of research are recommended for respiratory protect ion:\n• Research should be conducted to determine the extent of gamma radiation emitted from particles trapped on high-efficiency particulate air (HEPA) filters used on air-purifying respirators.\n• A study should also be conducted to evaluate the physiological stress placed on miners who must wear respiratory protection. This study should be conducted both in the laboratory and in the mines.\n# D. Environmental (W orkplace) M onitoring\nStudies needed for environmental (workplace) monitoring are as follows:\n• Research should be conducted to characterize and evaluate the importance of particle size, unattached fraction, and condensation nuclei concentrations in estimating the bronchial dose of radon progeny. The dose of alpha radiation affecting the bronchial airways depends on the size of the particles to which it is attached. Recent studies have shown that as particle size decreases, the concentration of radon progeny increases.\n• Continued research is also needed to determine which factors affect the equilibrium between radon progeny and radon gas in mines. These studies should examine how such information may be used to predict the extent of exposure to radon progeny. Additional development and field testing of personal sampling devices is also needed for more complete determination of a miner's daily exposure.\n# PUBLIC HEALTH PERSPECTIVE\n\n# V. PUBLIC HEALTH PERSPECTIVE\nIn developing this document, NIOSH has been challenged to carefully consider all of the Institute's legislative, scientific, and moral responsibilities. NIOSH has been required to review diverse scientific data that are subject to uncertainty and then, in keeping with its mandates, to recommend criteria that will attain the highest level of health protection and will at the same time account for other factors such as technical feasibility and insights gained through research and development.\nTo develop a public health perspective on the risk posed by occupational exposure to radon progeny, NIOSH must weigh a number of factors, as follows.\n1. Human and animal data both clearly establish that exposure to radon progeny increases the risk of lung cancer. The human data consist of a number of positive epidemiologic studies, several of which demonstrate an exposure-related health risk that is not accounted for by smoking behavior. The animal studies demonstrate that lung cancer risk increases with exposure in the absence of smoking.\nIt is important to note that smoking by miners appears to greatly exacerbate the risk of lung cancer posed by exposure to radon progeny alone.\n2. The NIOSH risk assessment, based on a USPHS study of uranium miners [Lundin et al. 1971], demonstrated a significant exposure-response relationship. This analysis indicates that exposure to radon progeny at the current MSHA occupational exposure limit of 4 WLM over a working lifetime will result in 42 excess lung cancers per thousand miners. A miner's working lifetime has been defined as 30 years (MSHA uses 30 years as a miner's working lifetime). Risk declines substantially if a lower annual cumulative exposure is received over the working lifetime. Any risk assessment is subject to uncertainty because risk assessment models may not reflect risk in a completely reliable way and because the data on which they are based are subject to uncertainties and Iimitat ions.\nThe Cox proportional hazards model, which was chosen for the NIOSH risk assessment, is considered one of the strongest analytical approaches for longitudinal epidemiologic data. But it is not clear how accurately the data can be extrapolated to predict risk below the levels of observed exposure. Current biological theory hypothesizes that carcinogenic processes involve an initiation stage that is followed by other stages before an actual malignancy is established. The essential characteristics of all of these stages remain to be delineated. The Cox proportional hazards model is very powerful in describing human risks based on epidemiologic data.\nIts strength is partly due to the model's ability to accommodate long follow-up periods during which changes occur in some of the risk factors, e.g., cumulative exposure. Nevertheless, it is not clear how accurately the Cox model or any other risk assessment model predicts the risk from a multistage cancer process when exposures are below levels that have been studied.\nThe USPHS study [Lundin et al . 1971] on which the NIOSH risk assessment was based is an extensive study, but the risk assessment is subject to uncertainties and limitations because of the nature of the data. For example, more uncertainty would be inherent in the risk estimates at the lower range of exposure because a relatively small proportion of this study population received the lowest cumulative exposures. Approximately 7% of the USPHS uranium miners (which included 7 lung cancers) had received cumulative occupational exposure levels of 30 WLM or less. At lower cumulative exposure levels, even smaller proportions of the cohort and fewer lung cancers were represented. Thus point estimates at these lower cumulative exposure levels would be more subject to the influence of chance occurrences.\nIn addition, exposure levels are subject to measurement error. The uncertainty of exposures have been estimated to range from a relative standard deviation of 38% [Schaiger et a l . 1981] to as high as 97% (see Appendix II).\n3. Radon progeny and its associated risk are present in our ambient environment as well as in the mining environment and cannot be totally eliminated. Radon progeny are ubiquitous in that they emanate from all ore-bearing deposits containing elements that decay to produce radon gas. The national average exposure to radon progeny has been estimated to be 0.2 WLM [NCRP 1975]. Areas containing large amounts of ore-bearing deposits (e.g., the Colorado Plateau) are likely to have higher-than-average background levels of radon progeny [NCRP 1975]. The NIOSH risk assessment uses a fitted estimate of 0.4 WLM as the background exposure (the average annual cumulative exposure incurred in nonoccupational environments) in the Colorado Plateau. Although no adequate measurement data are available to characterize the level and variability of exposure in the homes of the general population and of miners, it is clear that everyone is exposed and that the degree of exposure depends on each individual's home and work environment. The limits of concentration detection and the accuracy of the measurement techniques become a potential problem when quantifying the very low radon progeny exposure and concentration levels that may be found in the ambient environment (these levels are generally much lower than those found in underground mining environments). Extrapolation of risk to such low levels would become even more problematic than at higher levels because of the reduced accuracy of measuring such concentration levels. The elimination of radon progeny from the ambient and mining environments is not possible.\nThe primary engineering method for controlling radon progeny exposure is dilution ventilation. However, if radon progeny are ubiquitous in our ambient environment, no source of air is free of contamination. The only protective equipment that would eliminate exposure to radon progeny is the self-contained breathing apparatus (SCBA). SCBAs are unaccept able for wear in the ambient environment and represent a significant safety hazard if worn extensively in the mining environment.\n# 4.\nIt is valuable to compare the lung cancer risks associated with the miner's occupational and background exposures. No assessment has yet been made of the lung cancer risk associated with background exposures, either for the general U.S. population or for the population living in the Colorado Plateau. Until studies in homes are completed, it will be impossible to directly contrast the risks of occupational and background exposures.\nNonetheless, it is important to consider occupational risk in the context of the lung cancer risk experienced by the general population. On the basis of State vital statistics records, NIOSH estimates that the lifetime risk of lung cancer in the Colorado Plateau, uncorrected for smoking, is approximately 45 lung cancers per 1,000 white males. Unfortunately, accurate lung cancer rates are not available for nonsmokers in the Colorado Plateau.\nGiven this value for the lung cancer risk of background exposure, another question that must be considered is to what level it would be reasonable to control occupational risk.\nIn its benzene decision, the U.S. Supreme Court gave the following example for the basis of evaluating occupational risk of chemically induced leukemia. The example indicated that an exposure associated with 1 excess death per 1 million exposed persons might pose an acceptable risk, whereas an exposure associated with 1 excess death per 1,000 exposed persons would pose a significant risk that should be reduced. This example is useful but it cannot be strictly applied in all cases, since it was offered as an illustration and not a fixed rule.\nIn the specific case of lung cancer risk associated with radon progeny exposure, the example cannot be strictly applied because the risk of lung cancer is much greater than the risk of leukemia at background exposure levels and because cigarette smoking is known to create a confounding effect that greatly increases risk. An excess of 1 lung cancer death per 1,000 would probably not be detectable in a general population if the data were subject to considerable uncertainty, since it would necessitate differentiating between 46 and 45 deaths per 1,000.\n5. The technical feasibility of achieving lower exposure levels is subject to the limitations of available technology. A report commissioned by the Bureau of Mines [Bloomster et al. 1984a, 1984b has been the primary source for NIOSH's assessment of the technical feasibility of lower exposure levels. On the basis of an extensive engineering analysis of two uranium mines, these investigators indicated that it might be feasible to meet an operating standard of 1 WLM using the best available engineering controls. They expressed doubt about the technical feasibility of operating these uranium mines at a standard of 0.5 WLM. This analysis has been used by NIOSH to define exposure limits that are technically achievable with the best available technology.\nThese are some of the issues that have been considered by NIOSH in developing a recommended standard to prevent lung cancer associated with exposure to radon progeny. This process of weighing risk from a public health perspective parallels the philosophy of risk presented in the 1985 document entitled Risk Assessment and Risk Management of Toxic Substances: A Report to the Secretary [CCERP 1985].\nIn the process of developing this public health perspective, NIOSH has performed the following actions:\n• NIOSH has identified a public health hazard posed by an occupational exposure. Exposure to radon progeny that occurs in underground mines and the ambient environment has been shown to cause a significant increase in lung cancer among uranium and other underground miners.\n• NIOSH has developed recommendations in a manner that is prudent and in concert with the public need. This process was accomplished by complying with the Institute's legislative mandates to attain the highest level of health protection and at the same time consider other factors such as technical feasibility.\n• NIOSH has sought appropriate public participation by eliciting external reviews. Reviews were requested from more than 60 individuals or groups, including industry, labor, academia, and government representatives. NIOSH has received and considered the comments from more than 30 of these reviewers.\n• NIOSH has communicated risk understandably to both experts and lay persons. NIOSH has expressed risk as relative risk, which most epidemiologists and biostatisticians believe to be the most appropriate mode of expressing human cancer risk. NIOSH has also expressed risk as lifetime excess risk per 1,000 miners, an expression that can easily be interpreted by both experts and lay persons.\n• NIOSH has used all currently available information and the most extensive pertinent set of human data to estimate risk. The USPHS study of uranium miners [Lundin et a l . 1971] is the most extensive set of data available in the United States on the radon progeny exposure of underground miners. Unlike other analyses, this study used the entire qualifying cohort in the risk assessment, regardless of exposure level. These investigators felt this was the most valid way to analyze epidemiologic data using the selected model.\n• NIOSH has considered alternative recommendations for risk control that are based on viable exposure limits and engineering controls. The considered options ranged from proposing no REL to prohibiting all occupational exposure to radon progeny. The REL presented in this document was chosen after a thorough weighing of the available data and Institute mandates.\n• NIOSH has advanced the process of risk assessment and policy development by conducting the most thorough risk assessment possible on underground miners exposed to radon progeny. The NIOSH risk assessment permitted estimation of lung cancer risk at the lower range of the observed exposure levels. The assessment also suggested meaningful research areas such as lung cancer risks at low radon exposure levels, synergistic effects of other exposures such as cigarette smoke, effects of radon progeny on late versus early stage cancer, and the need for improved engineering control of exposure.\nAn extensive and complicated process has been used to develop the recommendations in this criteria document. After weighing the conclusions drawn from available data, the mandates of the Institute, and the public health issues, NIOSH recommends an annual cumulative exposure limit of no more than 1 WLM per year. However, as stated earlier, even this exposure poses a significant risk of lung cancer over a working lifetime. Thus NIOSH further recommends that mine operators regard this REL as an upper limit and that they make every effort to limit radon progeny to the lowest possible concentrations.\nIn addition, NIOSH wishes to emphasize the fact that this standard contains many important provisions in addition to the annual exposure limit. These include recommendations for limited work shift concentrations of radon progeny, sampling and analytical methods, recordkeeping, medical surveillance, posting of hazardous information, respiratory protection, worker education and notification, and sanitation. All of these recommendations help minimize risk.\nNIOSH recognizes its commitment to protect the health of the Nation's miners and will continue to reexamine this complex occupational health issue. Research on new and more effective methods for reducing occupational exposures will improve the available control technologies. Additional data on exposure levels and associated health risks will permit firmer estimates of risk and hence better recommendations. NIOSH will revise its recommended standard as important new data become available.\n# REFERENCES\nAIF [1984]. Exposure of U.S. underground uranium miners to radon daughters in 1982 as reported by 29 underground uranium mine operations, from a survey made April 24, 1984. Unpublished report submitted to Mine Safety and Health Administration by Atomic Industrial Forum.\nAIF [1986]. Exposure of U.S. underground uranium miners to radon daughters in 1984 as reported by 20 underground uranium mine operations, from a survey made December 11, 1986 Borak TB, Franco E, Schiager KJ, Johnson JA, Holub HF [1981]. Evaluation of recent developments in radon progeny measurements.\nIn: Gomez M, ed. International Conference: Radiation Hazards in Mining. New York, NY: Society of Mining Engineers of American Institute of Mining, Metallurgical, and Petroleum Engineers, Inc., pp. 419-425. Boyd JT, Doll R, Faulds JS, Leiper J [1970]. Cancer of the lung in iron ore (haematite) miners. Br J Ind Med 27:97-105. Breslin A J , George AC, Weinstein MS [1969].\nInvestigation of the radiological characteristics of uranium mine atmospheres. New York, NY: Atomic Energy Commission, New York Operations Office, Health and Safety Laboratory. HASL-220, December 1969. Brookins DG [1986.\nIndoor and soil Rn measurements in the Albuquerque, New Mexico, area. Health Phys 51:529-533 In fifteen epidemiologic studies, researchers reported excess lung cancer deaths among underground miners who worked in mines where radon progeny were present.\nIn addition, several studies show a dose-response relationship between radon progeny exposure and lung cancer mortality.\nIn two recent studies, investigators report excess lung cancer deaths due to mean cumulative radon progeny exposures below 100 Working Level Months (WLM) (specifically, at 40-90 WLM and 80 WLM).\nThe health risks from other exposures (i.e., arsenic, diesel exhaust, smoking, chromium, nickel, and radiation) in the mining environment can affect lung cancer risks due to radon progeny exposure. Unfortunately, the literature contains limited information about other exposures found in mines. The available information, concerning whether cigarette smoke and radon progeny exposures act together in an additive or multiplicative fashion is inconclusive; nevertheless, a combined exposure to radon progeny and cigarette smoke results in a higher risk than exposure to either one alone.\nX-ray surveillance and sputum cytology appear to be ineffective in the prevention of radon progeny-induced lung cancers in individual miners; therefore, these techniques are not recommended. Also, at this point, there is insufficient evidence to conclude that there is an association between one specific lung cancer cell type and radon progeny exposure.\nAccording to annual radon progeny exposure records from the Atomic Industrial Forum (AIF) and MSHA, it is technically feasible for the United States mining industry to meet a standard lower than the current annual exposure limit of 4 WLM. Recent engineering research suggests that it is technically feasible for mines to meet a standard as low as 1 WLM. Based upon qualitative analysis of these studies and public health policy, NIOSH recommends that the annual radon progeny permissible exposure limit (PEL) of 4 WLM be lowered. NIOSH wishes to withhold a recommendation for a specific PEL, until completion of a NIOSH quantitative risk assessment, which is now in progress.\n# II. INTRODUCTION\nThe National Institute for Occupational Safety and Health (NIOSH) submits this report in response to the Mine Safety and Health Administration's (MSHA) Advanced Notice of Proposed Rulemaking (ANPR) concerning radiation standards for metal and nonmetal mines. This report evaluates fifteen epidemiologic studies that examine the lung cancer mortality of underground miners exposed to radon progeny. The fifteen studies are divided into two groups: five primary studies and ten secondary studies. Overall, the ten secondary studies provide additional information about the association between lung cancer mortality and radon progeny exposure, yet have more limitations (in study design, study population size, radon exposure records, thoroughness of follow-up, etc.) than the five primary studies. Recommendations for the medical surveillance of underground miners exposed to radon progeny are included. The United States mining industry's ability to meet a radon progeny exposure standard lower than the present four Working Level Months (WLM), based solely on technical feasibility, is also discussed.\nA working level (WL) is a standard measure of the alpha radiation energy in air. This energy can result from the radioactive decay of radon (Rn-222) and thoron (Rn-220) gases. A WL is defined as any combination of short-lived radon decay products (polonium-218, lead-214, bismuth-214, polonium-214) per liter of air that will result in the emission of 1.3 X 10^ million electron volts (MeV) of alpha energy [1].\nNIOSH defines a WLM as an exposure to 1 WL for 170 hours.\nFor the information of the reader, two appendices and a glossary are included. Appendix A contains data from the Atomic Industrial Forum (AIF) an organization representing the interests of the United States uranium mining industry, and MSHA on the numbers and radon progeny exposures of underground miners in the United States. Appendix B lists methods currently in use for controlling radon progeny exposures underground.\nFinally, there is a glossary containing epidemiologic and health physics terms.\n# III. EVALUATI ON OF EPI DEM IOLOGIC EVIDENCE\n\n# A. In tro d u ct ion\nThis report examines five primary and ten secondary epidemiologic studies of underground miners. It describes the important points, strengths, and limitations of each study. The five primary epidemiologic studies examined lung cancer mortality among uranium miners in the United States, Czechoslovakia, and Ontario; iron miners in Malmberget, Sweden; and fluorspar miners in Newfoundland.\nThe ten secondary epidemiologic studies examined mortality among iron ore miners in Grangesberg, Gallivare, and Kiruna, Sweden; zinc-lead miners in Sweden; metal and Navajo uranium miners in the United States; tin and iron ore miners in Great Britain; uranium miners in France; and tin miners in Yunnan, China.\nFinally, two recent studies analyze the interaction between radon progeny exposure and smoking. This report focuses on the lung cancer experience of these fifteen underground mining cohorts.\nIn general, the study cohorts did not show excess mortality due to cancers other than lung, except for four studies that reported excess stomach cancers and one report of excess skin cancer among underground miners.\nExcess stomach cancers were reported among underground tin miners in Cornwall, England (standardized mortality ratio (SMR) = 200, p value unspecified by the authors, however estimated at p<0.05, from the observed deaths and the Poisson frequency distribution) [2]; gold miners in Ontario (SMR=148, p<0.001) [3]; metal miners in the United States (SMR=149, p<0.01) [4]; and iron ore miners in Sweden (SMR=189, p<0.01) [5]. Sevcova et al. (1978) [6] reported excess skin cancers among underground uranium miners in Czechoslovakia (an observed skin cancer incidence of 28.6 versus an expected of 6.3 per 10,000 workers; p<0.05), that they attributed to external alpha radiation from radon progeny. Arsenic is present in the Czechoslovakian uranium mines (arsenic levels unidentified) [7] and the association between arsenic and skin cancer is well documented [8,9]. The excess mortality from stomach and skin cancers among these cohorts needs further study. In all five primary epidemiologic studies, the exposure records for the individual miners lack precision.\nFrequently, an individual miner's exposure was calculated from an annual average radon progeny exposure estimate for a particular mine or mine area, thus, an individual miner's true exposure could vary greatly from the estimated exposure. Of the five primary epidemiologic studies, the Czechoslovakian study has the best records for radon progeny exposure [10]. The Swedish study has limited exposure records for their cohort (8 years of measurements for 44 years of follow-up), and the miners' mean exposures were about five WLM per year [5]. The lower radon progeny concentrations found in Swedish mines indicate that the potential error due to excursions in concentration was less than in mines in the United States, Newfoundland, and Ontario, where higher concentrations were measured (Table III-2). Overall, the radon progeny exposure records from the United States, Ontario, and Newfoundland have similar limitations (detailed in sections B, D, and F). WL measurements made in uranium mines in the United States and fluorspar mines in Newfoundland fluctuated greatly, reaching unusually high radon progeny concentrations: in the fluorspar mines, a maximum of 200 WL [11], and in the uranium mines, 3 out of 1,700 mines averaged over 200 WL [12]. NI0SH is currently investigating the variability and quality of the exposure records kept for uranium mines in the United States.\nExposure data quality, although important, does not solely determine a study's strength; one should also evaluate the epidemiologic and statistical methods used. This review reports both the attributable and relative risk estimates for lung cancer (see Glossary for definitions) when they are provided by the authors [3,5,13,14].\n# B. Uranium Miners in the U nited S tates\n\n# . Descr i p t i on\nThe United States Public Health Services (USPHS) conducted an epidemiologic study examining mortality among underground uranium miners from the Colorado Plateau [12,15] Job turnover in the uranium mines was substantial; the majority of miners worked less than 10 years underground (not accounting for gaps in employment) [14]. Nevertheless, approximately 33 percent of the cohort worked 10 or more years and 7 percent worked 20 or more years underground in uranium mines (not accounting for gaps in employment) [15]. The number of months worked underground ranged from 1 to 370 (over 30 years), with a median of 48 months (4 years). Some miners worked underground in uranium or nonuranium mines before they entered the USPHS study, and before radon progeny levels were recorded. Among these miners, 13.7 percent started mining before 1947 [15]. The cohort's early radon progeny exposures probably represented a small proportion of their total lifetime exposures; Lundin et al. (1971) noted that the study group accumulated only 16 percent of their total radon progeny exposure before 1950 [12].\nA bias toward overestimating exposure and a narrow sampling strategy were two major influences effecting the miners' exposure records. First, some of the USPHS exposure data records were biased by including disproportionately more measurements from mine areas with high radon progeny levels. Radon progeny samples taken during 1951-1960 were stated to be representative of the mine areas in which miners received exposures. Also, the U.S. Bureau of Mines (USBOM), the New Mexico State Health Department, and the Arizona mine inspector continued to take representative samples after 1960 [12]. During 1960-68, however, additional radon progeny samples were collected for control purposes by mine inspectors from Colorado, Utah, and Wyoming [12].\nIn this case, inspectors sampled disproportionately more mines and mine sections that had high radon progeny levels. This sampling bias also tended to increase estimates for geographic areas of mining (locality, district, or state) [12]. Thus, some average annual WL exposure records collected during 1960-68 overestimated the uranium miners' exposure.\nSecond, there is little exposure data available for some uranium mines, especially small mines.\nFor the entire period 1951-68, nearly 43,000 measurements were available to characterize about 2,500 uranium mines. More samples were usually taken in the larger mines that employed most of the miners.\nIn many mines, however, only one or two samples were ever taken [12].\nAt the present time, the USPHS exposure data set has 34,120 \"average\" (undefined by Lundin et al. 1971) annual WL exposure records from 1,706 surface and underground uranium mines, made over a 20-year period [12,17]. These records consist of \"guesstimates\", \"estimates\", \"extrapolations\", and actual WL measurements (Table 111-1 (1981) used the formula for attributable risk to determine that about 80 percent of the deaths due to lung cancer in this cohort were attributable to uranium mining [15]. As of 1971, statistically significant excess cancers were found in all radon progeny exposure categories above 120 WLM [12]; the exposure categories were: less than 120, 120-359, 360-839, 840-1799, 1800-3719, and 3720 and over, in WLM. NIOSH continues to monitor the mortality experience of this cohort, particularly those workers exposed at or below 120 WLM. The terms \"guesstimates,\" \"estimates,\" and \"extrapolations\" were defined in this manner by Lundin et al. (1971) [12]; NIOSH recognizes the limitations of these definitions, but uses them for consistency with published reports.\n# Strengths\nThis is a large, well traced, and analyzed study; the study cohort is clearly defined. It contains smoking histories and radon progeny exposure records for the same individuals. Although the radon progeny exposure data were measured by different persons, a standard sampling and counting technique was used and the technical quality of the measurements was good [12].\n# . L im ita tio n s\nThe major limitation in the exposure data quality are that there were few measurements for small mines, (although fewer miners worked in these mines) miners' work histories were self reported, and many exposures were overestimated during 1960-68 [12]. Another limitation is that many miners fell into high radon progeny exposure categories; however 20 pe-rcent of the miners were assigned to the category below 120 WLM [18].\nSeveral reviewers have found that the USPHS study gives lower estimates of risk per WLM for radon progeny exposure than the other four major epidemiologic studies [19,20,21]. This may be due to the overestimation of exposure by Lundin et al. (1971) [12] or other factors. \n# C. Uranium Miners in\n\n# Strengths\nOne positive feature of this study is the large amount of exposure data available.\nRadon gas measurements started in 1948, with a minimum mean of 101+8 measurements per mine [10]. Other strengths include the number of workers exposed to low radon progeny levels, a long period of follow-up (average of 26 years by 1975) [24], and the limited exposure to radon progeny from other underground mining (less than 2 percent of the study group members mined nonuranium ores) [10].\nIn addition, Sevc et al. (1984) investigated the hazards from other exposures, such as silica, arsenic, asbestos, chromium, nickel, and cobalt, and concluded that these were not causing the excess lung cancer risk of the uranium miners [7]. Sevc (1970) reported maximum dust levels between 2.0-10.0 mg/m3 during 1952-56, and stated that the miners' risk of silicosis was relatively low [26]. Chromium, nickel, and cobalt were present only in trace amounts in mine dusts. Although arsenic was present in these mines (concentration unspecified), there was no significant difference in lung cancer mortality between two mining areas with comparable radon progeny exposure levels, but fiftyfold differences in arsenic concentrations [27,28,29,30,31,32].\n# Limitations\nThe limitations of the Czechoslovakian study are that the exposure estimates made before 1960 were based on radon gas, rather than direct radon progeny measurements.\nA second limitation is that the cohort definition and the epidemiologic methods used by the Czechoslovakian researchers make it difficult to compare their findings with those from the other four primary studies.\nThe radon gas and progeny equilibrium ratio is necessary to estimate WL concentrations from radon gas measurements correctly. The authors provided insufficient detail about the equilibrium ratio in the Czechoslovakian uranium mines to allow evaluation of the data quality [10].\nIf Sevc et al. (1976) had equilibrium ratio records or a reliable way to estimate the equilibrium ratio, then using radon gas exposure measurements to estimate WL would not seriously bias their results.\nSevc, Kunz and associates defined their cohort as men who entered employment in the Czechoslovakian uranium mines in the years 1948-1953 (for Group A miners), and worked underground at least 4 years [22].\nIt is unclear from the published reports whether the Czechoslovakian miners accumulated their person-years at risk of dying (PYR) from the time they entered the cohort or from their time of first exposure. The cohorts' average 26 years of follow-up by 1975 [25], implies that the PYR were accumulated from a miner's time of first exposure [33].\nIn most epidemiologic studies, a miner's PYR accumulate after he enters the cohort. The Cze noslovakian method of accumulating PYR makes it difficult to directly compare their lifetable analysis and findings with those from other miner studies. Sevc et al. (1984) also neglected the effect of smoking in their data analysis, although they stated that this would not effect their results, because the percentage of cigarette smokers among miners (70 percent) was comparable to that among the general male population of Czechoslovakia [7]. \n# D. Uranium\n\n# Strengths\nThis study's greatest strength lies in the miners' low mean cumulative exposures (40-90 WLM) to radon progeny, exposures much lower than those reported in the United States, Czechoslovakian, and Newfoundland studies (see Table III-2, at the end of this Chapter). Another good feature of this study is that the researchers carefully traced uranium miners' work experience in other hard rock mines.\nLarge numbers of uranium miners in Ontario (66 percent of the study cohort) had some hard rock mining experience.\n# . L im ita tio n s\nThis study has three disadvantages; first, the cohort is severely truncated, with only about 18 years (median value) of follow-up and a median attained age of 39 years by 1977 [34]. A short follow-up on a young cohort creates problems because lung cancer is rarely manifested before age 40 [20,21]. Second, thoron progeny and gamma radiation levels vary and can reach substantial levels In some Ontario uranium mines [35,36,37]. For example, Cote and Townsend (1981) found that thoron progeny working levels were about half the radon progeny working levels in an Elliot Lake, Ontario uranium mine [37]. The Kusnetz method is frequently used to measure radon progeny in mines and can discriminate between radon and thoron progeny. When used improperly, however, the Kusnetz method can mistakenly count thoron progeny as radon progeny, so that the true radon progeny exposure may be overestimated [37]. From the limited information in the published reports [3,34], it is unclear whether measurement error was introduced by using the Kusnetz method improperly.\nThere are no epidemiologic data available to estimate the health risks due to thoron progeny. The Advisory Committee on Radiological Protection from the Canadian Atomic Energy Control Board (AECB) reviewed research on microdosimetry which indicated that the main contribution to the WLM from thoron progeny comes from the radioactive decay of long-lived Pb-212 (ThB, the half life=10.6 hours).\nIts half-life is long enough for the Pb-212 to translocate from the lungs into other tissue, where it emits much of its alpha energy. Radon progeny have shorter half-lives than Pb-212 and emit most of their alpha energy in the lung. Therefore, the AECB concluded that the risk of lung cancer induction by 1 WLM of thoron progeny is about one third of that for 1 WLM of radon progeny [38].\nFinally, Muller et al. (1985) published limited information about the smoking habits of these miners, and the researchers' present risk estimates are uncorrected for smoking [3]. Out of a group of 57 uranium miners who died of lung cancer, only one was a nonsmoker and the rest smoked [39]. Muller and associates plan to conduct a case-control study of the effects of smoking upon lung cancer risk in miners. Although they stated that correction for smoking will not substantially change their risk estimates [3], at low levels of radon progeny exposure, it is important to take into account the effect of smoking; thus, definitive conclusions regarding this study must await the smoking history analysis. \n# E. Iron Miners in\n\n# Strengths\nThe strengths of this study include the relatively low radon progeny exposures of the miners (mean of 4.8 WLM per year), the long follow-up period, and the stability of the work force. The ascertainment of vital status (99.5 percent), and the confirmation of diagnoses for causes of death was thorough (about 50 percent of all deaths in Sweden are followed by autopsy).\nIn addition, Radford and St. Clair Renard (1984) used case-control methods and environmental measurements to rule out health risks from diesel exhaust, iron ore dust, silica, arsenic, chromium, nickel, and asbestos in the mines [5].\n# . L im ita tio n s\nThe major limitations of the iron miners' study were the limited exposure data available for analysis and an unclear cohort definition; there was also a question about how the authors adjusted for lung cancer latency. Radon gas, in the Swedish iron mines, was first measured in 1968. That means that for the average 44 years of follow-up, there exist exposure estimates based on actual measurements for only 8 years. The researchers reconstructed past concentrations based on measurements made at each mine level and area during 1968-1972 and on knowledge of the natural and mechanical ventilation used previously.\nThey assumed that mine ventilation systems and radon progeny concentrations during 1968-72 were comparable with those in the past, by analogy with quartz dust levels measured in the mines since the 1930's [5].\nThe researchers calculated average yearly exposures in WLM for each decade from the average hours per month underground and radon progeny concentrations in each area, weighted by the number of man-hours worked underground [5]. These crude calculations make tenuous the connection between a given individual miner and a particular radon progeny exposure level. Nonetheless, the iron miners as a group, probably received very low average exposures to radon progeny compared to uranium miners [5,19]. Radford et a I., stated : \"...we consider that average exposures are probably accurate to + 30 percent\" [5];\nthus, the true average exposure could be between 56 and 104 WLM.\nExactly how Radford and St. Clair Renard defined the cohort, and calculated or excluded the PYR, was unclear from the article.\nTo account for a 10-year lung cancer latency, they excluded PYR for lung cancer during the first 10 years after mining was begun [5]. From their description, it is unclear when mining was begun and whether PYR were counted from the beginning of mining, January 1, 1951, or some other date.\nIt is assumed that most of the miners' PYR were excluded from the years prior to 1951, rather than the period 1951-1976 (years when the authors analyzed mortality), and that the mining population was stable. If one makes these assumptions (unstated by the authors), then adjusting for latency by excluding PYR during the first 10 years after the start of mining should produce unbiased SMR calculations. On the other hand, adjustments for latency that incorrectly exclude many PYR lower the expected number of deaths, thereby possibly overestimating the SMR and the risk due to radon progeny. Because of insufficient information, NIOSH is unable to completely evaluate the effect of the 10-year adjustment for latency on the SMR in this study, although it appears to be minor. \n# F. Fluorspar Miners in\n\n# Strengths\nOne strength of this study was the long follow-up period; workers were followed for an average of about 30 years of observation [11,19]. Also, the researchers obtained smoking history data for 41 percent of the cohort [11].\n# . L im ita tio n s\nThere were three principle limitations in this study. First, there was limited exposure data available before 1968 (See above).\nSecond, the study failed to trace large numbers of workers; 591 workers who lacked adequate personal identifying information (name and year of birth) were dropped from the analysis.\nThird, this study lacks an adequate basis for estimating expected deaths.\nLung cancer rate comparisons between the mining population, with its many smokers, and the Newfoundland or Canadian national populations, would exaggerate excess deaths due to radon progeny exposure. Morrison et al. (1985) tried to avoid this problem by generating the expected number of deaths among underground workers from a comparison with mortality rates among surface workers (adjusted for age, time period, and disease specific mortality) [11]. A problem with this study design is that the control group may be exposed to radon progeny. Some of the men classified as surface workers (controls) may have received some radiation exposure, by means of either misclassification or unrecorded short periods of working underground. Also, it is difficult to correctly adjust for age, time period, and disease specific mortality, when there are proportionately fewer workers in the control group (surface workers) than in the exposed group (as of 1971, underground workers accounted for 57 percent of the total person-years [40]). The lack of an adequate comparison group is a serious limitation, so risk estimates from this study must be viewed wi th caut ion.\n# G. Secondary Epidem iologic Studies\nThe ten epidemiologic studies reviewed herein examine mortality among miner populations in China, Sweden, the United States, Great Britain, France, and China.\nSeveral studies demonstrated elevated radon progeny levels and excess lung cancer deaths among underground miners, but lacked information about radon progeny exposure, or levels of other mine carcinogens.\nOther studies contained severe limitations or biases that also restricted their usefulness. Overall, the ten secondary studies provide additional information about the association between lung cancer mortality and radon progeny exposure, yet have more limitations (in study design, study population size, radon exposure records, thoroughness of followup, etc.) than the five primary studies. To be concise, the secondary studies are described in less detail than the primary studies.\n# 1.\nIron Ore Miners in Grangesberg, Sweden \n# Zinc-Lead M iners in Sweden\nThis case referent study examined lung cancer mortality during 1956-76 among residents from the parish of Hammar, Sweden, an area with two zinc-lead mines [42]. Twenty-nine subjects who died of lung cancer, including 21 who were underground miners, were matched with three referents who died before or after each case. Some problems with the study were the smalI number of cases and a fai lure to match for age or smoking status. Axelson and Sundell (1978) reported a sixteenfold increase (p<0.0001) in lung cancer mortality among the miners versus nonminers. Although they lacked individual information on exposure, they estimated a radon progeny level of about 1 WL in the mines, based on measurements made in the 1970's [42]. These results should be viewed with caution; since they demonstrated that age was a confounding factor, yet they did not match cases and referents for age.\n# . Iron Ore Miners in K iruna, Sweden\nThis study examined lung cancer mortality among residents of the Kiruna parish in Northern Sweden, an area containing two underground iron mines [43]. One strength of this study is that migration in the Kiruna area was slight, therefore, nearly all former miners' deaths were registered in Kiruna. From 1950 to 1970 a total of 41 men (in Kiruna) between the ages of 30-74 years died of lung cancer. Thirteen of these were underground miners, and it is possible, although unclear in the report, that 18 were surface workers. One limitation of this study is that the the age distribution of underground miners was unrecorded, and therefore, proportional mortality was used instead of the lifetable method to calculate the expected mortality. Another limitation is that the expected mortality was not adjusted for smoking status, since information from family and fellow workers indicated that 12 of the 13 underground miners smoked (8 smoked cigarettes, 4 smoked pipes). Jorgensen (1973) compared the 13 deaths observed among underground miners with expected deaths of 4.47, based on local rates, and 4.21, based on Swedish national rates.\nIn both cases, he reported significantly elevated mortality (p<0.05) among the underground miners [43]. Because this proportional mortality study involved few lung cancer cases, 13 for underground miners and 28 for all other men in Kiruna, the results should be viewed with caution. Radon progeny exposure records were unavailable for the underground miners, however, there were measurements of 10-100 pCi/l radon progeny (about 0.10-1.0 WL at 100 percent equilibrium).\n# .\nIro n Ore Miners in Kiruna and G a lliv a r e , Sweden \n# . Metal Miners in the U nited S tates\nThis cohort mortality study involved white male underground metal miners in the United States. The cohort was defined as miners who had completed, at a minimum, their fifteenth year of underground mining experience between January 1, 1937 and December 31,1948 For the period 1947-1955, there were no radon measurements available, however, a committee of experts estimated average monthly radon progeny exposures varied from 1-10 WLM.\n# T in M iners in C o rn w all, Great B r ita in\n\n# Uranium Miners in France\nIn 1956, 7,470 radon gas measurements were collected.\nFrom 1957 to 1970, about 20-30 radon gas measurements were collected per miner per year; from 1970 to the present, 57-70 per miner, per year. The only limitation of these records is that they are based on radon gas, rather than direct radon progeny measurements. At present, the mean factor of equilibrium in the French mines is 0.22. The miners' average annual radon progeny exposures varied from 2.5 to 4. There were many excess lung cancers at low radon progeny exposures, i.e., an SMR of 436 (p value unspecified by the authors, however estimated at p<0.05, from the number of observed deaths and the Poisson frequency distribution) at cumulative exposures below 140 WLM. Arsenic concentrations in ore samples were high, 1.50-3.53 percent [49]. For the years 1950-59, it was estimated that a miner inhaled 1.99-7.43 mg arsenic per year [48]. The authors suggested that the high arsenic content in the ore samples may cause lung cancer [49].\nThe strength of this study lies in the large number (12,243) of underground miners studied. One limitation is that the study cohort is ill-defined; the study design mixes aspects of a survey for incidence with a cohort study. Wang et al. (1984) [49] fail to describe when the workers started mining and how many were lost to follow-up; also, whether the 12,243 miners worked between 1975-81 or constituted all tin miners who ever worked underground. The major limitation appears when comparing these studies with other mining research studies because Wang and associates handled radon progeny measurement techniques and epidemiologic methods in a different manner. For instance, they did not mention if their mortality statistics were adjusted for age or smoking status. Their comparison population, male residents in urban Shanghai municipality, has much higher lung cancer rates than males in rural Yunnan province [50]. Therefore, the Shanghai comparison group was inappropriate and may have underestimated these miners' lung cancer r i sks.\nAnother limitation is that arsenic exposure has been associated with lung cancer among copper smelter and pesticide workers [8,9]. This research may be most useful for studying the interaction of two carcinogens, arsenic and alpha radiation from radon progeny, rather than for studying radon progeny lung cancer risks alone.\n# H. Smoking\nThe two most thorough studies of the interaction between smoking and radon progeny exposure are those by Whittemore and McMillan (1983), using the U.S. white uranium miners data set [14], and by Radford and St. Clair Renard (1984) using the Swedish iron miners data set [5]. The major flaw in other studies of the interaction between smoking and radon progeny exposure [13,16,42,51] is an inadequate sample size of miners with both exposure records and smoking histories.\n# . Uranium Miners in th e U nited S tates\nWhittemore and McMillan (1983) examined lung cancer mortality among the white USPHS uranium miners cohort, based on a mortality follow-up through December 31, 1977.\nIn their analysis, they included nine additional miner lung cancer deaths which occurred after December 31, 1977, for a total of 194 lung cancer cases [14] (see section III.B).\nFor each case, four control subjects were randomly selected from among those white miners born within 8 months of the case and known to survive him, yielding a total of 776 matched controls [14]. A regression analysis of the radon progeny exposure and smoking data for cases and controls revealed that the data fit a multiplicative linear relative risk model [R=(1+B-|WLM)(1+B2PKS)], but showed \"significantly poor fit\" (p<0.01) for the additive linear relative risk model [R=1+B-|WLM+B2PKS] [14]. The data demonstrated a synergistic effect, that is, the combined action of smoking and radon progeny was greater than the sum of the actions of each separately. [14].\n# Whittemore and McMillan, based on the multiplicative linear relative risk model [R=(1+B-|WLM)(1+B2PKS)], suggested that miners who have smoked 20 pack-years of cigarettes (excluding tobacco use within the past 10 years) experience radiat ion-induced lung cancer rates per WLM that are roughly five times those of nonsmoking miners\n(They estimated that B-j, the excess relative risk per unit of radon progeny, was 0.31X10~2 and B2 , the excess relative risk per unit of cigarette smoke exposure, was 0.51X103).\n# 2.\nIron Miners from Malmberget, Sweden \n# . Conclusions R elated to th e In te ra c tio n o f Radon Progeny Exposure and Smoking\nStudies of white uranium miners in the United States [14], and iron miners in Sweden [5], support different models of risk due to radon progeny and smoking; the first supports a multiplicative model, the second, an additive model. These two studies arrive at different conclusions which is not surprising, given the differences in statistical methods, cumulative exposure levels (the averages differed by a factor of 10), smoking histories, and method of calculating expected deaths between the studies. Based on the presently available information, it is impossible to conclude whether the additive or multiplicative model is the best. Nevertheless, present research indicates a higher risk from combined exposure; data from both radiation exposure and smoking histories are essential for an accurate estimation of radiogenic lung cancer risks.\n# I . Discussion and Conclusions R elated to the Epidem iologic E valu atio n 1. The Five Prim ary Epidem iologic S tudies\nThe five primary epidemiologic studies that examine lung cancer mortality among underground miners are the studies of uranium miners in the United States, Czechoslovakia, and Ontario, as well as iron miners in Sweden and fluorspar miners in Newfoundland.\nDespite the individual limitations of each study, the association of radon progeny exposure and lung cancer was shown to persist for all five studies, using different study populations and methodologies.\nThere was an elevated lung cancer SMR and a dose-response relationship for radon progeny exposure and lung cancer among the five underground miners' cohorts; the higher the estimated radon progeny exposure, the greater the number of excess deaths. Some studies [3,5,14] adjusted their mortality figures for the estimated latency of radiogenic lung cancer, yet the association between lung cancer cases and radon progeny exposure remained.\nTable III-2 is a summary of the observed and expected deaths and the SMR's in the five studies. These studies handled adjustments for latency, lagging dose, smoking history, or age as detailed in the footnotes in Table III-2. As yet, there is no one standard method to adjust person-years, expected deaths, or SMR's, or even agreement that these parameters should be adjusted.\nA M five studies [3,5,10,11,12] lacked adequate radon progeny exposure data for individuals because, in general, these data were originally collected for monitoring, and not research purposes.\nIn addition, some studies [5,10] based the exposure assessment upon radon gas measurements, which must be converted to radon progeny estimates. five studies, rather than eliminate a particular study because of exposure data quality.\n# It is reasonable, however, to extract what information is available from these\nThe primary studies of iron miners in Sweden and uranium miners in Czechoslovakia searched for other exposures [9,53,54] (i.e., mineral ores, radiation, diesel fumes) in the mining environment.\nThe Czechoslovakian uranium mines contained various amounts of arsenic, but only trace amounts of chromium, nickel, and arsenic [7,9,53,54]. Researchers examined lung cancer mortality in two uranium mining localities that had similar radon progeny levels, but a fiftyfold difference in arsenic concentrations.\nThey failed to find a significant difference in mortality between the two groups of miners [27,28,29,30,31], concluding that arsenic was not affecting the lung cancer rates of underground miners in Czechoslovakia. Arsenic, chromium and nickel were essentially absent in the Swedish iron mines. There were occasional inclusions of serpentine, but no identifiable asbestos fibers in dust samples [5]. The Swedish iron mines contained iron ore dust, but Stokinger (1984), after review of the literature from health reports involving underground iron ore miners, iron and steel workers, foundrymen, welders, workers in the magnetic tape industry, and others, concluded that these studies failed to clearly demonstrate the carcinogenicity of iron oxide dust [55].\nThe influence of other types of radiation present in the mines, such as long-lived alpha, beta, and gamma radiations, cannot be determined from these five studies. The miners do not show an excess mortality from leukemia, a disease linked to high gamma radiation exposures [1,3,15]. Most of the studies provided insufficient information about diesel fume exposures in the mines, so that it is impossible to reach conclusions regarding the effect of diesel fume exposure upon lung cancer risk.\nIn the Swedish iron mines, 70 percent of miners with lung cancer left underground work or died before diesel equipment was introduced in the 1960's ; the remaining miners had brief diesel fume exposures immediately before death [5]. Therefore, diesel fume exposure could not account for the excess mortality in the Swedish cohort [5]. Cigarette smoke appears to be the most important carcinogen common to the five primary studies. The proportion of cigarette smokers among underground miners in the United States, Newfoundland and Sweden was greater than among the general male population in those countries [5,12,40]. The influence of possible carcinogens in mines (in addition to radon progeny) upon lung cancer mortality needs further research.\n# . The Ten Secondary Epidem iologic Studies\nTen epidemiologic studies were identified by NIOSH as secondary studies, which strengthen the association between excess lung cancer mortality and radon progeny exposure, yet have more limitations (in study design, radon exposure records, follow-up, etc.) than the five primary studies. The ten epidemiologic studies examined lung cancer mortality among underground iron ore and zinc-lead miners in Sweden, metal and Navaho uranium miners in the United States, tin and iron ore miners in Great Britain, uranium miners in France, and tin miners in China. All ten studies have incomplete radon progeny exposure records. Nevertheless, all reported an elevated lung cancer mortality in underground miners and the presence of radon progeny in the mines. The studies of metal miners in the United States [4], and tin miners in China [49] also found arsenic in the mines; Wang et al. (1984) suggested that the high arsenic content of the ore may be a cause of lung cancer [8,9,49]. The study of tin miners in China found an exposure-response relationship between cumulative radon progeny exposure and excess lung cancer mortality, but at the lowest exposure level (less than 140 WLM), still found an unusually high SMR (436) [49]. The arsenic exposures of these underground miners may contribute to the high lung cancer SMR; arsenic exposure is associated with lung cancer in copper smelter and arsenical pesticide workers [8,9].\nThe study of iron ore miners in Grangesberg, Sweden estimated an attributable risk of 30-40 cases per 10® PY-WLM for miners over the age of 50 [13]. This attributable risk estimate is comparable to that reported by Radford and St. Clair Renard (1984) for miners in Malmberget, Sweden in the same age group [5].\n# The Lowest Cumulative Radon Progeny Exposures Associated w ith Excess Lung Cancer M o r ta lity\nThe five primary epidemiologic studies are far from completion, since the cohorts' follow-ups are truncated.\nFor example, the uranium miners in the United States were followed a mean of 19 years (by 1977), while the iron miners in Sweden were followed a mean of 44 years (the Swedish study has the longest follow-up period of the five primary studies). Lung cancer rarely is manifested before age 40, regardless of etiology [20,35].\nFrequently, the initial analyses performed on a cohort lack enough PYR and statistical power to show a statistically significant association between excess lung cancer mortality and low radon progeny exposure levels. Later analyses accumulate additional PYR for the entire cohort and specific subgroups, increasing the ability to detect an effect due to radon progeny. This point is important when determining the lowest radon progeny exposures associated with excess lung cancers. A longer follow-up period, resulting in more PYR and statistical power in a study, may reveal an association between excess lung cancer mortality and radon progeny at lower cumulative exposures. [12] had an average of about 10 years of follow-up (by 1968) and found excess cancers above 120 WLM. The study of uranium miners in Czechoslovakia found excess mortality above 100 WLM [10,24]. Two recent studies, of miners in Ontario and Sweden, reported excess cancers at cumulative radon progeny exposure levels of 40-90 WLM and 80 WLM, respectively [3,5]. Thus, two epidemiologic studies found excess lung cancer mortality associated with radon progeny exposure levels below 100 WLM.\n# The study of uranium miners in the United States by Lundin et al . (1971)\nIn addition, studies suggest that both radon progeny exposure and smoking are involved in the lung cancer mortality of underground miners; however, the available information does not allow one to state whether radon progeny and smoking interact in an additive or multiplicative fashion [5,14]. One estimate is that miners who smoked 20 pack-years of cigarettes have radiat ion-induced lung cancer rates per WLM that are roughly five times those of nonsmoking miners [14].\nFinally, the five primary and ten secondary mining epidemiologic studies all demonstrate excess lung cancer mortality among underground miners working in the presence of radon progeny. \n# IV . MEDICAL SCREENING AND SURVEILLANCE OF UNDERGROUND MINERS EXPOSED TO SHORT-LIVED ALPHA PARTICLES\n\n# A. Q u a litie s o f E ffe c tiv e Medical Screening and S u rv e illa n c e\n\n# B. Screening and Lung Cancer Prevention\nAlpha radiat ion-induced lung cancer may be preventable (by limiting exposures to radon and thoron progeny) but not treatable. By the time radiogenic lung cancer is detected among individuals in an exposed work force by routine periodic screening, the affected workers fail to benefit from any further preventive or therapeutic measures.\n# Available screening tests may detect radiat ion-induced, premalignant abnormalities in asymptomatic exposed workers years before disease appears. At the current state of knowledge, however, it is unknown whether medical removal of asymptomatic workers with these abnormalities will prevent progression to malignant disease. A recent study by NIOSH tested the within-reader reliability of an expert in sputum cytologic and histopathology. The reader reliably detected malignant changes, but frequently read early changes as \"premalignant\" on one occasion and as \"within normal limits\" on other occasions [65].\nTo date, there is no convincing evidence that routine periodic medical screening of workers exposed to pulmonary carcinogens is an effective means of prevention of mortality due to lung cancer in these workers.\nCoke oven workers are presently the only group of workers covered by a mandatory rule for periodic screening by sputum cytology and chest X-rays. Although the effectiveness of that regulation has not yet been evaluated, such studies are now underway.\nIn addition, NIOSH is currently collecting data on lung cancer rates and the results of sputum cytologic tests for some miners in the USPHS cohort [66]. Also, frequent exposures of underground miners to chest X-rays for screening purposes are not recommended at present. \n# CRITERIA FOR DETERMINING THE SUITABILITY OF A CANCER SCREENING TEST FOR USE IN THE WORKPLACE\n\n# Coles and Morrison (1980) [61]:\n1. The test should be \"effective\" in terms of its validity, reliability, sensitivity, specificity, and opera tional characteristics (such as predictive value).\n# 2.\nThe test should be \"acceptable\" to workers in terms of its cost, convenience, accessibility, lack of morbidity.\n# Halperin et al. (1984) [62]:\n1.\nThe test should be \"effective\" in terms of its validity, relia bility, sensitivity, specificity, and operational characteristics (such as predictive value).\n# 2.\nThe test need not be uncompli cated or inexpensive, but its performance and interpretation must be done by competent profes sionals.\n# 3.\nThe test must be \"acceptable\" to workers in terms of its cost, convenience, accessibility, lack of morbidi t y .\n# 4.\nThe test results must be eval uated by comparison to a suitable population, not necessarily the general population. \n# Action levels and related medical decisions must be deter mined in advance of screening (based on #1 above).\n\n# Adapted from [61,62]\n\n# 2.\nEffective treatment is avail able if asymptomatic disease is detected.\n# Detectable preclinical phase must be highly prevalent among screened population.\n\n# Halperin et al. (1984)[62]\n1. The disease has important individual and public health consequences.\n2. Disease need not be treatable, but must be preventable.\n# A detectable preclinical phase (DPCP) must exist and a target population (exhibiting a high\nprevalence of DPCP) be identified.\n# 4.\nFollow-up care (diagnostic, treatment, and social services) must be avaiI able.\n# 5.\nNatural history of the disease determines the feasibility and frequency of testing.\n# Adapted from [61,62]\nA review of studies reporting histopathologic associations with radon progeny exposures lacked sufficient information to conclude definitely that only one specific lung cancer cell type was associated with these exposures [67].\nIn addition, a case-control study using data from the Third National Cancer Survey found that cigarette smoking was significantly associated with all three histologic types of lung cancer [68]; the relationship with small-cell carcinoma was strongest overall (odds ratio = 5.1), whereas those with squamous and adenocarcinoma were approximately equivalent (odds ratio = 3.1). The issue of histopathologic associations with radon progeny exposures needs further research, especially considering that many underground miners smoked cigarettes.\n# Both cessation of smoking [69] and reduction of the radon progeny exposures\nof underground miners will lower their risks for lung cancer.\n# C. Recommendat i ons 1. Smoking\nSince it appears that inhaled radon progeny either add to or multiply the underlying high lung cancer risk in smokers, a smoking cessation program is recommended. The combined effects of a lower (more protective) Permissible Exposure Limit (PEL) and cessation of cigarette smoking [69] would probably provide a significant reduction in lifetime risks.\n# Lung Function Tests\nA baseline chest X-ray and annual spirometrie lung function tests, performed and interpreted according to the criteria of NIOSH or the American Thoracic Society, would be appropriate for medical decision-making concerning job placement, medical removal protection, and disability compensation should work-related respiratory problems develop.at a later time.\n# . X -ra y Screening\nWhile chest X-ray screening is not an effective means of prevention of death due to occupational lung cancer, examination at 5-year intervals, and industry-wide analyses of the results of such tests may be an effective means of supplementing the primary prevention of other lung diseases, such as pneumoconioses.\n# . R a d ia tio n Exposure Records\nThe lifetime radiation exposure record of underground miners should include information about the dose and frequency of medical irradiation.\nIf radiation exposed workers are routinely screened for lung diseases by baseline and periodic follow-up chest X-rays, they will receive an average of about 0.025 rad per examination of external X-irradiation (where an \"examination\" consists of a postero-anterior and a lateral exposure) [70].\nIf examinations are conducted every 5 years, the average lung dose would be about 0.005 per year. Furthermore, because of the frequency of on-the-job accidents and injuries in underground mining [15], underground miners may receive considerably more medical X-irradiation over a working lifetime than workers exposed to other sources of ionizing radiation. For each of the following diagnostic examinations, the approximate X-ray dose to the lung is indicated in parentheses: thoracic spine (0.421 rad), ribs (0.324 rad), lumbar spine (0.133 rad), one shoulder (0.039 rad), lumbosacral spine (0.035 rad), and skull (0.002 rad) [ \n# V. FEASIBILITY OF LOWERING THE STANDARD\nThis section examines the feasibility of lowering the current radon progeny exposure standard, including differences between current exposures and lower projected standards.\n# A. Comparison o f Current U.S. Underground Miner Radon Progeny Exposures with D iffe r e n t Standards\nThe uranium mining industry in the United States has recorded the annual exposures of underground miners, and the Atomic Industrial Forum (AIF) figures are displayed in Appendix Tables A-9 to A-11. There has been some discrepancy between MSHA records and AIF records [73]. Overall, the industry has been successful in controlling exposures to 4 WLM. Furthermore, the percentage of miners exposed to 3 WLM or higher decreased between 1973 and 1982 (Tables A-9 to A-11, [74]).\nThere has been substantial mobility among the uranium miners, with many people working for short periods of time at different mines, so that the AIF separated the annual exposure data into two sets, \"all persons assigned to work underground\" and \"persons who worked underground 1,500 hours or more\" i.e., full time.\nIt appears that, for most underground uranium mine workers, the mining industry already can meet a radon progeny standard below the current level of 4 WLM annual exposure.\nIf the radon progeny exposure standard was set at 1 WLM, approximately one-third of all underground workers and less than two-thirds of the full-time underground workers would be exposed above a \n# In the case of nonuranium mines in the United States, it is clear they can meet a lower exposure standard, based on the limited data submitted by the mining companies to MSHA (Appendix Table A-5).\nOf those nonuranium mine workers whose exposures to radon progeny were recorded, the upper limits of exposure varied from 0.16 to 2.20 WL, depending upon the mining industry (Appendix Table A-1). Acknowledging the limitations on the way exposure data is collected (Appendix A, section A.2.a.), the mining companies submitted information to MSHA which suggests that no more than 450 individuals are occasionally exposed to substantial radon progeny levels (i.e., 0.3 WL and above) (Appendix Table A-5). During 1983, these radon progeny exposed employees were found in only 4 nonuranium mines, out of a total of about 574 U.S. nonuranium metal and nonmetal underground mines. Therefore, it should be feasible to control the radon progeny exposures encountered by these 450 (or fewer) miners.\n# B. The Technological C apacity to F u rth er Reduce Exposure\nSome of the highest radon progeny exposures are received by people working in the smallest uranium mines, those employing less than ten people [73]. Probably, these small mines can improve their ventilation systems and reduce worker exposures. Currently, many of these small mines are not operating due to the depressed prices for uranium.\n# There are a variety of techniques besides ventilation that can reduce workers' radiation exposures (Appendix B).\nIn general, these techniques are more costly and less effective than ventilation. Nevertheless, these methods, in addition to ventilation, could be used to decrease the exposures of the relatively small number of uranium workers (46 during 1982) It should be technically feasible for the mining industry to control the radon progeny exposures of these relatively few workers receiving substantial exposures. Also, an engineering analysis (based on data from only two mines) suggested that it is technically feasible for uranium mines to meet a standard as low as 1 WLM, using control techniques such as ventilation, bulkheads, and backfilling.\n# VI. CONCLUSION\n\n# Each of the five primary epidemiologic studies contained strengths and limitations.\nAll of the studies [3,5,10,11,12] rely on incomplete radon progeny exposure estimates to calculate the cumulative exposures of the underground miner cohorts. Nevertheless, they contain sufficient strength to demonstrate an excess lung cancer risk associated with radon progeny exposure. Also, an exposure-response relationship exists between cumulative radon progeny exposure and lung cancer mortality [3,10,11,12,24]. Statistically significant SMR's above 400 were observed in three studies, where workers accumulated mean exposures above 100 WLM [10,11,15,24], Statistically significant SMR's between 140 and 390 were observed in two studies [3,5], where workers accumulated mean exposures below 100 WLM, and in preliminary findings from a third study by Tirmarche et al. (1985) where workers probably accumulated mean exposures below 100 WLM [47], NIOSH acknowledges the efforts of various groups [19,21,35,77] to compare attributable and relative risk estimates across different epidemiologic studies. NIOSH can neither validate nor refute these findings.\nAt this point, without access to the raw data and more specific information about epidemiologic methods, NIOSH is unwilling to speculate or make comparisons between the attributable or relative risk estimates in the five primary studies.\nThere were several classifications for identifying a substance as a carcinogen. \"Potential occupational carcinogen\" means any substance, or combination or mixture of substances, which causes an increased incidence of benign and/or malignant neoplasms, or a substantial decrease in the latency period between exposure and onset of neoplasms in humans or in one or more experimental mammalian species as the result of any oral, respiratory or dermal exposure, or any other exposure which results in the induction of tumors at a site other than the site of administration.\n# Such classifications have been developed by the National\nThis definition also includes any substance which is metabolized into one or more potential occupational carcinogens by mammals.\nSince exposure to radon progeny has been shown to produce lung cancer in underground miners, it meets the OSHA criteria; thus, radon progeny should be considered an occupational carcinogen. Data on the current radon progeny exposures of uranium, metal, and nonmetal miners suggests that the mining industry, overall, is already capable of meeting a radon progeny standard below the current annual limit of 4 WLM. Recent limited research (based on data from only 2 mines) suggests that, using ventilation, bulkheads, and backfilling, it is technically feasible for mines to meet a standard as low as 1 WLM.\nAt the present time, there is no effective medical method to prevent or treat lung cancer to radon progeny exposure. Also, there is insufficient evidence to support an association between a specific lung cancer cell type and radon progeny exposure [67,68]. Only exposure prevention measures are effective in lowering radon progeny induced lung cancer rates. These preventive measures include lowering the radon progeny exposures of underground uranium miners (and perhaps some underground metal and nonmetal miners), especially those that receive annual cumulative exposures near the present limit of 4 WLM. An additional measure is to encourage miners to stop smoking, because smoking and radon progeny exposure may act multiplicatively, or at least additively, to cause lung cancer.\nFinally, a lowering of exposure, especially for the workers currently exposed near 4 WLM, is recommended. Recent information suggests that it is technically feasible to control radon progeny exposures to levels as low as 1 WLM. NIOSH wishes to withhold a recommendation for a specific PEL, until completion of a quantitative risk assessment, which is now in progress.\nIn addition, the specific medical recommendations listed in Chapter IV should be implemented. \n# A. Current Work Force\n\n# Uranium Miners a. M iners in th e U nited S tates\nThe number of underground mine workers (including miners and service and support staff) dropped from approximately 5,037 in 1980 to 2,150 in 1982 (Table A-2). The number of underground miners, the group receiving the highest exposures, dropped from 2,760 to 1,275. This decrease was due to a recent fall in the price of uranium and reduced uranium demand.\nIn the mines in the United States there are numerous temporary, short-term workers; in 1978, out of all employees who worked underground, only 46 percent worked 1,500 or more hours underground (i.e., full-time).\n# b. M iners Outside th e U nited S tates\nCzechoslovakia, China, France, Italy, Australia, Canada, and Argentina have underground uranium mines (see Table A-3 \n# Ill\n\n# B. C urrent Exposures in M ining\n\n# Stanley\nEquity Gold Inc.\n--------------\n# 11\n--------------\n# Leadv i 1 1 e Un i t Asarco\n---------------------\n# 95\n-------\n# Revenue -Vi rginius Ranchers\n\" \" \" \n-- -- -- Baryte 0.2 -- -- -- Coal 0.1 -- -- --\n# South Africa 1973\n-- In mines where production employees also perform maintenance, service and supervisory duties., such employees were classified as production workers. In cases where corporations had widely separated operations under different managers, each was considered a separate operation. cProduction includes production and development miners.\n# Exposure of U.S. underground uranium miners to radon daughters in 1979 as\nIn mines where production employees also perform maintenance, service and supervisory duties, such employees were classified as production workers. \"Maintenance includes mechanics and electricians.\nService includes motormen, haulage crews, drift repairmen, station tenders, skip tenders, etc. 'Salaried includes engineers, supervisors, geologists and ventilation personnel. uranium mines in the United States, this figure is somewhat misleading. These workers can receive high exposures, and because they only work for short periods of time, their annual average exposure is low. The average exposure for those miners working full time, that is over 1,500 hours underground, was higher; 1.45 WLM in 1978.\nUnderground mining exposure records were placed into four general job categories by the AIF, i.e., production, maintenance, service, and salaried. As a group, the production workers who worked more than 1,500 hours underground should have higher exposures than the remaining uranium mining work force.\nIn 1978, the average exposure of these workers was 1.74 WLM (see Table A-7) and in 1979 their average exposure was approximately 1.88 WLM [57].\nIn contrast, in 1979 and 1980, MSHA inspectors recorded average radon progeny WL concentrations for underground uranium mining production workers of 0.30 WL or higher, which means that some of these workers could receive 4 WLM or more per year. Cooper estimated that the average annual exposure of full-time underground production workers was about 2. 9 WLM during 1979 [57]. The number of workers that receive these high exposure levels may be small; AIF reported that among full-time underground uranium miners in 1979, only 3 out of 1,711 production workers and 3 out of 488 maintenance workers received more than 4 WLM annually (see Tables A-10 and A-11).\nOverall, most uranium mine workers' (including those workers who spend only part of their time underground) exposure is well below the standard of 4 WLM and on the average may be about 1 WLM [82], (see Table A -7). A relatively small number of workers, primarily full-time underground production and maintenance workers, have exposures above the 4 WLM standard (see Tables A-9 through A-11). The most recent available data, for 1982, showed that only 2 underground employees (0.1 percent) received radon progeny exposures of 4.0-5.0 WLM and 44 employees (1.6 percent) received exposures of 3.0-4.0 WLM. [58].\nIt should be possible to lower radon progeny exposure levels for this relatively small number of miners.\n# b. Miners Outside the United States\nThe exposure of underground uranium miners depends on the quality of the uranium ore body and the ventilation rate.\nIn other countries, (excepting Canada) the uranium ore is frequently of a lower grade than the ore in the United States, so with good ventilation techniques, the foreign uranium miners should receive lower exposures than the miners in the United States. Recent figures for radiation exposure in underground uranium mines in Canada, France, India, Argentina, and China have been published in the literature (see Table A-3\n) [82].\nThe underground uranium miners of Canada had an average annual exposure to radon progeny of 0.74 WLM in 1978.\nIn 1980, the median exposure for miners in three underground mines in Saskatchewan was below 0.6 WLM and only about three workers in one mine were exposed to 3-4 WLM.\nIn addition, some of these miners had substantial gamma exposure.\nIn the Cluff mine, gamma exposures were as high as 3.5 rem and above, and in the Eldorado and Cluff mines many workers (approximately 60) were exposed to 1-3 rem [90].\nThe French uranium miners had average annual radon progeny exposures of 2.0 WLM and 1.4 WLM in 1978 and1979, respectively [82].\nIn 1975, the median radon progeny exposure was below 0.10 WL, yet as many as 5.35 percent of the workers were exposed to 0.30 to 0.80 WL, potentially receiving more than 4 WLM annually (see Table A-12) [91].\nIn 1975, there was also a record of gamma exposure in French underground uranium mines. The mean annual dose was 0.49 rem, but some miners received much higher doses; 9.16 percent received 1.0-1.5 rem, 5.3 percent received 1.5-2.5 rem and 0.65 percent received 2.5-3.0 rem [91].\nIn the underground uranium mines in France, gamma exposure may constitute a major part of the total radiation.\nThere is limited information available concerning typical radon progeny exposures in underground uranium mines in India, Argentina,and China [82]. For the mines in India, figures for potential exposure are given by job category.\nIn 1979, the drilling crew received an estimate of 2.6 WLM of potential alpha energy exposure, the mucking crew about 2.1 WLM, and \"others\" about 1.7 WLM (see Table A -13) [82],\nIn Argentina, the average annual radon progeny exposure was about 2.4 WLM during 1980.\n# Nonuranium Miners a. Hard Rock Miners in the United States\nSome of the highest radon progeny exposures are found in the iron, zinc, fluorspar, and bauxite mines (Table A-1).\nIn 1975, iron miners were exposed to 0.14-0.90 WL, zinc miners to 0.07-1.40 WL, fluorspar miners to 0.30-2.20 WL and bauxite miners to 0.07-1. 40 WL [83,84].\nIf these readings are typical, some hard rock miners in the United States, especially those in fluorspar mines, could have radon progeny exposures much higher than 4 WLM. However, recent data submitted by U.S. metal and non metal mining companies to MSHA suggests that no more than 450 individuals are occasionally exposed to 0.3 WL (Table A -5). During 1983, only 4 companies, 2 molybdenum, 1 phosphate and 1 tungsten, submitted individual exposure records for their employees to MSHA.\nIt is possible that the mining companies failed to report additional employees who received radon exposures, but this is the only data available. From this data, one concludes that, except for a few molybdeum, phosphate, and tungsten mines, radon progeny exposure is not a problem in U.S. hard rock mines. Thus, in general, hard rock mines should be able to meet an annual radon progeny standard below 4 WLM. , 1982, p. 199 [82].\n# b. Hard Rock Miners Outside the United States\nRadon progeny exposure levels have been measured in nonuranium mines in Finland, Italy, Norway, South Africa, Sweden, the United Kingdom and Poland (Tables A-14 to A-16) [82,81]. The most recent figures for all of these countries show annual average radon progeny exposures of 2.6 WLM or less. However, in many of these countries the average potential alpha energy concentrations exceed 0.3 WL, suggesting that individual miners may be exposed to more than 4 WLM per year (if they work full time during the year). Nonuranium miners (especially iron, zinc, lead, copper, or gold miners) in Italy, Poland, South Africa, and Great Britain may be exposed to more than 4 WLM annually [82].\nIn the United Kingdom, 4 percent of the noncoal miners were exposed to 4 WLM or more, however, many of the miners did not work full 8-hour shifts.\nIf the underground noncoal miners in the United Kingdom worked full 8-hour shifts, as many as 20 percent of the workers could be exposed above 4 WLM/yr [81]. Recent reports for five Chinese tin mines showed radon progeny levels of 0.67 to 1.73 WL during 1978 [40]. 22 It may be most effective to combine some of these techniques, e.g., to use positive pressure ventilation in combination with procedures to decrease the volume of the mine air needing ventilation, such as bulkheads or backfilling. Bulkheads could be made more secure against radon gas leaks by maintaining a slight negative pressure behind the bulkhead and painting sealant on nearby exposed rock. Finally, most of the techniques described in Table B-1 and in this chapter will decrease inhalation exposure to alpha radiation from the decay products of radon and thoron gases, but won't affect gamma radiation levels.\n# Mechanical Ventilation\nMechanical ventilation is the primary and most successful technique currently in use for reducing exposure to radon decay products. In uranium mines in the United States, during the early 1950's before mechanical ventilation became prevalent, average measurements of 2-200 WL of radon decay products were common [11].\nIn contrast, during 1979 and 1980, the highest average working level for radon progeny recorded by MSHA was 0.46 WL (Table B-2). Thus, there has been a great decrease in exposure to radon decay products in uranium mines primarily due to improvement in ventilation.\nSweden has also successfully reduced radon progeny levels in nonuranium mines with mechanical ventilation.\nThe average annual exposure for the nonuranium miners of Sweden was 4.7 WLM in 1970, due to ventilation improvements, and decreased to 0.7 WLM in 1980 [95].\nIn the case of uranium miners in the United States, it is not clear whether there could be significant further decreases in exposures to radon decay products with ventilation improvements alone. These few mines may need to use other techniques, besides dilution ventilation, to reduce miners' exposure to radon progeny (Table B-1).\n# Other Dust Control Methods\nSpraying water and delaying blasting until the end of shifts are two other dust control methods currently in use in most underground uranium mines. Most mines use these methods to control silica dust, but in uranium mines these methods can help control uranium ore dust.\nDrilling and blasting are two mining activities that generate high levels of uranium ore dust. Exposure to uranium ore dust alone may be carcinogenic, and high dust or smoke levels may modify the respiratory tract distribution of a miner's exposure to radon progeny (by increasing the proportion of radon progeny attached to respirable and nonrespirable size dust particles).\nIn wet drilling, water sprays from the drill onto If a person approaches or exceeds the lifetime limit on exposure, they are trans ferred to another job at a lower exposure level with retention of pay, if available, or are removed from work at full pay if another job is not available. Advantages: Protects individual miners against high cumulative exposures. Disadvantages: Spreads exposure over a larger number of people. This system works best when used with a reliable bioassay for exposure, which is not available in the case of radon gas or progeny. Medical removal may not be effective if intense, short-term exposure to inhaled alpha radiation is more hazardous than cumulative radiation exposure.\n(Cont i nued) The drills are equipped with automatic water valves that turn the water and compressed air on simultaneously. (These techniques have been used in mines since the 1930's.) Advantages: The water cuts down on radioactive uranium ore dust. Disadvantages: Difficult to set up in areas where water is scarce. The miners us i ng the drill get w e t .\nDynamite blasting at the end of shift, instead of throughout the day, reduces exposure to dust and smoke. Also, radon gas levels tend to be high immediately after blasting [93].\nAdvantages: Most miners have less exposure to dust and smoke particles and thus less radiation exposure. Disadvantages: Extra production schedule planning is necessary.\nThis involves the use of fan maintenance, backup electrical systems, and spare fans to minimize fan shutdowns during working hours.\nPositive pressure at the rock surface is a barrier to radon flow. One drawback is that high positive pressure in one area may force the radon into nearby low pressure areas [92,93].\n(Cont inued) Exhaust ventilation removes radon, thoron and daughters, as well as diesel fumes, but it also increases the emission of radon from the surrounding rock by creating a negative pressure.\nPositive pressure ventilation is shut down during times when the mine is inactive, creating a temporary negative pressure. This results in energy savings during the shut down periods.\nThe best ventilation method to use depends on the mine topography and production schedule. Ventilation methods may be most effective when used in combination with techniques that cut down on the area needing ventilation, such as bulkheads and backfilling [92,93].\nThe filter respirator covers the miner's mouth and nose and filters the mine air through fiber filters [94].\nAdvantages: As a temporary short-term protective measure, the half-mask respirator affords approximately greater than 90 percent efficiency in reduction of miner's exposure to radon daughters attached to dusts, fumes, and mists. Disadvantages: The respirators may hinder vision, be warm to use under some working conditions, add significant resistance to the miner's breathing and require careful maintenance to assure their continued effectiveness. Filter respirators must be carefully fitted to each wearer, using quantitative respirator fit tests. Only MSHA/NIOSH-certified respirators shall be u s e d .\n(Cont inued) the rock while the drill operates, thus decreasing dust levels. Miners also wet down muck piles and the walls of some tunnels to control dust. Since the 1930's these two techniques have been used in some mines. Blasting increases uranium ore dust and radon gas levels remain high for about an hour afterwards [93]. Delaying blasting until the end of the work-shift removes the miner from an area with high dust and radon gas levels, and allows the ventilation system to reduce these levels before the miner returns to work.\n# Additional Control Methods\nAir cleaning equipment, filter respirators, and separate air supplies are seldom used in the underground mining environment. An air cleaning apparatus can remove dust, but it is expensive compared to traditional ventilation methods and is most useful in circumscribed areas [92].\nFilter respirators and supplied-air respirators are difficult to use in the mining environment and their use should be limited to emergency conditions, such as temporary excursions of the radon progeny concentrations above 1 WL. Respirators tend to restrict movement and vision, may be too warm to wear, have significant breathing resistance, and require careful maintenance and fitting to assure their continued effectiveness. Only MSHA/NIOSH-certified respirators shall be used. Another radon progeny control method is robotics or increased automation. Techniques, such as robotics, that minimize the time the miner spends in the high exposure areas of the mine and in activities such as drilling, blasting, or loading ore, will decrease the miner's radiation exposure. Although, at present, robotics has a limited place in the mines, it may be possible in the future to further automate the uranium ore mining process.\n# B. A dm inistrative Controls\n\n# Medical Removal Protection\nOne type of administrative control is a medical removal protection (MRP) program. Under this program, when an individual's exposure approaches or exceeds a certain limit, the person is reassigned to an area with a lower exposure level. The MRP program has been very effective in reducing exposure in the (noncarcinogenic) lead industries [96]. In this case, blood lead levels could be used as a method to biologically monitor a worker's lead exposure. However, MRP has certain drawbacks when used as an administrative control for exposure to a known human carcinogen such as radon progeny in underground uranium mines.\nFirst, according to our current knowledge of radiation carcinogenesis, it is prudent public health policy to presume that there is no threshold for radon-progeny-induced cancer, and thus no exposure can be assumed to be safe. Therefore, the high exposure individuals who are removed from the job are protected against further radon progeny risk, but the radon progeny exposure (and risk) is spread out over a larger population of workers. Second, at this time, there is no good biological monitoring method for radon progeny exposure because the primary health effect is a carcinogenic, rather than a toxicologic, response. Routine, periodic 132 sputum cytological examinations and chest X-rays are not effective screening tests for the detection of early reversible signs of lung cancer, and cancer itself may only appear after years of exposure. Finally, respirators (as they are presently designed) are very difficult to use in the underground mining environment.\n# Alarm Systems\nAnother type of administrative control involves the use of alarm systems. This method has been fairly effective in coal mines where continuous monitors for methane gas have been tied to alarm systems. Reliable continuous monitors for radon progeny are now technically feasible (see [89]) and could be connected to alarm systems, as well as the control center for the ventilation system. The person who controls the ventilation could increase air movement in mine areas with high radon progeny levels. Also, the continuous monitors might be useful for enforcement purposes, because the MSHA inspector would have a record of excessive radon progeny measurements levels since the last inspection. For recordkeeping and enforcement purposes, the use of data from continuous alarm-monitors would depend heavily on the reliability and validity of these devices, as well as their durability and security from tampering in the mine environment.\n# Contract Mining\nMany underground uranium miners, especially those that drill, blast, and move ore, are given incentive bonuses for the volume of ore removed. Such a system encourages high productivity from the workers, but any time they spend on safety measures means less time to spend mining ore. The contract mining system also encourages miners to work overtime, thus increasing their cumulative internal and external radiation exposures. In addition, some miners, especially before the reduced demand for uranium, went from mine to mine working uranium ore one month and gold the next, getting radon progeny exposures in both locations. This mobility of the work force makes it harder to monitor and track the miners' total radiation exposure, making it more likely that a miner could receive cumulative exposures in excess of current and future standards. One type of administrative control is to modify the contract mining system so that workers would have more incentive to protect their own health on the job. This issue needs further study and discussion, including input from the mining industries, unions, and contract miners.\n# GLOSSARY\nAbsorbed Do s e : The amount of energy absorbed by ionizing radiation per unit mass. Absorbed doses are expressed in units of rads or grays, or in prefixed forms of these units such as millirad (mrad, 10~3 rad), microrad (urad, 10-® rad), etc.* The gray (Gy) is equal to 1 joule per kilogram (1 J/kg). The £ad is equal to 6.24 x 10® MeV per gram, or 100 ergs per gram. One gray = 100 rad.\nAdditive Relative Risk Mod e l : The relative risk from the combined exposure to radon progeny and smoking equals the sum of the risks from each exposure considered separately. One example of an additive linear relative risk mode I is: Person-Years at Risk (PYR): In a lifetable analysis, the number of PY at risk of dying from disease, usually calculated from the time the miner enters the cohort until death or the end of follow-up. Some authors adjust the PYR for an assumed 10-year latent period for lung cancer by subtracting PYR accumulated during the first 10 years after a miner starts to work underground (see above, (Lagging)).\nR = 1+B,\nPotential Alpha Energy Concentration (PAEC): May cause biological damage during the radioactive decay of radon or thoron gases and their progeny, is measured in units called Working Levels (see below).\n# Proportional Mortality Ratio (PMR):\nThe ratio of two mortality proportions, expressed as a percentage, often adjusted for age or time differences between the two groups being compared.* Prospect ive: A study characteristic. Disease has not occurred in study groups at the start of a study.** Units of Radioactivity: Curie and BecguereI 1 curie = 2.22 x 10^2 disintegrations/minute 1 becquerel (Bq) = 1 d/sec 1 picocurie (pCi) = 2.22 d/minute Radioactive Decay: Disintegration of the nucleus of an unstable nuclide by spontaneous emission of charged particles, photons, or both. Radon (Rn) or Radon and its Progeny: Specifically refers to the \"parent\" noble gas (Rn-222), and its short-lived alpha-radiation-emitting radioactive decay products (\"progeny\" or \"daughters\"). Radon is a gas, the radon progeny are radioactive solids. Rads and rems are comparable (i.e., the quality factor (QF) = 1) when dealing with beta particles and gamma photons. The QF for alpha particles from inhaled radon progeny are generally considered to be in the range of 10 to 20.\nRetrospective: A study characteristic. Disease has already occurred in study groups at the start of a study.** Standardization: A procedure to reduce the biasing effect of a confounding variable. A feature of data analysis.**\n# Standardized Mortality Ratio (SMR):\nThe ratio of mortality rates, expressed as percentage, usually adjusted for age or time differences between the two groups being compared.** Synergism: The combined action of two factors which is greater than the sum of the actions of each of them.\nThoron: A radioactive gas (Rn-220), sometimes found in the presence of radon (Rn-222). Thoron progeny are the solid, short-lived, alpha radiation emitting decay products (progeny or daughters) of thoron gas.\nWorking Level (WL): A standard measure of the alpha radiation energy in air. This energy can come from the radioactive decay of radon (Rn-222) and thoron (Rn-220) gases. The working level is defined as any combination of short-lived radon decay products per liter of air that will result in the emission of 1.3 x 10^ million electron volts (MeV) of alpha energy.\nWorking Level Month (WLM): A person exposed to 1 WL for 170 hours is said to have acquired an exposure of one Working Level Month. The Mine Safety and Health Administration defines a Working Level Month as a person's exposure to 1 WL for 173 hours.\n# *\nTaken from Shapiro (1981) [1]. ** Taken from Monson (1980) [98]. + Taken from Thomas et a I., (1985) [99].\n# I. INTRODUCTION\nA report evaluating epidemiologic studies of lung cancer in underground miners was recently sent to the Mine Safety and Health Administration (MSHA) by the National Institute for Occupational Safety and Health (NIOSH).\nThat report concluded that prolonged exposure to radon progeny at the current standard of 4 WLM/year produced an elevated risk of death from lung cancer. It is the objective of this report to make quantitative risk estimates for various levels of cumulative exposure. In addition, other factors influencing the exposure-risk relationship will be identified and quantified whenever possible.\nThis report is based upon data collected from a cohort consisting of 3366 white underground uranium miners working in the Colorado Plateau (located within the states of Colorado, Utah, New Mexico and Arizona).\nThe actual risk estimates were computed from data on 3346 members of the cohort.\nTen original members were determined to have had no record of underground mining, four were non-white, and six had inadequate cigarette smoking i nformat ion.\nEntry into the cohort was defined by race, sex, working at least one month in underground uranium mines, volunteering for at least one medical survey between 1950 and 1960, and providing social and occupational data of sufficient detail [Lundin et al . 1971].\nNIOSH has now updated the mortality experience of the cohort through December 31, 1982. Lung Cancer mortality was defined as anyone assigned an International Classification of Disease (ICD) code of 162 or 163 (same designation in Sixth through Ninth Revisions).\nPrevious analyses of this cohort reported by Waxwei ler et a l . [1981] and Whittemore and McMillan [1983] considered follow-up only through 1977. Table 1 presents a comparison of vital status of the cohort at the end of 1977 and 1982. \n# II. PROTOCOL FOR STATISTICAL ANALYSIS\nMuch of the epidemiologic work in the past regarding the analysis of mortality in occupational cohorts has involved modified life table analysis. This form of analysis has a strong appeal due to its familiarity and ease of interpretation.\nIt is mathematically straight forward since person-years at risk are simply divided into a number of strata and age-calendar year specific mortality rates from some reference population are applied to each.\nThe U.S. population is often used as the reference population in such life table analyses.\nThis expected mortality is then compared to the observed mortality via a ratio defined as:\n# A. Type of Analysis Used\n2 o SMR; = i i j 2 E ij i\nwhere SMR = standardized mortality ratio for cause j Ojj = the observed number of deaths for cause j in stratum i and Ejj = the expected number of deaths for cause j in stratum i from reference population rates If the total number of observed deaths in all of the strata of interest is large and if the reference population is the appropriate comparison group, this would be the method of choice. No modeling would be needed in such a situation.\nHowever, after stratification by age, race, sex, calendar year, other confounders, and finally the exposure of interest, there are seldom enough observed deaths to make rates in these strata reliable.\nAnother problem frequently encountered is a fundamental difference in certain etiologic characteristics between the study population and the reference population.\nFor example, the study group may smoke at substantially different rates than the reference population.\nOften the occupational study group is \"healthier\" than the reference population due to selection criteria for employment (Enterline [1976]). This is usually referred to as the \"healthy worker effect.\"\nAn alternative to use of the modified life table approach is some form of statistical modeling. Modeling to estimate health risks is necessary when conclusions must be drawn about risk in regions of the exposure-response relationship for which data are too sparse to estimate risk directly.\nThe use of models also permits risk estimates to be simultaneously adjusted for confounders, such as age or co-carcinogenic exposures, as well as interactions between exposure and other risk factors.\nThis flexibility is particularly important in making risk estimates at relatively low cumulative exposures when using the Colorado Plateau data.\nMost miners in this cohort were exposed to high levels of radon progeny (mean exposure = 834 WLM).\nSince primary interest in risk estimates is below 120 WLM based on current exposures, some type of statistical model is essential.\nThere have been a number of types of models suggested for examination of cause-specific mortality as a function of various risk factors.\nThe two most popular types of models are the absolute risk model and the relative risk model. The absolute risk model can be written as: R(t ;z) = Rg(t) + R ( z , /?) where R9t;z) is the incidence at age t for someone with risk factors z, Rg(t) is the baseline or background incidence at age t and R(z, ) is the incremental incidence as a function of the risk factors z, and coefficients which are estimated from the data.\nThis form of risk model was not used in the risk assessment since it had been rejected due to poor fit to the U.S. uranium miner data by Lundin et al. [1979].\nIn contrast, the relative risk model generally takes the form: R(t;z) = R0 (t) R(z,0). This model assumes that excess risk is proportional to background incidence rates.\nRelative risk models have become increasingly popular in recent years and were found to provide good fits to the data from earlier follow-ups of the U.S. uranium miners cohort by Lundin et al. [1979] and Whittemore and McMillan [1983]. This type of model has been selected as the basic analytical method for this report.\n# B. The Proportional Hazards Modei\nA relative risk model which is particularly well-suited to longitudinal mortality studies is one proposed by Cox [1972].\nThis model is commonly referred to as the Cox proportional hazards model.\nA major advantage of this approach over the more common life table method is that it permits the use of internal comparison groups while controlling simultaneously for such confounders as cigarette smoking, age, and year of birth.\nIn addition, time-dependent covariates such as cumulative exposure may be incorporated into the model. This is essential in any longitudinal study where follow-up and the exposure period overlap.\nRelative risk estimates are based on rate ratios similar to those produced in the modified life table analysis.\nThat is, the Cox model operates in a dynamic framework by considering incidence rates over the entire period of follow-up.\nThe Cox model can be expressed mathematically as:\nX(t;z) = X 0 (t)exp(£z(t))\nwhere X(t;z) for this study is the age-specific lung cancer mortality rate for a miner with exposure and other risk factors represented by a covariate vector z.\nThe underlying age-specific lung cancer mortality rate for the unexposed is represented byAo(t).\nThe function exp(J3z) is generally used to model risk of death from the cause of interest which depends upon the risk factors z and the coefficients ^ which are estimated from the data.\n# C. Alternative Forms of the Risk Function\nAlthough the exponential or log-linear function exp(0z) is the usual choice of a model for risk, any positive function may be used as long as the risk function is equal to 1.0 when the coefficients are all equal to zero. The most common alternative risk functions are the linear (1 + 0z) and the power function (exp( /?1nz) = z^ ).\nAll three forms of risk functions were considered in modeling the U.S. uranium miners data.\n# D. Results of Model Development\n\n# Ident i f ic a t ion of Confounders and/or E ffe c t Mod i f iers\nCumulative exposure as measured by total WLM for each miner was the primary exposure variable. Since cigarette smoking is known to have a strong effect upon the risk of lung cancer, cumulative smoking history as measured in pack-years was also included in the model.\nAnother risk factor strongly associated with lung cancer mortality is age.\nThis was tightly controlled by using age as the time dimension t in the model A(t;z).\nThat is, the age at death of each lung cancer victim was recorded and all other miners alive and at risk were compared to him at that age.\nIn this way, the cumulative exposure to radon daughters and pack-years of cigarettes were incorporated as time-dependent covariates by calculating their values at each age of death from lung cancer. This assures that proper age-adjusted comparisons were made throughout the period of follow-up.\nA number of other variables were examined in developing the appropriate risk model.\nA list of all potential risk factors considered for inclusion in the model are provided in Table 2.\nThese variables were considered independently as potential confounders in a stepwise fashion (both backward and forward selection procedures) and also as potential effect modifiers by assessing their interaction with cumulative radon daughter exposure.\nAn attempt was made to compare the fit of each of the three models during the model development stage of the analysis.\nHowever, it soon became apparent that the linear model did not fit well over the full range of radon daughter exposures and cumulative smoking levels. In fact, the iterative solution to the likelihood equations would not converge when using the linear model when both cumulative exposure and pack-years of smoking were both entered simultaneously (either as linear or linear-quadratic forms).\nThe linear model could only be made to converge when the model was restricted to cumulative exposure below 600 WLM with no other covariates included.\nThe restricted linear model resulted in a non-significant result in this exposure range and was subsequently eliminated from consideration.\nOf the remaining two types of relative risk models (log-linear and power function), the covariates found to be most highly associated with lung cancer incidence rates were cumulative exposure (WLM), cumulative smoking (packs), and age at initial exposure (months). Table 3 illustrates the form and degree of fit as measured by the likelihood 1BGR -background radon exposure = 0.2 WLM/year BGS = background cigarette smoking = 0.005 packs/day ratio for these two models.\nThe log-linear model required the addition of quadratic terms in cumulative exposure and cigarette smoking to provide an adequate fit.\nThis was not necessary when developing the power function model.\nAs shown in Table 3, the power function model provided the best fit to the data and will be used hereafter in the risk assessment.\nSince the power function model involves the natural logarithms of cumulative exposure and cumulative cigarette smoking, zero values of these variables were not permitted.\nIn order to avoid this an estimate of cumulative background exposure was added to each miner's cumulative radon daughter and cigarette totals.\nBased upon estimates of the NCRP (Report No. 77, 1984), 0.2 WLM per year since birth were added to each miner's exposure totals. This is the estimated background exposure in the U.S. and is also the amount used by Whittemore and McMillan [1983] in an earlier analysis.\nIn a similar fashion 0.005 packs per day were added for each day since birth to the cumulative smoking totals based upon estimates of Hinds and First [1975].\nOf particular interest is the joint effect of exposure to radon daughters and cigarette smoking.\nTherefore, the interaction of radon daughter exposure and cigarette smoking was included in the multiplicative power function model.\nThe results showed a negative, borderline significant result ( |3=0.087,p=0.058). When a similar analysis was run with mortality data complete only through 1977, there was no indication of a significant negative effect. Therefore, based on more complete follow-up through 1982, the joint effect of radon daughter exposure and cigarette smoking appears to be slightly less than multiplicative but greater than additive. This is similar to the finding of Thomas and McNeill [1985] in their grouped data analysis of the five major radon daughter cohorts.\nIt is still consistent with a synergistic effect of radon exposure and cigarette smoking which is usually defined as a joint effect exceeding the sum of the individual effects.\n# Weighting Exposure Over Time\nAn important consideration in fitting any of these models was the proper time-weighting of exposure.\nSince most forms of cancer, including lung cancer, have relatively long latency periods between exposure and manifestation of the disease, some weighting of exposure over time is appropriate.\nThe most common weighting scheme is commonly referred to as lagging.\nThis involves elimination of any exposure accumulated in a specified period of years before death from lung cancer.\nThis provides a way of considering only that exposure that had a reasonable chance of causing death from lung cancer.\nObviously exposures received in the few years immediately prior to lung cancer deaths are ineffective in the exposure-response relationship.\nIn order to investigate the appropriate number of years to lag exposure in this cohort, a series of lags ranging from 0 to 12 years was used. Figure 1 illustrates the results of these trials.\nIt is evident from the improved fit, as measured by the log-likelihood of the model, that a lag of 6 years for cumulative exposure is the best choice for this analysis.\nCumulative cigarette smoking was rather insensitive to the amount of lag in the range of 0 to 12 years. Therefore, for the purpose of consistency cumulative smoking was also lagged 6 years. This contrasts to the lag of 10 years chosen by Whittemore and McMillan [1983] for these data and also by Muller et al. for the Canadian data. Their choices were somewhat arbitrary and largely based on knowledge that most cancers involve relatively long latency periods. The implications of a shorter lag will be discussed in a later section of this report.\nAn issue related to lagging of cumulative exposure and cumulative cigarette smoking is the lack of information on these variables in recent years.\nRadon daughter exposure was last updated in 1969. However, the absence of current exposure information should have minimal impact upon this analysis since over 90% of the miners in the cohort had retired from uranium mining for more than one year by 1969.\nThose few who continued mining were exposed at levels considerably less than those experienced in earlier years.\nSince cigarette smoking status was also unknown after 1969, all miners still smoking at that time were assumed to continue at their last recorded smoking rate.\nNIOSH is currently conducting a survey of radon daughter exposure and cigarette smoking status subsequent to 1969, but this information will not be available for at least another year.\nThe aim of lagging exposure is the elimination of exposure which is not etiologically responsible for lung cancer mortality. An implicit assumption in the use of this technique is that exposure changes from completely effective to completely ineffective at one instant in time. The actual form of this weighting function is illustrated in Figure 2. Because of the biological implausibi Iity of such a situation, Land [1976] proposed that the effectiveness of cumulative exposure be linearly phased in over a period of several years.\nAn illustration of such a weighting function is provided in Figure 3.\nConsequently, we tried various combinations of lagging and linear partial weighting with the combination illustrated in Figure 3 providing the best fit, i.e. a lag of 4 years followed by linear partial weighting in the period 4-10 years prior to death from lung cancer.\nThis scheme provided a fit essentially the same as that of a simple lag of six years but was chosen over lagging because of its biological plausibility. \n# INFLUENCE OF TEMPORAL FACTORS\nPerhaps the most difficult aspect of producing a valid quantitative risk assessment is dealing with the effects of various time-related factors upon the exposure-risk relationship.\nOne very important temporal influence concerns the two components of cumulative exposure itself.\nIn most longitudinal studies the quantitative exposure index is some form of cumulative exposure.\nHowever, cumulative exposure is actually the product of duration of exposure and intensity or rate of exposure.\nWhen one uses cumulative exposure in assessing risk, the implicit assumption is that high exposure rates for short periods of time are equivalent etiologically to low exposures for long periods of time, all else being equal.\nA number of investigators have examined the effect of exposure rate in the U.S. uranium miner data. Whittemore and McMillan [198]) found no statistically significant effect of exposure rate.\nLundin et al . in the 1971 monograph concluded that there was no significant evidence of an exposure rate effect in the 120-360 WLM cumulative exposure range. These investigators apparently defined exposure rate as the ratio of total cumulative exposure and duration of employment (defined as the period of time between first and last employment in underground uranium mining work histories).\nFor most forms of employment, this is the accepted definition of average exposure rate.\nHowever, underground uranium mining is a very sporadic form of employment.\nThe actual time spent underground was often a relatively small fraction of the total employment history. Therefore, exposure rate as defined by cumulative exposure divided by the number of months actually spent underground is often a very different measure than that obtained by using duration of employment in the denominator.\nConsequently, the effect of exposure rate was re-examined using the actual average exposure rate experienced while underground, eliminating any gaps in employment.\nAlthough earlier analyses using total duration of employment produced negative but non-significant results, the refined definition showed a statistically significant negative exposure rate effect (p =-0.043, p<0.001) as shown in Table 4.\nThis implies that among groups of miners receiving equivalent cumulative exposures, those exposed to lower levels for longer periods of time are at greater risk of lung cancer.\nBecause the coefficient is relatively small, however, an appreciable effect upon risk of lung cancer would not be expected unless rates were different by an order of magnitude, i.e., a miner with exposure received at a rate ten times lower than a miner of the same age, smoking habits, and cumulative exposure would have (0.1)~-043= i i o 4 or 10.4% greater risk of lung cancer.\nBecause a negative exposure rate effect is very important and potentially controversial, it was examined in more depth.\nOf particular interest was the possibility that this effect was different at low versus high cumulative exposure levels.\nConsequently, the homogeneity of this effect across the full exposure range was examined by forming two sub-cohorts: one below the mean exposure (834 WLM) and one above the mean.\nThe interaction of the exposure rate effect with these two strata was then tested. Results showed a significant interaction ( P=0.157, P=0.019). The direction of the A. Exposure-Rate Effect Background for cumulative radon daughter exposure: BGR=0.4 WLM/year Background for cumulative cigarette smoking: BGS=0.005 packs/day interaction indicated that the exposure rate effect was stronger in the lower cumulative exposure range (0-834 WLM). Specifically, a miner who received total exposure below 834 WLM at rate one tenth as great as another miner of the same age, smoking status and cumulative exposure would have a 58 percent greater risk of lung cancer.\nHowever, the increased risk would only be 10 percent at the lower exposure rate for miners in the 834-10,000 WLM range.\nAlthough a statistically significant negative exposure-rate effect had not been found previously in this U.S. cohort, there is considerable evidence of such findings in animal studies of high LET radiation. Raabe et al . [1983] reported a strong low dose-rate effect in beagles exposed to internally deposited isotopes of radium and strontium.\nRisk of bone cancer was as much as ten times as great per unit dose for low rates as compared to the highest rates used. Cross et a l . [1980] found a negative dose-rate effect for risk of lung tumors in rats exposed to airborne radon daughters. Chameaud et al. [1981] found similar results in a French study of Sprague-Dawley rats exposed to inhalation of radon decay products.\nHill et a l . [1982] found reduced dose rates of fission-spectrum neutrons produced significantly higher neoplastic transformation rates per rad in cell cultures of C3H mouse embryos. Although all of these studies show low dose-rate effects, no study as yet, animal or human, has investigated such effects at the very low dose rates currently found in well-ventilated uranium mines.\n# B. Calendar Time\nIt is well-known that mortality patterns change over time.\nSuch exogenous risk factors as the prevalence of smoking and alcohol consumption, medical care, and various life style characteristics are all influenced by a changing society.\nTherefore, the effect of calendar time upon risk estimates, often called the cohort effect, must be controlled.\nThe analysis of the U.S. uranium miners cohort was stratified by decade of birth so that miners dying of lung cancer were compared only to those members of the cohort at the same age and who were born within 10 years of the case.\nThe usual assumption in a stratified analysis is that baseline mortality rates may be different from stratum to stratum but the relat i ve risk is the same across all strata for miners with comparable risk factors.\nIn order to check this assumption, the interaction of cumulative radon daughter exposure and birth decade was examined.\nResults indicated a statistically significant positive interaction ( P=0.173,P=0.002). This implies that miners born in later decades are at a greater risk of lung cancer per unit of exposure when compared to miners of the same age born earlier.\nSince miners born in later decades were exposed at lower exposure rates, this result could be associated with the negative exposure rate effect described ear Iier.\n# C. M ultistage Theory of Carcinogenesis\nOne of the most popular theories for explaining the temporal patterns in mortality studies of carcinogenesis is the multistage model. Originally proposed by Muller [1951] and Nordling [1953] and later refined by Armitage and Doll [1961], the multistage theory predicts an increase in cancer incidence as a function of time since exposure to some carcinogen. In general, the theory proposes that a malignant tumor arises from a single cell which has undergone a series of heritable changes. The changes may be thought of as distinct stages in the carcinogenic process, each with a low probability of occurrence and a slow progression time in the absence of carcinogenic exposures.\nA carcinogen may act on any or all of the stages in this process.\nCarcinogens affecting the first stage are commonly referred to as initiators, while those affecting later stages are called promoters or progressors.\nInitiators are characterized by long latency periods between initial exposure and death, often exceeding 20 years.\nPromoters, on the other hand, usually have shorter latent periods since fewer stages must be transgressed before a malignant cell is produced.\nIt is impossible to prove whether or not the mathematical form of the multistage model actually holds in a given situation.\nHowever, a number of its predictions have been verified experimentally by Peto et al. [1975].\nTherefore, if one subscribes to some form of the multistage model, it is possible to predict whether exposure acts at an early or late stage in the carcinogenic process by examining the temporal patterns in the data. Whittemore [1977], Day and Brown [1980], and Brown and Chu [1983] have all reported the effect on excess relative risk of age at initial exposure and time since cessation of exposure.\nBy examining these factors, we may better understand the underlying cancer mechanism operative in this cohort.\n# D. Age a t I n i t i a l Exposure\nWhittemore [1977] considered the multistage model using three exposure scenarios:\nsingle exposure at one point in time, continuous exposure at a constant rate, and exposure of varying intensity.\nWhen considering the latter category (the usual occupational situation) she found that excess relative risk was a decreasing function of age at initial exposure if an early stage was affected.\nWhen a late stage is affected by exposure, however, excess relative risk is an increasing function of age at initial exposure. Day and Brown [1980] predicted the functional relationship between excess relative risk and age at initial exposure for the first four stages of a five-stage process when duration was held constant. Figure 4 illustrates their findings which are in qualitative agreement with those of Whittemore. Results of the analysis in our data, as illustrated in Table 4, indicate a positive and statistically significant coefficient for age at initial exposure (P=0.0023, P=0.003). This implies that miners initially exposed at later ages are at greater risk of lung cancer than those exposed at younger ages, all else being equal.\nSpecifically, a miner with the same radon daughter exposure and smoking history who was initially exposed ten years (120 months) later in age than another miner, would have exp(0.0023x120)=1.32 or 32% higher risk of lung cancer.\nThis result is consistent with the effect of radon daughters occurring at a late stage in the carcinogenic process.\nA similar age effect was reported by Mancuso et al. [1977] in an analysis of cancer risk in the Hanford workers exposed to who I e-body radiation.\nAn analysis of age at start of smoking amona miners resulted in a negative but non-significant coefficient (3=0. 0016,p=0.22).\nThis would imply that cigarette smoking in this cohort acted at an early to intermediate stage. It could also be consistent with the hypothesis of Doll and Peto [1978] that smoking acts at both early and late stages, which would tend to obscure predictive ability of age at start of smoking.\nA plot of the effect of age at initial exposure for both radon daughters and cigarette smoking is given in Figure 5. Day and Brown [1980] predicted the effect upon relative risk of time since cessation of exposure when a multistage model is assumed.\n# E. Time Since Cessation of Exposure\nThey found that when exposure begins some time after infancy, excess relative risk increases, peaks, and then decreases with time since termination of exposure when the first stage is affected. When the penultimate (next to last) stage is affected, relative risk strictly decreases with time after last exposure.\nFigure 6 illustrates their predictions for the effect of time since cessation of exposure on the first four stages in a five stage model with duration of exposure fixed at five years.\nIn order to investigate the effect of cessation of exposure on this cohort, all miners were identified who had indicated retirement from uranium mining during the course of follow-up. Approximately 95% of the cohort had retired for more than one year prior to 1970.\nThe average time since last exposure was 18.0 years for those miners not dying of lung cancer and 9.9 years for lung cancer cases.\nThe time in months since last exposure was entered as a time-dependent covariable in the original model containing log of exposure, log of smoking, and age at initial exposure.\nThe estimated coefficient of this term was negative and highly significant ( P=-0.0056,p<0.001).\nThus a miner's chances of surviving lung cancer increase dramatically with each year outside the mines.\nSpecifically, the model predicts that the risk of lung cancer 10 years after mining uranium is exp(-0.0056x120)=0.511 relative to someone still mining with the same cumulative exposure, smoking history, and age.\nWhen a similar analysis of time since cessation of cigarette smoking was run, the results were inconclusive.\nThe coefficient was very small and non-significant (P=0.003,p=0.75). However, since a relatively small number of miners were ex-smokers (7.7%) there is little power for detection of such an effect even if it actually exists.\nFigure 7 illustrates the effect of time since last exposure for both radon daughters and cigarette smoking.\nThe implication of these results are essentially the same as that obtained by examination of age at initial exposure.\nThe strong negative effect of time since last exposure implies that radon daughters act at a late stage in the carcinogenic process.\nThe effect of stopping cigarette smoking, while based on a small amount of data, still indicates either an intermediate stage effect or a combination of early and late stage effects. \n# E F F E C T OF T IM E S IN C E L A S T E X PO SU R E ON E X C E S S R E L A T IV E R IS K T IM E S IN C E L A S T E X P O S U R E (Y E A R S !) LE G E N D . E X PO SU R E -------------RADON S M O K IN G\n\n# IV. ERRORS IN EXPOSURE DATA AND THEIR EFFECT UPON RISK ASSESSMENT\nIn animal carcinogenesis studies, exposures or doses are usually known with a high degree of accuracy and precision. However, the same cannot be said regarding epidemiologic quantitative risk studies.\nIn most epidemiologic studies, the actual dose to target organs can only be estimated by dosimetric modeling. This is seldom attempted in quantitative risk assessments.\nThe dosimetry of radon daughter exposure is very complex, involving such factors as respiration rates, particle size distribution, deposition in the lung, and radon/radon daughter equilibrium.\nMost risk assessments are modeled as functions of some exposure index, which is the method used in this report.\nIt is the purpose of this section to estimate the magnitude of exposure errors and their effect upon quantitative risk models.\nAccording to Lundin et a l . [1971], exposures in a given mine and year were estimated in one of four ways:\n1. actual measurements 2.\ninterpolation or extrapolation in time 3. geographic area estimation 4. estimates prior to 1950 based upon knowledge of ore bodies, ventilation practices, and earliest measurements.\nThese methods will subsequently be called Methods 1,2,3,and 4. In assessing the error associated with individual exposure determinations, it is first necessary to consider the variability introduced by each of the four methods.\n# A. Magnitude of Error in Exposure Data\n\n# Method 1\nTable 5 provides a frequency count of white miners working underground from 1950-68 and the mean number of samples taken in each mine visited in those years. The Kusnetz procedure for measuring radon daughters was most often used during the period of study (Johnson and Schiager 1981). This is an area monitoring method based on alpha counts collected on a filter/pump apparatus.\nThe resulting data were generally thought to be of good quality (Lundin et al., 1971).\nData from mines in which 5 or more measurements were taken in a given year were analyzed.\nThese data followed a lognormal distribution with little change over the period 1951-1968. Prior to 1960 were taken largely by the U.S. Public Health Service, while post-1960 sampling was conducted by state mine inspectors.\nTherefore, data were separated into pre and post 1960 periods and estimates of the coefficient of variation (CV) were made for each period. Results indicated a slight but non-significant increase in CV's after 1960 (106.6% vs 118.3%).\nSince the measurements were grab samples taken at different times within each mine, the total pooled CV=112.5% over the period 1951-1968 is assumed to include sampling errors, counting errors, and environmental fluctuations over time. This estimate agrees well with the CV of 110% found in an independent study of U.S. mines in the period 1973-79 when exposure levels were much lower (Schiager et al. 1981).\nIn other studies, however, an average CV of 30% was reported for area samples in Canadian mines (Makepeace and Stocker 1980) while fluctuations of 20-30% around daily means were found for radon measurements in non-uranium Norwegian mines (Berteig and Stranden 1981).\n# Method 2\nIn order to assess the error in interpolating for gaps in sampling of 1 to 3 years, a simulation procedure was used.\nMines having the longest periods of continuous annual measurements were identified.\nThen the even years' averages wee omitted and the average of the two adjacent years was substituted.\nIn this way it was possible to compare the observed annual average with the expected average had that year been missing.\nThis strategy was repeated by imposing three year gaps in the data and again using the average of adjacent years to estimate the three intervening years.\nThe error variance attributable to Method 2 was then calculated by:\n0 2 , S dofliOj/E.»2 i N-1\nwhere 0j = actual measurements for intervening years Ej = interpolated values estimated by average of adjacent years.\nThe resulting CV was 120.8% for 1 year interpolation and 137.3% for 3 year interpolation. Since these results were not significantly different, they were pooled to yield a CV=131.9%.\n# Method 3\nThis method used annual mine averages in the same geographic locality to estimate radon daughter levels in mines for which Methods 1 and 2 could not be used.\nIn order to assess the error associated with this method, four of the uranium mining localities with the greatest number of annual measurements were selected. A simulation procedure similar to that used for Method 2 was employed.\nAnnual averages for selected mines in these localities were omitted for 1 to 4 years. The averages for mines in the nearest district were substituted as the expected radon level if the annual average actually had been missing.\nThe error variance was calculated in the same way as Method 2. The resulting CV was 148.6% for this method.\n# Method 4\nNo measurements were available in the period prior to 1950.\nTherefore, the estimates made using knowledge of ore bodies, ventilation, and earliest known measurements in these mines could not be verified. These estimates comprised less than 6% of the 34,120 annual averages used in exposure assessment.\nIn addition, since only 8 percent of the total underground exposure time for the cohort occurred prior to 1950, the influence of these measurements should be minimal. However, since the error for this method was probably the greatest of the methods used, we estimated the overall CV for Method 4 to be 25% greater than that for Method 3, i.e. CV=186%.\nTable 6 shows the number of annual averages for each of the four methods. Actual measurements comprised only about 10% of the data.\nIn order to obtain an overall estimate of the relative error, a weighted average of the CV's for each method was calculated based on the number of determinations for each method. The resulting overall CV=137%.\nThe error associated with each miner's cumulative exposure can then be calculated using our estimate of the error in each radon daughter level (WL). The total cumulative exposure (WLM) for each miner is obtained from: wlm = S ( « -¡jH u a io v ■, j where WL j j is the estimated exposure for mine i in year j and UGMONjj is the number of months spent underground in mine i during year j. The variance of WLM assuming independence of WL j j is then:\nVar(WLM) = X (UGMON..)2 var (WL..) i , j 1J 1J = 2 (UGMON..)2 (CV)2 (WL..)2 . . iJ ij ' -J 1 1\nwhere CV is the coefficient of variation for the estimated exposure WL j j .\nIf we substitute our estimate of the overall CV=137% and use total cumulative exposure divided by total months underground (WLM/TOTMON) as an estimate of WL j j for each individual miner, the average CV for cumulative exposure (WLM) is 0.97 or a relative standard deviation of 97% of the total WLM for each miner. Since radon daughter measurements were taken in different areas of each mine and often at different times of the day or week, we will assume that the variance in these measurements reflects the variance in exposure levels among individual miners, i.e.\n# Var(»LMij).\nwhere 0jj|< = variance in exposure measurement for miner k in mine i and year j . \n# B. E ffe c t on R ela tiv e Risk Estimation of Exposure Measurement Errors\nThere appears to be a general impression that errors in exposure measurements usually cause an underestimation of relative risk. Indeed, Bross [1954] originally demonstrated that if misclassification was equal in two comparison populations, one would tend to underestimate differences in proportions of diseased persons. Keys and Kihlberg [1963] qualified this concept by showing that relative risk is underestimated when misclassification errors are independent of disease and exposure relationships.\nIn general, it has been shown by Copeland et a l . [1977] among others, that relative risk estimates are biased too low in the presence of non differential misclassification (equal misclassification of disease in both exposed and unexposed groups).\nLittle work has been done concerning the effects of errors in continuous measures of exposure upon relative risk estimates obtained from statistical models.\nIt is this situation that is a potential problem to the analysis in this report. Prentice [1982] introduced a method for dealing with errors in individual exposure measures when using the Cox proportional hazards model.\nPrentice, and more recently Hornung [1985], have shown that the direction of bias in relative risk estimation depends upon the error distribution and the shape of the exposure-response model.\nIn general, when the variability in individual exposure errors increases with the level of exposure and the relative risk model is supra-linear (curving upward), relative risk will actually be overestimated when exposure errors are ignored.\nThe popular log-1 inear or exponential risk function is an example of a model which may often overestimate relative risk in the presence of errors whose magnitude increases with increasing levels of cumulative exposure.\nAs was reported earlier, the log-linear model did not provide the best fit to the data.\nInstead, the power function model which involved the logarithms of cumulative exposure and cumulative cigarette smoking provided a better fit.\nThe effect upon risk estimates using this model was investigated when errors in exposure are lognormal as indicated in the previous section.\nWithout presenting the statistical details, it is sufficient to say that under these conditions (power function model and lognormal distribution of exposure errors) the effect upon relative risk estimates is negligible.\nIf the exposure measurements were generally higher than those actually experienced by the miners, as mentioned in the 1971 Monograph, relative risk per WLM would be underestimated regardless of the distribution of exposure measurement errors.\nIn summary, the degree of error in individual exposure measurements was quite high, an estimated CV of 97%. If, however, these individual errors were lognormally distributed about the annual average concentration in each mine, the degree of bias in relative risk estimates generated by the power function model would be minimal.\nRegardless of the form of the error distribution, the relative risks generated by the exposure-response model would be too low if the exposure measurements were systematically too high. Therefore, examination of the pattern of error in the exposure data would suggest that relative risks produced by the power function model are either unbiased or possibly a bit low.\n# V. QUANTITATIVE RISK ESTIMATES\nThe previous sections have outlined the protocol for the risk model development, the selection of an appropriate quantitative risk model, the temporal factors influencing risk estimation, and the magnitude and effect of exposure measurement errors.\nThese are factors requiring careful study before attempting to make valid quantitative risk estimates.\nIn most risk assessments, results are reported relative to some unexposed population.\nIn animal studies, a control group is generally used for this purpose.\nIn life table, analyses expected mortality is obtained from some standard population, often that of the U.S.\nThe problems inherent with the use of such external referents have been well documented [Enterline 1976]. Although a subcohort of miners unexposed to radon daughters would be ideal for a referent group, there were no unexposed miners in the U.S. cohort. Since the proportional hazards model uses internal comparisons in generating risk estimates, risk projections relative to an unexposed population necessarily involve an extrapolation to zero exposure.\nIn the case of the power function model, a background exposure of 0.2 WLM/year of age was added to every miner's cumulative total.\nAll risk estimates are relative to someone exposed to these background rates. Therefore, quantitative relative risk estimates are somewhat sensitive to the choice of a background exposure rate.\nOne way of checking the appropriateness of the model is to divide cumulative exposure into discrete intervals and calculate lung cancer risks in each interval relative to risks experienced in the lowest interval.\nIn this way, relative risk estimates are free of any exposure-response function.\nIf the risk model then fits the risk estimates in the selected intervals, one would be assured that the model is appropriate for quantitative risk estimation.\nThe cumulative exposure intervals chosen for this analysis were: less than 20 WLM, 20-120, 120-240, 240-480, 480-960, 960-1920, 1920-3720, and greater than 3720 WLM.\nRisk estimates in each interval are calculated relative to the risk in the interval less than 20 WLM. and are plotted at the mean exposure in each interval: 66.6, 179, 351, 698, 1352, 2579, and 5416 WLM, respectively.\nFigure 8 illustrates how these interval estimates are uniformly lower than those produced by the risk model when using 0.2 WLM/year as a background rate of exposure. The shape of the risk model, however, shows remarkably good agreement with the pattern of relative risk estimates in the selected intervals.\nThis implies that the quantitative risk model is appropriate exclusive of the intercept.\nThis could be due to either an improper choice of baseline exposure rate or the fact that all interval estimates are relative to exposure in the lowest interval, 0-20 WLM.\nIf there is some level of excess risk in this interval relative to an actual unexposed population, the interval estimates would be too low.\nThe cumulative exposure of 0.2 WLM/year is an estimate is an estimate of the background exposure in the overall U.S. population [NCRP Report No. 77, 1984], Exposures near ore-bearing lands are known to be considerably higher than average [NCRP Report No. 45, 1975].\nTherefore, it is probable that background exposures in the Colorado Plateau area are higher than average U.S. levels. \n# DOTTED LINES AND VERTICAL BARS REPRESENT 95% CONFIDENCE LIMITS\nIn the interest of using a background more in line with exposures received by persons living in the Colorado Plateau, the background exposure was increased to 0.4 WLM/year. This produced a quantitative risk model that agreed very well with the interval estimates, as can be seen in Figure 9.\nUsing this model, relative risk estimates were calculated for cumulative radon daughter exposures in the range 30 to 120 WLM corresponding to exposure levels of from one to four WLM/year over a 30-year working lifetime.\nThese estimates range from a relative risk of 1.42 at 30 WLM to 2.07 at 120 WLM compared to someone of the same age and smoking habits with a cumulative lifetime background exposure of 24 WLM and a background exposure rate of 0.4 WLM/year.\nThese estimates (0.9 to 1.4 excess relative risk per 100 WLM) are slightly higher than those reported by Muller et al. [1983] for the Ontario miners, but somewhat less than the estimates of Radford and Renard [1984] for the Swedish iron miners.\nObviously, these estimates are subject to the usual caveats concerning extrapolation from higher cumulative exposures and exposure rates.\nBecause relatively few data are currently available in this cohort below 120 WLM (10 lung cancer deaths out of 709 miners), there may be some doubt that the model used actually is appropriate at these low levels.\nHowever, the pattern of relative risk estimates produced in each of the categorized exposure levels would suggest that this model fits the data well in range of 60 to 6000 WLM. \n# Magnitude and Effect of Errors in Exposure Measurements\nAnalyses of the errors associated with the four methods of estimating uranium mine exposure levels indicated a lognormal distribution of errors with the relative standard deviation or CV=97 percent.\nAlthough errors of this magnitude may cause overestimation of relative risk when using the log-linear risk model, the better-fitting power function model is generally insensitive to errors of this type.\nIn fact, if estimated exposure levels were systematically higher than those actually received by the miners [Lundin et al. 1971], relative risks per unit WLM would be underestimated for this data.\n# Q u a n tita tiv e Risk Estimates\nPresent day radon daughter exposures are considerably less than those experienced in the past by uranium miners.\nThere is also current interest in low-level exposure to the general population from indoor radon and its decay products.\nConsequently, the primary cumulative exposure range of interest in risk assessment appears to be below 120 WLM. Although approximately 20 percent of the cumulative exposures in this study were below this level, there have been only 10 lung cancer deaths among this subgroup as of the end of 1982. Until this cohort is followed to extinction, epidemiologic models such as that produced in this report will be necessary to evaluate the risk of lung cancer mortality at these lower exposures.\nThe model developed for this report provides a very good fit to the data in the range 60 to 6000 WLM.\nIt seems reasonable that predictions based upon this model would be reliable at least for occupational exposure to adult white males.\nThere is little or no mortality data available regarding women and children.\nThe risk estimates provided in Table 7 are presented as an evaluation based upon careful consideration of all factors thought to influence such long-term mortality studies.\nAll of the caveats associated with such evaluations apply to some degree to these results. Exclusive of background exposure. 2Risks are calculated using exposure rate interaction model in Table 6 relative to miners of the same age and smoking habits with a cumulative lifetime background exposure of 24 WLM and background exposure rate of 0.4 WLM/year.\n# APPENDIX III\n\n# A. Introduction\nThis appendix contains examples of engineering control methods that can be used to reduce miners' exposure to radon progeny in underground uranium mines, although the same methods are applicable to other hard rock mines. Many of these control methods have been traditionally used in uranium mines, yet only recently have researchers (primarily from the Bureau of Mines) studied the efficacy of these methods [Bates and Franklin 1977;Bloomster et al. 1984aBloomster et al. , 1984bFranklin et al. 1975aFranklin et al. , 1975bFranklin et al. , 1977Franklin et al. , 1981Franklin et al. , 1982Steinhausler et al. 1981].\n# B. Meehan i caI Vent i I a t i on\nMechanical ventilation is the primary and most successful technique for reducing exposure to radon progeny. Average measurements of 2 to 200 working levels (WL) of radon progeny were common in U.S. uranium mines during the early 1950's before mechanical ventilation became prevalent [Lundin et al. 1971].\nIn contrast, during 1979 and 1980, the average concentrations of radon progeny recorded by MSHA ranged from 0.30 to 0.46 WL in the production areas of 61 underground uranium mines [Cooper 1981]. Thus the concentration of radon progeny in U.S. uranium mines has been greatly decreased, mainly because of improved ventilation. Sweden has also successfully reduced radon progeny concentrations in mines with improved mechanical ventilation; the average annual exposure for nonuranium miners in Sweden decreased from 4.7 working level months (WLM) in 1970 to 0.7 WLM in 1980 [Snihs 1981].\n# General P rin c ip le s\nDilution ventilation in large mines consists of primary and secondary ventilation systems.\nIn the primary system, fresh air is brought into the mine either through separate air shafts or through mine entrances used for miner access and equipment transport. The air can be blown in by a fan located at the surface or drawn in by a fan located inside the mine. Once in the mine, the air is blown or drawn through the main active passageways and then is pushed or drawn out of the mine through special ventilation shafts or openings used to remove ore.\nThe secondary or auxiliary ventilation system provides fresh air to miners working in areas that include stopes and faces where access comes from a single shaft or drift and thus the work area is a dead end. For these areas, the air is often removed through the same shaft that was used to bring in the air. The source of fresh air for the secondary system is provided from the primary air system in the main passageway.\nTo prevent mixing fresh air and contaminated air in the shaft or drift leading to the dead end, the secondary system usually consists of ductwork with a fan to blow or exhaust fresh air from the main passageway to the face. The contaminated air then passively returns to ENGINEERING CONTROL METHODS the main passageway (because of a pressure gradient) through the shaft without contaminating the supply air. The contaminated air at the stope may also be brought back to the main passageway through a second duct and fan system. Once returned to the main passageway, the contaminated air joins the primary exhaust air stream which is then carried out of the mine.\n# Designing a Dilution Ventilation System\nVentilation requirements must be considered when planning and designing the mine. Adding mine ventilation as an afterthought once the mine has been designed or completed is usually more expensive and less efficient. Consideration should be given to the following when designing the ventilation plan for a mine [Ferdinand and Cleveland 1984;Bossard et a I. 1983]:\n• Identify the outline of the ore body that will be mined;\n• Determine the rate of emanation of radon from the rock in which the ore occurs;\n• Place as much of the primary ventilation system as possible including entrances and passageways in barren ground (i.e., ground not containing ore);\n• Set up passageways so that a split or parallel system of ventilation can be used;\n• Set up the mine so that working faces ventilated in a series are minimized;\n• Design the mine so that air inlets are located on one side of the ore body and exhaust airways on the opposite side of the ore body;\n• Design the mine so that the distances ventilation air travels in the mine are minimized (reduce or eliminate reentrainment and short ci rcui ts);\n• Design the mine so that adequate volumes of air can be provided without having high pressure drops across air controls in haulage and production areas;\n• Design the ventilation system to account for increasing concentrations of radon gas, and therefore radon progeny, since as the mine ages there will be more surface area for gas exchange into the mine; and\n• Consider control devices, fans, push-pull systems, and minimizing leaks when designing the system. The primary ventilation system delivers fresh air for the secondary air system and removes contaminated air from the secondary air system. The design of the primary air system is discussed in the following paragraphs.\na. S p lit or P a ra lle l V e n tila tio n Systems A \"split\" or \"parallel\" ventilation system involves providing all or just a few working areas with fresh air that has not been previously used to ventilate other working areas. After the working areas are ventilated, the air is then pushed or drawn back into the primary system where it is moved out of the mine. By contrast, in a \"series\" ventilation system, all areas are ventilated by a single continuous air circuit.\nThe advantages of a split or parallel system include the reduction of both the residence time and cumulative air contamination [Ferdinand and Cleveland 1984]. A series system, on the other hand, has several disadvantages.\nIn addition to its long residence air times and a cumulative build-up of air contaminants from one area to another, other disadvantages include the following:\n• High air velocities which are often required;\n• Higher power costs associated with moving air at high velocities because of increased static pressures, unless additional ventilation shafts are constructed [Rock et al. 1971]; and\n• The potential spread of toxic gases to all areas of the mine in the event of a fi re.\nHowever, to keep residence time down in a split or parallel ventilation system, the air velocities to the multiple drifts must be maintained. This will increase the fan and power requirements; additional ventilation shafts may also be necessary.\n# b. Control Devices\nSliding door regulators are used to prevent air from passing where miners and equipment need to pass through periodically. The problem with doors is that to be effective they must be closed after being used. Doors must also be well-constructed to remain secure with repeated usage; steel doors in substantial frames are most commonly used in Canada [Rock and Walker 1970].\n# c. Pushing Versus P u llin g V e n tila tio n Systems\nThe pressure on the air intake side of a mine is always greater than on the exhaust side regardless of whether a pushing or pulling ventilation system is used. The difference is that the intake side\n# Primary Ventilation System\npressure is greater than atmospheric pressure for a pushing system, whereas in an exhaust or pulling system, the pressure on the intake side is below atmospheric pressure.\nExhausting (pulling) offers some advantages over a pushing system. For example, forcing air into haulageways and escape areas often requires air locks and other equipment. Exhaust systems draw air from these locations without the need for air locks and remove air from the mine through special airways to exhaust fans.\n# . Secondary ( A u x ilia r y ) V e n tila tio n System\nThe secondary (auxiliary) ventilation system brings sufficient fresh air to the working area from the primary air system without mixing it with the returning contaminated air from the face.\n# a .\nUse o f Ducts Another advantage of an air-blowing system is that it increases pressure. Measurements of radon gas content in air exhausted from mines have shown that the radon gas emitted into the atmosphere was 20% less with the air-blowing system than with an exhaust system [Franklin 1981]. This indicates that less radon gas diffused into the ventilated areas when an air-blowing system was utilized than when an exhaust system was used.\n# c . Exhaust Duct System (P u ll System)\nIn the exhausting or pulling system, contaminated air is drawn from the working face by a duct that runs from the face to the main passageway in the primary air system through the access tunnel. Fresh air is then drawn into the access tunnel toward the work area by the pressure gradient created by removing air. Exhausting (pulling) air from the face instead of blowing (pushing) offers the fo 11ow i ng advan tages:\n• Fresh incoming air is maintained in the tunnel used by miners to access the active stope, and \n# d . Push-Pu11 System\nA push-pull system contains two ducts in the accessway, one for pushing clean air to the face and the other for exhausting air from the face back to the primary air system. This system has many of the advantages of both the push and the pull systems including the following:\n• The blowing of air that sweeps across and ventilates the active face, thus providing good dilution in work areas;\n• The efficient collection of contaminants near the work face; and\n• Reducing the contamination of air in the access tunnel.\nThe main disadvantages are the cost and that it occupies more drift area [Rock et al. 1971].\nThe amount of radon gas diffusing into mine spaces from interstitial rock is dependent on the pressure in the mine space. The lower the atmospheric pressure in the mine space as compared to the pressure in the interstitial rock, the more radon gas will pass from the rock to the mine space. Conversely, the greater the pressure in the mine space as compared to the rock, the less radon gas will seep into the mine space. Overpressurization and mine pumping are two control measures which take advantage of this principle to reduce concentrations of radon gas.\nIn overpressurization, more ventilation air is pushed into mine spaces than is removed. Although Edwards and Bates [1980] have stated \"nothing that we have found provides mining companies with sufficient guidelines for applying the overpressurized ventilation system effectively,\" they conducted a mathematical study of overpressurization and drew the following conclusion: overpressurization does decrease the radon flux. It was estimated that a 2% pressure differential in a sandstone matrix would result in a 50% reduction in radon flux with mine sink lengths of 100 meters or less. A mine sink is an area either in the mine itself or a naturally occurring space or lattice in the matrix where the interstitial air can flow.\nIf the distance between the sink and the mine space approaches 200 meters, the benefit of overpressurization is lost. Because of the dramatic increase in radon gas in the sink area during overpressurization of work areas, no miners should be allowed in those sinks without proper respiratory protection. However, many open spaces that can serve as sinks are filled in and cannot be occupied.\nThe Bureau of Mines is gathering information on the effects of overpressurization in mines. Data from the pressurization of an enclosed chamber in a mine indicated that the radon concentration was 99% lower than the concentration under static conditions and 92% lower than the concentration under controlled ventilation conditions [Bates and Franklin 1977],\nIn a study by Schroeder et al . [1966] of mine areas that were pressurized by 10 mm of mercury, the radon flux decreased from 5 to 20 fold as compared to normal ventilation conditions.\nIn mine pumping, a negative pressure is created in the mine space by sealing air intake openings and permitting the exhaust fans to operate. This is done during an offshift when no miners are in the mine. Because of the negative pressure created in the mine with respect to the surrounding rock, radon is drawn into the mine space from the inter stitial rock at a rate higher than would occur under static conditions. The air intakes must be opened well before miners enter the mine to permit the ventilation system to remove the radon gas and radon progeny that have accumulated in the mine spaces. After this accumulation has been removed, the mine spaces should have lower concentrations of radon gas (and therefore radon progeny) when the miners reenter the mine. This is because much of the radon gas in the surrounding interstitial rock has been removed and is not available to diffuse into the mine working areas. However, monitoring of these areas would be required prior to allowing miners to enter. More studies are needed to determine the effectiveness of this control procedure [Bates and Franklin 1977].\n# Overpressurization and Mine Pumping\n\n# activities.\nSummers et al. [1982] tested the efficacy of this procedure and found that the amount of radon gas escaping through the surrounding rock was insufficient to warrant the uniform use of a wall sealant, provided that all cracks, fissures, and holes were sealed to prevent major leaks. \n# . Membrane S ealants Used on Bulkheads\n\n# . N egative A ir Pressure Behind a Bulkhead\nA slight negative pressure behind the bulkhead of about 0.03 cm water with respect to active areas will prevent radon gas leaks into fresh ventilation air [Thomas et al. 1981 (1) covering the backfill with one meter of clean sand, (2) sealing the surface of the tailings, (3) using a bulkhead to seal the backfilled stope and maintaining a negative pressure behind the bulkhead, and (4) using nonradioactive materials as backfill instead of mill tai Iings.\n# . E ffic ie n c y\nIn summary, backfilling with uranium tailings can be as effective as bulkheading in reducing radon progeny emissions, although it is more costly. Because high radon progeny concentrations are emitted from wet backfill and during the backfilling process, backfilling should not be used in active mine areas and miners should be protected from overexposure during backfilling operations.\n# E. S ealants Used on Mine W alls\nThis section describes sealants used as diffusion barriers against radon gas, including how the sealants are applied and the best materials used as sealants. Also, the effectiveness of sealants for reducing radon emanation and exposure will be discussed. \n# G. Automation\nAnother radon progeny control method is increased automation.\nTechniques such as robotics that minimize the time the miner spends in the high exposure areas of the mine and in activities such as drilling, blasting, or loading ore, will decrease the miner's radiation exposure. Although, at present, robotics has a limited place in the mines, it may be possible in the future to further automate the ore mining process.\n1. Two different sampling days are randomly selected from each 2-week block of t ime.\n2. The stations within a cluster are to be sampled on the same workdays and work shifts. All stations within a cluster are to be alternately sampled, seven times on each sampling day, each time in independent random order. During the work shift, the seven periods for sampling of the entire cluster shall be equally spaced in time. For example, the three stations A, B, and C could be considered a cluster and sampled as ABC, BCA, ACB, CBA, CAB, BAC, and ACB during seven successive intervals of approximately equal durations.\nIf it is not feasible to sample in this manner, then sampling can be conducted along the most efficient path but with a different, randomly determined starting point on each day (e.g., BCA, BCA,..., BCA during one sampling day and ABC, ABC,..., ABC or CAB, CAB,..., CAB during other sampling days).\n3. The estimated average work shift concentration (ftj) for each sampling day (i = 1,2,...12) is computed from an analysis of the seven grab samples taken on that day. Formulae for this computation are contained in section G. 4. Whenever a; for a particular station exceeds 0.14 WL, then that station shall be resampled the next workday.\n[Note:\nIn this case, f t ; = and sampling on the \"next workday\" (day B) is in addition to the two randomly selected sampling days required in a 2-week block of time.] a.\nI f oLq (the estimated average work shift concentration on the next workday) is < 0.14 WL, then exposure monitoring shall continue as described starting at section C,1. b. 'If also exceeds 0.14 WL, then:\n(1) steps shall be taken to reduce the radon progeny concentration in that work area by implementing work practices and engineering controls, (2) respiratory protection shall be required for all miners entering that work area, and (3) grab sampling as described in section C,2 shall be conducted on a consecutive daily basis.\nGrab sampling shall continue on a consecutive daily basis until the estimated average work shift concentrations on any two consecutive workdays (ft^ and are both < 0.10 WL. When and are both < 0.10 WL, then the requirements for respiratory protection are waived and exposure monitoring can revert to the schedule described starting at section C ,1. [Note: A new reference period shall begin at this time, requiring 12 randomly selected sampling days, the first of which is to be coded as i = 1.] This criterion (as discussed in section H,2) serves to provide early confirmation that the corrective steps taken by the mine operator have been effective in limiting the average work shift concentration of radon progeny to a level not exceeding 1.5 times the recommended exposure limit (REL) of 1/12 WL.\n# G. Statistical Considerations and Data Analysis Formulae\nThe following are the statistical notations used in the sampling strategy: Cjj = measured concentration of radon progeny in the jth grab sample taken on the ith sampling day, where j = 1,2,...,7 for each day and i = 1,2,...,12 (2 workdays selected at random from each of six consecutive blocks of time).\n# c>\\j\n= measured concentration of radon progeny in the jth grab sample taken on day A, where j = 1,2,...,7.\n# CBj\n= measured concentration of radon progeny in the jth grab sample taken on the next workday following day A, where j = 1,2, ■ ■ •,7. than 0.14 WL on two consecutive workdays, substantial evidence exists that the long-term average work shift concentration exceeds 1/12 WL. Therefore, when aA and ftg both exceed 0.14 WL in a work area, NIOSH recommends that radon progeny concentrations be reduced in that work area by implementing work practices and engineering controls, and that the use of respiratory protection be required for all miners entering that work area. These recommendations are also made when the 95% lower confidence limit for the long-term average work shift concentration (LCL) exceeds 1/12 WL (see section D,4).\n# Return to Compliance with the REL\nThe NIOSH sampling strategy uses criteria with approximately 90% confidence for an initial determination that a work area is tentatively back to compliance with the REL. Specifically, estimated average work shift concentrations from two consecutive workdays (i.e., and ftg) in which both are < 0.10 WL was chosen as a criterion that demonstrates reasonable evidence that the average radon progeny concent rat ion is bei ng cont roI led to < 0.125 WL (i.e., 1.5 t imes the REL). Given the levels of intraday and interday variabilities observed in the Johnson [1978] data set, a work area with an average work shift concentration of 0.125 WL (i.e., 50% above the REL of 1/12 WL) has 0.90 probability to have one or both of a pair of consecutive estimated average work shift concentrations above 0.10 WL. This \"2-day\" decision rule limits the magnitude with which a work area's average work shift concentration may exceed 1/12 WL and be undetected. This rule also has the advantage of permitting an early return to normal operations after a period of corrective actions to reduce exposure concentrations, at the expense of having less than high confidence that the REL is not being exceeded by more than 50%. However, only a small proportion of time passes until the next sampling day (as specified in the sampling strategy relative to the year), so that the 2-day rule limits the contribution of a temporarily excessive exposure in a work area to a miner's cumulative annual exposure.\nAt a later time, the lower confidence limit criterion for noncompliance determined after 12 randomly selected sampling days (i.e., LCL > 1/12 WL) would be likely to detect a statistically significant increase above the REL if the long-term average work shift concentration were as high as 0.125 WL.\n# Less Frequent Exposure Monitoring\nThe upper confidence limit criterion (i.e., UCL < 1/12 WL) gives 95% confidence that the long-term average work shift concentration is not above 1/12 WL, under the assumption that aj's exhibit log-normally distributed random variations.\nThe additional requirement that &j and &j+i do not exceed 0.14 WL is meant to detect a temporarily or periodically high average work shift concentration (i.e., high aj's that are not sustained for the full block of time from which 12 sampling days were selected). When both of these requirements are met, only 2 randomly selected sampling days are then required per 26-week block of t ime.\n2 0 1 UCL< 0.063 WL gives greater than 95% confidence that the long-term average work shift concentration (a,) is < 0.063 WL (i.e., a. is no larger than 75% of the REL), under the assumption that ftj's exhibit log-normally distributed random variations. Under the additional assumption that geometric standard deviations (GSDs) for intraday and interday (log-normal) variability are similar to those reported in Johnson [1978], the criterion that &12 (the estimated average work shift concentration on the last of the 12 sampling days) be < 0.033 WL gives 95% confidence that a projected future reference period would have a long-term average work shift concentration < 0.063 WL.\n# Cessation of Exposure Monitoring\n2 0 2 reported [Meyer et al. 1975]. However, several recent studies suggest that this is not a practical concern, at least not in healthy individuals [Bjurstedt et al. 1979;Arborelius et al. 1983;Dahlback and BalId in 1984].\nTheoretically, the increased fluctuations in thoracic pressure caused by breathing with a respirator might constitute an increased risk to subjects with a history of spontaneous pneumothorax.\nFew data are available in this area. While an individual is using a negative-pressure respirator with relatively high resistance during very heavy exercise, the usual maximal-peak negative oral pressure during inhalation is about 15-17 cm of water [Dahlback and Balldin 1984]. Similarly, the usual maximal-peak positive oral pressure during exhalation is about 15-17 cm of water, which might occur with a respirator in a positive-pressure mode, again during very heavy exercise [Dahlback and Balldin 1984]. By comparison, maximal positive pressures such as those during a vigorous cough can generate 200 cm of water pressure [Black and Hyatt 1969]. The normal maximal negative pleural pressure at full inspiration is -40 cm of water [Bates et al. 1971], and normal subjects can generate -80 to -160 cm of negative water pressure [Black and Hyatt 1969]. Thus while vigorous exercise with a respirator does alter pleural pressures, the risk of barotrauma would seem to be substantially less than that of coughing.\nIn some asthmatics, an asthmatic attack may be exacerbated or induced by a variety of factors including exercise, cold air, and stress, all of which may be associated with wearing a respirator. While most asthmatics who are able to control their condition should not have problems with respirators, a physician's judgment and a field trial may be needed in selected cases.\n# Cardiac E ffe c ts\nThe added work of breathing from respirators is small and could not be detected in several studies [Gee et al. 1968;Hodous et al. 1983]. A typical respirator might double the work of breathing (from 3% to 6% of the total oxygen consumption), but this is probably not of clinical significance [Gee et al. 1968].\nIn concordance with this view, several other studies indicated that at the same workloads heart rate does not change with the wearing of a respirator [Raven et al. 1982;Harber et al. 1982;Hodous et al. 1983;Arborelius et al. 1983;Petsonk et al. 1983].\nIn contrast, the added cardiac stress due to the weight of a heavy respirator may be considerable.\nA self-contained breathing apparatus (SCBA) may weigh up to 35 pounds.\nHeavier respirators can reduce maximum external workloads by 20% and similarly increase heart rate at a given submaximal workload [Raven et al. 1977].\nIn addition, it should be noted that many uses of SCBA (e.g., for firefighting and hazardous waste site work) also necessitate the wearing of 10-25 pounds of protective clothing.\n# Miscellaneous Health Effects\nIn addition to the health effects (described above) associated with wearing respirators, specific groups of respirator wearers may be affected by the following factors: (1) Corneal Irritation or Abrasion Corneal irritation or abrasion might occur with the exposure. This would, of course, be a problem primarily with quarter-and half-face masks, especially with particulate exposures. However, exposures could occur with full-face respirators because of leaks or inadvisable removal of the respirator for any reason. While corneal irritation or abrasion might also occur without contact lenses, their presence is known to substantially increase this risk.\n# .(2) Loss or Misplacement of a Contact Lens\nThe loss or misplacement of a contact lens by an individual wearing a respirator might prompt the wearer to remove the respirator, thereby resulting in exposure to the hazard as well as to the potential problems noted above.\n# (3) Eye Irritation from Respirator Airflow\nThe constant airflow of some respirators, such as powered air-purifying respirators (PAPR's) or continuous flow air-line respirators, might irritate the eyes of a contact lens wearer.\n# B. Suggested Medical E valu atio n and C r i t e r i a f o r R e s p ira to r Use\nThe following NIOSH recommendations allow latitude for the physician in determining a medical evaluation for a specific situation. More specific guidelines may become available as knowledge increases regarding human stresses from the complex interactions of worker health status, respirator usage, and job tasks. While some of the following recommendations should be part of any medical evaluation of workers who wear respirators, others are applicable for specific situations.\n• A physician should determine fitness to wear a respirator by considering the worker's health, the type of respirator, and the conditions of respirator use.\nThe recommendation above leaves the final decision of an individual's fitness to wear a respirator to the person who is best qualified to evaluate the multiple clinical and other variables. Much of the clinical and other data could be gathered by other personnel.\nIt should be emphasized that the clinical examination alone is only one part of the fitness determination. Collaboration with foremen, industrial hygienists, and others may often be needed to better assess the work conditions and other factors that affect an individual's fitness to wear a respirator.\n• A medical history and at least a limited physical examination are recommended.\nThe medical history and physical examination should emphasize the evaluation of the cardiopulmonary system and should elicit any history of respirator use. The history is an important tool in medical diagnosis and can be used to detect most problems that might require further evaluation. Objectives of the physical examination should be to confirm the clinical impression based on the history and to detect important medical conditions (such as hypertension) that may be essentially asymptomatic.\n• While chest X-ray and/or spirometry may be medically indicated in some fitness determinations, these should not be routinely performed.\nIn most cases, the hazardous situations requiring the wearing of respirators will also mandate periodic chest X-rays and/or spirometry for exposed workers. When such information is available, it should be used in the determination of fitness to wear respirators.\nData from routine chest X-rays and spirometry are not recommended solely for determining if a respirator should be worn. In most cases, with an essentially normal clinical examination (history and physical) these data are unlikely to influence the respirator fitness determination; additionally, the X-ray would be an unnecessary source of radiation exposure to the worker. Chest X-rays in general do not accurately reflect a person's cardiopulmonary physiologic status, and limited studies suggest that mild to moderate impairment detected by spirometry would not preclude the wearing of respirators in most cases. Thus it is recommended that chest X-rays and/or spirometry be done only when clinically indicated.\n• The recommended periodicity of medical fitness determinations varies according to several factors but could be as infrequent as every 5 years.\nFederal or other applicable regulations shall be followed regarding the frequency of respirator fitness determinations. The guidelines for most work conditions for which respirators are required are shown in • The respirator wearer should be observed during a trial period to evaluate potential physiological problems.\nIn addition to considering the physical effects of wearing respirators, the physician should determine if wearing a given respirator would cause extreme anxiety or claustrophobic reaction in the individual. This could be done during training while the worker is wearing the respirator and is engaged in some exercise that approximates the actual work situation.\nPresent OSHA regulations state that a worker should be provided the opportunity to wear the respirator \"in normal air for a long familiarity period...\" [29 CFR 1910.134(e)( 5)].* This trial period should also be used to evaluate the ability and tolerance of the worker to wear the respirator [Harber 1984]. This trial period need not be associated with respirator fit testing and should not compromise the effectiveness of the vital fit testing procedure. CFR = Code of Federal Regulations. See CFR in references.\n• Examining physicians should realize that the main stress of heavy exercise while using a respirator is usually on the cardiovascular system and that heavy respirators (e.g., SCBA) can substantially increase this stress. Accordingly, physicians may want to consider exercise stress tests with electrocardiographic monitoring when heavy respirators are used, when cardiovascular risk factors are present, or when extremely stressful conditions are expected.\nSome respirators may weigh up to 35 pounds and may increase workloads by 20 percent. Although a lower activity level could compensate for this added stress [Manning and Griggs 1983], a lower activity level might not always be possible. Physicians should also be aware of other added stresses, such as heavy protective clothing and intense ambient heat, that would increase the worker's cardiac demand. As an extreme example, firefighters who use a SCBA inside burning buildings may work at maximal exercise levels under life-threatening conditions.\nIn such cases, the detection of occult cardiac disease, which might manifest itself during heavy stress, may be important. Some authors have either recommended stress testing [Kilbom 1980] or at least its consideration in the fitness determination [ANSI 1984]. Kilbom [1980] has recommended stress testing at 5-year intervals for firefighters below age 40 who use SCBA and at 2-year intervals for those aged 40-50. He further suggested that firemen over age 50 not be allowed to wear SCBA. Exercise stress testing has not been recommended for medical screening for coronary artery disease in the general population [Weiner et al. 1979;Epstein 1979].\nIt has an estimated sensitivity and specificity of 78% and 69%, respectively, when the disease is defined by coronary angiography [Weiner et al. 1979;Nicklin and Balaban 1984],\nIn a recent 6-year prospective study, stress testing to determine the potential for heart attacks indicated a positive predictive value of 27% when the prevalence of disease was 3.5% [Giagnoni et al. 1983;Folli 1984]. While stress testing has limited effectiveness in medical screening, it could detect individuals who may not be able to complete the heavy exercise required in some jobs.\nA definitive recommendation regarding exercise stress testing cannot be made at this time. Further research may determine whether this is a useful tool in selected circumstances.\n• An important concept is that \"general work limitations and restrictions identified for other work activities also shall apply for respirator use\" [ANSI 1984].\nIn many cases, if a worker is physically able to do an assigned job while not wearing a respirator, the worker will in most situations not be at increased risk when performing the same job while wearing a respirator.\n• Because of the variability in the types of respirators, work conditions, and workers' health status, many employers may wish to designate categories of fitness to wear respirators, thereby excluding some workers from strenuous work situations involving the wearing of respirators.\nDepending on the various circumstances, several permissible categories of respirator usage are possible. One conceivable scheme would consist of three overall categories: full respirator use, no respirator use, and limited respirator use including \"escape only\" respirators. The latter category excludes heavy respirators and strenuous work conditions. Before identifying the conditions that would be used to classify workers into various categories, it is critical that the physician be aware that these conditions have not been validated and are presented only for consideration. The physician should modify the use of these conditions based on actual experience, further research, and individual worker sensitivities.\nHe may also wish to consider the following conditions in selecting or permitting the use of respirators:\n-History of spontaneous pneumothorax; -CIaus t rophob i a/anxi ety reac t i on; -Use of contact lenses (for some respirators); -Moderate or severe pulmonary disease; -Angina pectoris, significant arrhythmias, recent myocardial infarction; -Symptomatic or uncontrolled hypertension; and -Advanced age.\nWearing a respirator would probably not play a significant role in causing lung damage such as pneumothorax.\nHowever, without good evidence that wearing a respirator would not cause such lung damage, the physician would be prudent to prohibit the individual with a history of spontaneous pneumothorax from wearing a respirator.\nModerate lung disease is defined by the Intermountain Thoracic Society [Kanner and Morris 1975] as being present when the following conditions exist-a forced expiratory volume in one second (FEV-|) divided by the forced vital capacity (FVC) (i.e., FEV-|/FVC) of 0.45 to 0.60, or an FVC of 51% to 65% of the predicted FVC value. Similar arbitrary limits could be set for age and hypertension.\nIt would seem more reasonable, however, to combine several risk factors into an overall estimate of fitness to wear respirators under certain conditions. Here the judgment and clinical experience of the physician are needed. Many impaired workers would even be able to work safely while wearing respirators if they could control their own work pace, including having sufficient time to rest.\n# C. Cone Ius ion\nIndividual judgment is needed to determine the factors affecting an individual's fitness to wear a respirator. While many of the preceding guidelines are based on limited evidence, they should provide a useful starting point for a respirator fitness screening program.\nFurther research is needed to validate these and other recommendations currently in use. Of particular interest would be laboratory studies involving physiologically impaired individuals and field studies conducted under actual day-to-day work condi t ions. \n# C E N T E R S F O R D IS E A S E C O N T R O L N A T IO N A L IN S T IT U T E F O R O C C U P A T IO N A L S A F E T Y A N D H E A L T H R O B E R T A . T A F T L A B O R\n\n# APPENDICES\n\n# APPENDIX I\n\n# EVALUATION OF EPIDEMIOLOGIC STUDIES EXAMINING THE LUNG CANCER MORTALITY OF UNDERGROUND MINERS\nConfounding Bias: A potential attribute of data.\nIn measuring an association between an exposure and a disease, a confounding factor is one that is associated with the exposure and independently is a cause of the disease. Confounding bias can be controlled if information on the confounding factor is present.\nCoulomb: The charge flowing past a point of a circuit in one second, when there is a current of one ampere in the circuit; also, the aggregate charge carried by 6 x 10^ electrons.\nElectron Vo 11: The change in potential energy of a particle having a charge equal to the electronic charge (1.60 x 10-^ coulombs), moving through a potential difference of 1 volt.\nHalf-Li fe: The time required for a radioactive substance to decay to one half of its initial activity.\nFollow-up Period: The length of time between a person entering an epidemiological study cohort and the present report (or the end of the study).\nIncidence Ra t e : The number of new cases of disease per unit of population per unit of time, e.g., 3/1000/year.** Interaction: The association of one factor (occupation) with disease modified by the effect of another factor (smoking). The measure of association can be the rate or odds ratio. This follows a nonmult ip Iicative model (may be additive).\nIonizing Radi at ion: Any electromagnetic or particulate radiation capable of producing ions, directly or indirectly, in its passage through matter.\nLagging Exposures: Lagging of the cumulative exposure assigned to a miner. Some authors consider that radon progeny exposures are \"redundant\" if they occur after lung cancer is induced. Some authors believe that cumulative exposures should be lagged by a certain number of years (5 or 10), to exclude redundant exposures occurring during these years. For example, Radford and St. Clair Renard [5] discounted the last 5 years of exposures from the cumulative total WLM assigned to each case of lung cancer in their analysi s . Biologic Latent Period: The time between an increment of exposure and the increase in risk attributable to it.+ Epidemiologic Latent Period: The time between first exposure and death in those developing the disease during the study interval.\nLinear Hypothesis: The hypothesis that excess risk is proportional to dose. \n# FIGURE 4\n\n# EFFECT OF ACE AT INITIAL EXPOSURE ON A MU LT IS TA GE MODEL\n\n# A G E A T INITIAL E X P O S U R E\n\n# VI. SUMMARY AND CONCLUSIONS\nA valid quantitative risk assessment is much more than simply fitting an exposure-response curve to mortality data. This is especially true when considering an epidemiologic risk assessment.\nThere are a great variety of risk factors and temporal effects that may alter the interpretation of the data analysis.\nThis report is an attempt to address such modifying influences in an effort to better understand the underlying cancer mechanisms operative in the cohort of U.S. uranium mi daughters.\nThere were a number of findings which are important in lung cancer in the U.S. cohort.\n# 1.\nInfluence of C ig a re tte Smoking\nThe joint effect of cumulative cigarette smoking daughter exposure was found to be intermediate multiplicative.\nThis would imply a synergistic usual definition as an effect exceeding the sum risks.\n# Exposure-Rate E ffe c t\nAnalysis of this data revealed that modeling cumulative exposure alone may not adequately predict the relative risk of lung cancer from chronic exposure to radon daughters.\nMiners receiving a given amount of cumulative exposure at lower rates for longer periods of time were at greater risk relative to those with the same cumulative exposure received at higher rates for shorter periods of time.\nThis This implies that results extrapolated from historical exposures at high rates may yield conservative results at current lower rates.\nIndeed, it is possible that lower risk estimates in the U.S. study, when compared to the four other major radon studies, as reported by Thomas et al. [1985] may be due to the higher exposure rates received by U.S. miners.\n# Late-Stage Carcinogenic E ffect\nCareful examination of temporal effects implies that exposure to radon daughters acts at a late stage in the carcinogenic process.\nAll temporal factors agreed in this respect.\nThe appropriate lag to remove redundant exposure was a relatively short six years.\nOlder miners at initial exposure were at greater risk than those exposed at younger ages.\nThe relative risk of lung cancer decreases with the length of time after cessation of exposure.\nWhether or not the mathematical form of the multistage theory of carcinogenesis applies to this cohort, the temporal patterns are worth noting. \n# C. BuIkheads\n\n# D e s c rip tio n\nThe second most important control measure used in underground mines today is the construction of bulkheads across inactive stopes or drifts [Bates and Franklin 1977]. Bulkheads isolate inactive stopes, prevent the mixture of contaminated air from these stopes with fresh air, and help control the direction of air flow to working areas.\nMaintaining a negative air pressure behind a bulkhead will prevent leaks [Franklin 1981]; this is important because radon progeny concentrations can exceed 1,000 WL behind a bulkhead [Bates and Franklin 1977].\nIn addition, bulkheads must be strong and flexible enough to maintain an airtight seal during typical mining conditions, such as the ground movement and air shocks from blasting and the impact from accidental contact with mining equipment.\n# A bulkhead consists of three functional parts:\n(1) the primary structure, (2) the seal between the primary structure and the rock, and (3) a surface seal on the rock within one meter from the plane of the bulkhead [Summers et al. 1982\n# ],\nThe primary bulkhead structure fills most of the opening in the stope and provides resistance to shocks from blasting or contact with machinery.\nThe primary structure consists of timber or an expanded metal lath covered with a continuous non-porous membrane. The membrane may be attached to, or sprayed upon, the timber in the primary structure. The membrane must not crack or develop holes or leaks during mining activities [Franklin 1981;Summers et al. 1982].\nThe second part of the bulkhead, the seal between the primary structure and the surrounding rock, must resist running water and the air shocks and rock movements due to blasting.\nThe third part of the bulkhead, the seal on the surface of the rock within one meter from the plane of the bulkhead, must be made of a material that adheres to damp rock surfaces and can withstand mining 6. Fan Operation estimate that 100 bulkheads sealing 12.5 stopes would reduce the overall radon gas emissions into mine air by 2.25 Ci/day, a reduction of 25%.\nIn summary, bulkheads are very effective in reducing radon gas (and thus radon progeny) in mine air. Especially promising are the new bulkheads designed by Summers et al. [1982] and further tested by Bloomster et al.\n[1984b]. These bulkheads may eventually replace the leakier and more flammable polyurethane bulkheads presently being used underground.\n# D. Backf i11in q\nIn the uranium mining process, large quantities of ore are brought to the surface, leaving voids which may collapse if they are not stabilized.\nThe tailings remaining after the uranium is extracted are often used as backfill.\nThere are three benefits of backfilling stopes:\n(1) ground stabilization, ( 2 Next, the coarse tailings \"sand' ' is mixed with water to form a slurry and pumped into worked-out stopes.\nSometimes the slurry is mixed with cement before pumping. After the water in the slurry percolates away, the stope is left filled with densely packed sand or cement.\nThe radon progeny hazard can be increased, at least temporarily, by backfilling. Although the sand has considerably less radium than the ore or host rock, the finely divided sand has a larger surface area and many fine interstices between the grains through which radon gas can move. Therefore, the radon gas emanation rate of the sand is much higher than the ore or host rock [Raghavayya and Khan 1973; Thompkins 1982]. During backfilling, agitation of the slurry releases high concentrations of radon gas [Bates and Franklin 1977]. Also, high concentrations of radon gas can collect above the sand in the newly filled stope (possibly reaching 65,000-75,000 pCi/l). Thus the advantage of decreasing the ventilation volume with the backfill must be weighed against the increased emanation rate of the backfill [Bates and Franklin 1977]. Mixing the slurry with cement will not prevent this increase in emanation rate because the radon gas can also travel freely through fine pores in the cement, especially water-filled pores.\nIndeed, radon gas emanates from porous cement, sand, or ore at a higher rate when it is wet than when it is dry unless the dry material is overlain with a thick During experiments in a mine, Franklin et al. [1981] found that backfilling 90% of a stope reduced the total radon progeny emissions from the stope by 85%. A feasibility study estimated that backfilling can be as effective as problem unless there were several thousand visible pinholes per square meter of sealant.\n# E ffe c tiv e n e s s o f S ealants in Reducing Radon Emanation Rates\nThe effectiveness of sealants depends, in part, upon the porosity of the rock walls. Sealants produce the greatest decrease in radon emanation when applied to sandstone or other porous rock; sealants applied to granite will appear to be less effective because granite provides a natural barrier to radon emanation [Lindsay et al. 1981a]. Thus results from the tests for the effectiveness of sealants vary greatly depending on the porosity of the rock walls along with the mine ventilation rate, the grade of the uranium ore, and other factors. estimated that the overall decrease in radon emissions would be 56% if the same sealant coating was applied to 80% of the mine surfaces. Although sealants were less effective and more costly than bulkheads, the use of sealants is less disruptive to the mining process than the use of bulkheads [Bloomster et al. 1984b].\nIn summary, there are at least seven materials available that make effective mine sealants. These materials can reduce radon emanation from mine walls by 50-75%. \n# F. C o n tro llin g R ad io active Water Underground\n\n# APPENDIX IV\n\n# GRAB SAMPLING STRATEGY REQUIREMENTS FOR DETERMINATION OF RADON PROGENY EXPOSURES\nA.\n# Introduct ion\nAirborne concentrations of radon progeny must be monitored regularly to provide the basis for their control. Miners' exposures must be limited to no more than 1.0 WLM per year and the average concentration of radon progeny in any work area must not exceed 1/12 WL during any work shift. The sampling strategy described here was developed after an evaluation of mine sampling data and the typical variability of radon progeny concentrations in underground mines. This strategy will allow the collection of timely and reliable environmental data that can be used as the basis for control of cumulative exposures.\nThis sampling strategy allows for the determination of the arithmetic average of time-varying concentrations of radon progeny during a work shift in a given work area. The determination is based on an unbiased estimate made from grab samples taken at random intervals through out the work shift. Random sampling of work shifts during a reference period is also included for determination of a long-term arithmetic average work shift concentration.\nThe formulae needed to calculate the statistical quantities used in this sampling strategy are contained in section G of this appendix. The rationale for the critical decision points used in the sampling strategy are contained in section H.\n# B. Definition of Terms and Notations\nSTATION: A sampling location within a work area that represents the radon progeny concentration to which miners are exposed. CLUSTER: Two or more stations at which sampling will be conducted during any work shift. The stations in a cluster should be located at different work areas but must be in close proximity to each other so that alternating grab samples could be taken during the same work shi ft.\n# BLOCK OF TIME:\nA period in which two different sampling days are randomly selected.\n# AVERAGE WORK SHIFT CONCENTRATION: The average concentration of radon progeny in working levels (WL) during a work shift at a given station.\n\n# AVERAGE: The arithmetic mean.\nThe same term can be used for the average of several sample results or for the arithmetic mean of a distribution of concentrations that vary during a continuous period of time.\nIn the latter case, the terms \"average,\" \"arithmetic average,\" and \"time-weighted average\" are synonymous.\n# otj :\nAverage work shift concentration for day i, where i = 1,2,...,12 and day i is the ittl day in a time-ordered sequence of the 12 days that were randomly selected from the reference period. \n# LCL:\n95% one-sided lower confidence limit for a.\n# UCL:\n95% one-sided upper confidence limit for a.\n# 5.\nIf is < 0.14 WL, then: (a) continue collecting seven grab samples on each of the two randomly selected sampling days in each 2-week block of time, and (b) continue using the criteria given in section C. After 12 weeks of sampling in which no two consecutive sampling days ( f t ; and &j+i) were in excess of 0.14 WL, use the criteria given in section D for assurance, based on 12 days of sampling, that the average work shift concentration of radon progeny is in compliance with the REL, which, if verified, will result in less frequent exposure monitoring requirements.\n# D. Criteria for Less Frequent Exposure Monitoring\nTo determine if less frequent exposure monitoring can be conducted at a specific work area, the following statistical decision criteria must be used 1. Compute a. (the estimated average work shift concentration using seven grab samples per sampling day) for a work area during the reference period in which 12 samples were taken and no two consecutive sampling days ($j and &j+-|) were in excess of 0.14 WL. Formulae for this computation are contained in section G.\n2. Compute LCL and UCL, the 95% one-sided lower and 95% one-sided upper confidence limits, respectively, for the average work shift concentration during the reference period from which the 12 sampling days were taken. Formulae for these computations are contained in section G; o i . from section D,1 is a quantity used in the formulae for LCL and UCL. \n# The block length can be increased\n\n# 4.\nIf LCL exceeds 1/12 WL, then: (a) steps shall be taken to reduce the radon progeny concentration in that work area by implementing work practices and engineering controls, (b) respiratory protection shall be required for all miners entering that work area, and (c) grab sampling as described in section C,2 shall be conducted on a consecutive daily bas i s .\nGrab sampling shall continue on a consecutive daily basis until the estimated average work shift concentrations on any two consecutive workdays (&^ and o^) are both < 0.10 WL. When ^ and ag are both < 0.10 WL, then the requirements for respiratory protection are waived and exposure monitoring can revert to the schedule described starting at section C , 1. [Note: A new reference period shall begin at this time, requiring 12 randomly selected sampling days, the first of which is to be coded as i = 1.]\n# E . Criteria for Continuation of Less Frequent Exposure Monitoring\nAfter completion of two additional sampling days during the subsequent 26-week period, the data from the last 12 days sampled must be used to compute a new UCL for the period in which the 12 sampling days occurred.\n1. Sampling may continue under the less frequent sampling schedule (i.e., 2 days per 26-week block of time) if both of the following results occur at a station:\n(a) UCL for the reference period from which the last 12 sampling days were taken is < 1/12 WL, and (b) the estimated average work shift concentrations on the last two of the 12 sampling days (&11 and &12) were both < 0.14 WL.\nIn this case, an updated UCL shall be recomputed after completion of sampling in each subsequent 26-week block of time to determine if less frequent sampling (i.e., on two days during a 26-week period) should be continued according to the criteria of this part.\nIf ei ther of these conditions are not met, then LCL must be computed from data obtained from the last 12 days sampled (see section E,2 which follows).\n# 2.\nIf LCL for the reference period from which the 12 sampling days were taken at a station exceeds 1/12 WL, then:\n(a) steps shall be taken to reduce the radon progeny concentration in that work area by implementing work practices and engineering controls, (b) respiratory protection shall be required for all miners entering that work area, and (c) grab sampling as described in section C,2 shall be conducted on a consecutive dai ly basis.\nGrab sampling shall continue on a consecutive daily basis until the estimated average work shift concentrations on any two consecutive workdays and ftg) are both < 0.10 WL. When and are both < 0.10 WL, then the requirements for respiratory protection are waived and exposure monitoring can revert to the schedule described starting at section C,1.\n# 3.\nIf LCL for the reference period from which the 12 sampling days were randomly taken is < 1/12 WL, but the estimated average work shift concentration determined for either of the last two of the 12 sampling days (&11 or &12) exceeds 0.14 WL, then monitoring at that station shall return to the more frequent sampling schedule (2 days per 2-week block of time).\nIn this case, &11 or &12 becomes ^ and sampling is required on the next workday to obtain ag, as described starting at section C,4,a.\n# F . Criteria for Cessation of Exposure Monitoring\nSampling can be discontinued at a station if both of the following results occur at that station:\n(1) UCL for the reference period from which 12 sampling days were taken is < 0.063 WL, and (2) the estimated average work shift concentration for the last of the 12 sampling days (&12) is < 0.033 WL. However, sampling should return to the regular schedule, as described starting at section C,1 if an environmental change or a change in mining operations occurs that may alter radon progeny concentrations in that work area.\n# APPENDIX V\nIn recommending medical evaluation criteria for respirator use, one should apply rigorous decision-making principles [Halperin et al. 1986]; tests used should be chosen for operating characteristics such as sensitivity, specificity, and predictive value. Unfortunately, many knowledge gaps exist in this area. The problem is complicated by the large variety of respirators, their conditions of use, and individual differences in the physiologic and psychologic responses to them. For these reasons, the following guidelines are to be considered as informed suggestions rather than established NIOSH policy recommendations.\nThey are intended primarily to assist the physician in developing medical evaluation criteria for respi rator use. \n# A. Background Info rm ation\n\n# Pulmonary E ffe c ts\nIn general, the added inspiratory and expiratory resistances and dead space of most respirators cause an increase in tidal volume and a decrease in respiratory rate and ventilation (including a small decrease in alveolar ventilation). These respirator effects have usually been small both among healthy individuals and, in limited studies, among individuals with impaired lung function [Gee et al. 1968;Altose et al. 1977;Raven et al. 1981;Hodous et al. 1983;Hodous et al. 1986]. This generalization is applicable to most respirators when resistances (particularly expiratory resistance) are low [Bentley et al. 1973;Love et al. 1977]. While most studies report minimal physiologic effects during submaximal exercise, the resistances commonly lead to reduced endurance and reduced maximal exercise performance [Craig et al. 1970;Raven et al. 1977;Stemler and Craig 1977;Myhre et al. 1979;Deno et al. 1981]. The dead space of a respirator (reflecting the amount of expired air that must be rebreathed before fresh air is obtained) tends to cause increased ventilation. At least one study has shown substantially increased ventilation with a full-face respirator, a type that can have a large effective dead space [James et al. 1984]. However, the net effect of a respirator's added resistances and dead space is usually a small decrease in ventilation [Craig et al. 1970;Hermansen et al. 1972;Raven et al. 1977;Stemler and Craig 1977;Deno et al. 1981;Hodous et al. 1983].\nThe potential for adverse effects, particularly decreased cardiac output, from the positive pressure feature of some respirators has been Raven et al. [1982] found statistically significant higher systolic and/or diastolic blood pressures during exercise for persons wearing respirators. Arborelius et al. [1983] did not find significant differences for persons wearing respirators during exercise.\n# Body Temperature E ffe c ts\nProper regulation of body temperature is primarily of concern with the closed circuit SCBA that produces oxygen via an exothermic chemical reaction.\nInspired air within these respirators may reach 120°F (49°C), thus depriving the wearer of a minor cooling mechanism and causing discomfort. Obviously this can be more of a problem with heavy exercise and when ambient conditions and/or protective clothing further reduce the body's ability to lose heat. The increase in heart rate because of increasing temperature represents an additional cardiac stress.\nClosed-circuit breathing units of any type have the potential for causing heat stress since warm expired gases (after exothermic carbon dioxide removal with or without oxygen addition) are rebreathed. Respirators with large dead spaces also have this potential problem, again because of partial rebreathing of warmed expired air [James et al. 1984],\n# . Sensory E ffe c ts\nRespirators may reduce visual fields, decrease voice clarity and loudness, and decrease hearing ability. Besides the potential for reduced productivity, these effects may result in reduced industrial safety. These factors may also contribute to a general feeling of stress [Morgan 1983a].\n# Psychologic E ffe c ts\nThis important topic is discussed in recent reviews by Morgan [Morgan 1983a[Morgan , 1983b. There is little doubt that virtually everyone suffers some discomfort when wearing a respirator. The large variability and the subjective nature of the psycho-physiologic aspects of wearing a respirator, however, make studies and specific recommendations difficult.\nFit testing obviously serves an important additional function by providing a trial to determine if the wearer can psychologically tolerate the respirator. The great majority of workers can tolerate respirators, and experience in wearing them aids in this tolerance [Morgan 1983b]. However, some individuals are likely to remain psychologically unfit for wearing respirators.\n# . Local I r r i t a t i o n E ffe c ts\nAllergic skin reactions may occur occasionally from wearing a respirator, and skin occlusion may cause irritation or exacerbation of preexisting conditions such as pseudofolliculitis barbae. Facial discomfort from the pressure of the mask may occur, particularly when the fit is unsatisfactory."},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":291,"cells":{"id":{"kind":"string","value":"df3f848209ed7779016aeedd817b3c01bec92a8f"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"# CONTENTS\nC D C encourages organizations that have previously relied on copying and posting PDFs o f the schedules to their websites to instead use a safer m ethod to consistently display current schedules. This form o f \"content syndication\" ensures that the most current and accurate immunization schedule information is on each organization's website. This one-time step assures that your website displays current yearly schedules as soon as they are published, or revised.\nTo place the schedules on a website, organizations simply include two lines o f CDC-furnished com puter code on their Web page. Each organization's Web developer places the code into their existing website; the code automatically loads the current C D C schedule and footnotes. T he schedule is visible within the organization's Web page, and all other images and Web navigation display unchanged. Any C D C revisions or updates will automatically and immediately be reflected on the organization's Web page.\nThis form o f content syndication also gives organizations the ability to offer a PDF o f each schedule on their website. Staff members and Web visitors can print as well as view im m unization schedules and be confident they have the most current versions. Instructions for copying and placing syndication code are available at / schedules/syndicate.html.\nC D C offers technical assistance for organizations implementing this form o f content syndication. For assistance, readers can complete the e-mail form on the N C IR D Web support page (), and a N CIRD Web team staff member will contact them and provide assistance. Each year, the Advisory Committee on Immunization Practices (ACIP) reviews the current recom m ended im m unization schedules for persons aged 0 through 18 years to ensure that the schedule reflects current recommendations for licensed vaccines. In October 2012, ACIP approved the recommended immunization schedules for persons aged 0 through 18 years for 2013, which includes several changes from 2012.\n\n# Advisory C o m m itte e on Im m u n iza tio n Practices (ACIP) R ecom m ended Im m u n iza tio n Schedule fo r Persons\nHealth-care providers are advised to use both the recommended schedule and the catch-up schedule (Figures 1 and 2) in com bination w ith their footnotes (pages 6-8) and not as stand-alones. For guidance on the use o f all the vaccines in the schedules, including contraindications and precautions to use o f a vaccine, providers are referred to the respective ACIP vaccine recommendations.\nPrintable versions o f the regular and catch-up schedules are available at in various formats, including landscape and pocket-sized, in regular paper or laminated versions. A \"parent friendly\" regular schedule is available at l#print.\nFor 2013, several new references and links to additional inform ation have been added, including one for travel vaccine requirements and recommendations (1). New references also are provided for vaccination o f persons w ith prim ary and secondary im m unodeficiencies. Changes to the previous schedules (2) include the following:\n- Figure 1, \"Recommended immunization schedule for persons aged 0 through 18 years\" replaces \"Recommended immunization schedule for persons aged 0 through 6 years\" and \"Recommended immunization schedule for persons aged 7 through 18 years.\" -W ording was added to bars to represent the respective vaccine dose numbers in the series.\n-T he meningococcal conjugate vaccine (MCV4) purple bar was extended to age 6 weeks, to reflect licensure of Hib-M enCY vaccine. These recom m endationsmu st be read with the footnotes that foilow. For those w h o fa ll behind or start late, provide catch-up va ccination at the earliest opportunity as indica ted by the greet bars in Figure 1. To determine minimum intesvals between doses,see the catch-up schedule (Figute 2). School entry and adolescent vaccine age groups are in bold. The figure below provides catch-up schedules and minimum intervals between doses for children whose vaccinations have? been delayed. A vaccine series does not need to be restarted, regfrdl ess o fth e tim e that has elapsed between doces. Use the sectior appropriate for thechild'sage. Alwcys use this table in co n ju n ition wieh Figure 1 and the footnotes that follow.\n\n# Footnotes: Recommended Immunization Schedule for Persons Aged 0 Through 18 Years -United States, 2013\n\n# Additional guidance for use o f the vaccines described in this publication is available at \n\n# Hepatitis B (HepB) vaccine. (Minimum age: birth)\nRoutine vaccination: At birth - Administer monovalent HepB vaccine to all newborns before hospital discharge. - For infants born to hepatitis B surface antigen (HBsAg)-positive mothers, administer HepB vaccine and 0.5 mL o f hepatitis B im mune globulin (HBIG) w ithin 12 hours o f birth. These infants should be tested for HBsAg and antibody to HBsAg (anti-HBs) 1 to 2 months after completion o f the HepB series, at age 9 through 18 months (preferably at the next well-child visit). - If mother's HBsAg status is unknown, w ithin 12 hours o f birth administer HepB vaccine to all infants regardless o f birth weight. For infants weigh ing 2,000 grams (no later than age 1 week).\n\n# Doses following the birth dose\n\n# Rotavirus (RV) vaccines. (Minimum age: 6 weeks for both RV-1 and RV-5 ). Routine vaccination:\n- Administer a series of RV vaccine to all infants as follows:\n1. If RV-1 is used, administer a 2-dose series at 2 and 4 months o f age.\n2. If RV-5 is used, administer a 3-dose series at ages 2, 4, and 6 months.\n3. If any dose in series was RV-5 or vaccine product is unknown for any dose in the series, a total o f 3 doses o f RV vaccine should be administered.\n\n# Catch-up vaccination:\n- The maximum age for the first dose in the series is 14 weeks, 6 days. - Vaccination should not be initiated for infants aged 15 weeks 0 days or older. - The maximum age for the final dose in the series is 8 months, 0 days. - If RV-1(Rotarix) is administered for the first and second doses, a third dose is not indicated. - For other catch-up issues, see Figure 2. S u p p le m e n t Please note: An erratum has been published for this issue. To view the erratum, please click here. - Administer 2 doses o f MMR vaccine to children aged 12 months and older, before departure from the United States for international travel. The first dose should be administered on or after age 12 months and the second dose at least 4 weeks later.\n\n# Diphtheria and tetanus toxoids and acellular pertussis (\n\n# Catch-up vaccination:\n- Ensure that all school-aged children and adolescents have had 2 doses of MMR vaccine; the minimum interval between the 2 doses is 4 weeks. months to all adolescents aged 11-12 years. Either HPV4 or HPV2 may be used for females, and only HPV4 may be used for males. - The vaccine series can be started beginning at age 9 years. - Administer the second dose 1 to 2 months after the first dose and the third dose 6 months after the first dose (at least 24 weeks after the first dose).\n\n# Catch-up vaccination:\n- Administer the vaccine series to females (either HPV2 or HPV4) and males (HPV4) at age 13 through 18 years if not previously vaccinated. Please note: An erratum has been published for this issue. To view the erratum, please click here. The Advisory Committee on Immunization Practices (ACIP) annually reviews and updates the adult immunization schedule, which is designed to provide vaccine providers with a summary o f existing ACIP recommendations regarding the routine use o f vaccines for adults (Figures 1 and 2). The adult schedule also includes a table summarizing the primary contraindications and precautions for routinely recommended vaccines (Table ). In October 2012, ACIP approved the adult immunization schedule for 2013. This schedule also incorporates changes to vaccine recommendations voted on by ACIP at its October 24-25, 2012 meeting.\n\n# Additional Vaccine Information\nThe primary updates include adding information for the first time on the use o f 13-valent pneumococcal conjugate vaccine (PCV13) and the timing of administration ofPCV13 relative to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in adults (4). PCV13 is recommended for adults aged 19 years and older with immunocompromising conditions (including chronic renal failure and nephrotic syndrome), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants. The schedule also clarifies which adults need 1 or 2 doses of PPSV23 before age 65 years. O ther changes to the PPSV23 footnote include adding information regarding recommendations for vaccination when vaccination status is unknown.\nFor tetanus, diphtheria, and acellular pertussis (Tdap) vaccine, recom m endations have been expanded to include routine vaccination o f adults aged 65 years and older and for pregnant women to receive Tdap vaccine with each pregnancy. T he ideal tim ing o f Tdap vaccination during pregnancy is during 27-36 weeks' gestation. This recom m endation was made to increase the likelihood o f optimal protection for the pregnant woman and her infant during the first few m onths of the infant's life, when the child is too young for vaccination but at highest risk for severe illness and death from pertussis (5,6).\nM anufacturers o f the live, attenuated influenza vaccine (LAIV) have obtained Food and Drug Administration (FDA) approval for a quadrivalent influenza vaccine that contains one influenza A (H 3N 2), one influenza A (H 1N 1) and two influenza B vaccine virus strains, one from each lineage o f circulating influenza B viruses. In approxim ately h alf of the recent influenza seasons, the trivalent influenza vaccine has included an influenza B vaccine virus from the lineage different from the predom inant circulating influenza B strains (7). Inclusion o f both lineages o f influenza B virus is intended to increase the likelihood that the vaccine provides cross reactive antibody against a higher proportion o f circulating influenza B viruses. For LAIV, beginning with the 2013-14 season, it is expected that only the quadrivalent formulation will be available and manufacture o f the trivalent formulation will cease. It is possible that quadrivalent inactivated influenza vaccine formulations might be available for the 2013-14 season as well. Because a mix o f quadrivalent and trivalent influenza vaccines might be available in 2013-14, the abbreviation for inactivated influenza vaccine has been changed from trivalent inactivated influenza vaccine (TIV) to inactivated influenza vaccine (IIV). T he abbreviation for LAIV remains unchanged.\nM inor wording changes, clarifications, or simplifications have been made to footnotes for measles, m um ps, rubella vaccine (MMR), hum an papillomavirus vaccine (HPV), zoster vaccine, and hepatitis A and hepatitis B vaccines. A correction has been made to Figure 1 for M M R vaccine: the bar that indicated the vaccine might be used in certain situations by persons born before 1957 has been removed. Persons born before 1957 are considered im mune, and routine vaccination is not recommended. Considerations for the possible use of M M R vaccine in outbreak situations are included in the 2011 M M W R publication on vaccination o f health-care personnel (8). In addition, a correction was made to Figure 2 for PPSV23. This vaccine is indicated for men who have sex with men if they have another risk factor (e.g., age or underlying condition); the bar has been changed from yellow to purple to more accurately reflect the recommendation.\nVaccine providers are reminded to consult the full ACIP vaccine recommendations if they have questions and to bear in m ind that additional updates might be made for specific vaccines during the year between updates to the adult schedule. Printable versions o f the 2013 adult im m unization schedule and other inform ation is available at / vaccines/schedules/hcp/adult.html. Inform ation about adult vaccination is available at . h tm . ACIP statements and inform ation for specific vaccines is available at .cdc.gov/vaccines/pubs/acip-list. h tm . Adverse events from vaccination should be reported at or by telephone, 800-822-7967. This schedule has been approved by the American Academy o f Family Physicians, the American College o f Physicians, the American College o f Obstetricians and Gynecologists, and the American College o f Nurse-Midwives. T he adult im m unization schedule is published in the Annals o f Internal Medicine at the same time that it is published in M M W R.\n\n# Changes for 2013\n\n# Footnotes\n- Inform ation was added to footnote #1 to direct readers to additional inform ation regarding recommendations for vaccination when vaccination status is unknown. - T he influenza vaccination footnote (#2) now uses the abbreviation IIV for inactivated influenza vaccine and drops the abbreviation T IV for trivalent inactivated vaccine (TIV). For the 2013-14 influenza season, it is expected that the LAIV will be available only in a quadrivalent formulation; IIV might be available in both trivalent and quadrivalent formulations. - The tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination footnote (#3) is updated to include the recommendation to vaccinate pregnant women with Tdap during each pregnancy, regardless of the interval since prior Td/Tdap vaccination and to include the recommendation for all other adults, including persons aged 65 years and older, to receive 1 dose of Tdap vaccine.\n- T he varicella (#4) and H PV (#5) footnotes were simplified; no changes in recommendations were made. Additional inform ation was added to the H P V footnote regarding H PV vaccination and pregnancy. - T he zoster footnote (#6) was changed to clarify that ACIP recommends vaccination o f persons beginning at age 60 years both for persons with and w ithout underlying health conditions for whom the vaccine is not contraindicated. - The measles, mumps, rubella (MMR) vaccine footnote (#7) was modified to reflect the new recommendation that a provider diagnosis of measles, mumps, or rubella is not considered acceptable evidence of immunity. Previously, a provider diagnosis of measles or mumps, but not rubella, was considered acceptable evidence of immunity. - Inform ation was added to the pneumococcal polysaccharide (PPSV23) vaccination footnote (#8) and PPSV23 revaccination footnote (#9) to clarify that persons with certain medical conditions are recommended to receive 2 doses o f PPSV23 before age 65 years. In addition, even those who receive 2 doses of PPSV23 before age 65 years are recommended to receive PPSV23 at age 65 years, as long as it has been 5 years since the most recent dose. T he PPSV23 footnote refers to footnote #10 for pneumococcal conjugate 13-valent vaccine (PCV13) regarding the timing of PCV13 vaccine relative to PPSV23 for those persons recommended to be vaccinated with both pneumococcal vaccines. - A new footnote (#10) was added for PCV13 vaccine.\nThis vaccine is recommended for adults aged 19 years and older with im m unocomprom ising conditions (including chronic renal failure and nephrotic syndrome), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants. Those not previously vaccinated with PCV13 or PPSV23 should receive a single dose o f PCV13, followed by a dose o f PPSV23 at least 8 weeks later. Those previously vaccinated with PPSV23 should be vaccinated with PCV13 one year or more after PPSV23 vaccination (4). - The hepatitis A vaccine footnote (#12) was updated to clarify that vaccination is recommended for persons with a history o f either injection or noninjection illicit drug use.\n- The hepatitis B vaccine footnote (#13) includes minor wording changes and adds information on the vaccine schedule for hepatitis B vaccine series for the Recombivax HB vaccine. The dosing schedules for other hepatitis B vaccines were included in prior years' schedules.\n\n# Figures\n- For figure 1, the bar for T dap/T d for persons aged 65 years and older has been changed to solid yellow because all adults, including those 65 years and older, are now recommended to receive one dose of Tdap vaccine (5). - T he bar for M M R vaccine for persons born before 1957 has been removed. M M R vaccine is not recommended routinely for persons born before 1957. Considerations for vaccination in measles or mumps outbreak settings are discussed in the ACIP recommendations for health care personnel (8).\n- A new row for PCV13 vaccine has been added.\n- For Figure 2, the recom m endation for Tdap vaccination with each pregnancy is included, with a single dose of Tdap recommended for all other groups (6). - A correction was made to change the color for PPSV23 from yellow to purple for men who have sex with men (MSM). PPSV23 is recommended for M SM who have another risk factor such as age group or medical condition. - A row for PCV13 was added (4).\n\n# Contraindications and Precautions Table\n- T he inactivated influenza vaccine precautions were updated to indicate that persons who experience only hives with exposure to eggs should receive IIV rather than LAIV.\n- Pregnancy was removed as a precaution for hepatitis A vaccine. This is an inactivated vaccine, and similar to hepatitis B vaccines, is recommended if another high risk condition or other indication is present. - Language was clarified regarding the precaution for use o f antiviral medications and vaccination with varicella or zoster vaccines.\n\n# ACIP Adult Immunization Work Group\nWork\n\n# Human papillomavirus (HPV) vaccination\n- Two vaccines are licensed for use in females, bivalent HPV vaccine (HPV2) and quadrivalent HPV vaccine (HPV4), and one HPV vaccine for use in males (HPV4). - For females, either HPV4 or HPV2 is recommended in a 3-dose series for routine vaccination at age 11 or 12 years, and for those aged 13 through 26 years, if not previously vaccinated. - For males, HPV4 is recommended in a 3-dose series for routine vaccination at age 11 or 12 years, and for those aged 13 through 21 years, if not previ ously vaccinated. Males aged 22 through 26 years may be vaccinated. - HPV4 is recommended for men who have sex with men (MSM) through age 26 years for those who did not get any or all doses when they were younger. - Vaccination is recommended for immunocompromised persons (including those with HIV infection) through age 26 years for those who did not get any or all doses when they were younger. - A complete series for either HPV4 or HPV2 consists o f 3 doses. The second dose should be administered 1-2 months after the first dose; the third dose should be administered 6 months after the first dose (at least 24 weeks after the first dose). - HPV vaccines are not recommended for use in pregnant women. However, pregnancy testing is not needed before vaccination. If a woman is found to be pregnant after initiating the vaccination series, no intervention is needed; the remainder o f the 3-dose series should be delayed until completion o f pregnancy. - Although HPV vaccination is not specifically recommended for health-care personnel (HCP) based on their occupation, HCP should receive the HPV vaccine as recommended (see above).\n\n# Zoster vaccination\n- A single dose o f zoster vaccine is recommended for adults aged 60 years and older regardless o f whether they report a prior episode o f herpes zoster.\nAlthough the vaccine is licensed by the Food and Drug Administration (FDA) for use among and can be administered to persons aged 50 years and older, ACIP recommends that vaccination begins at age 60 years. - Persons aged 60 years and older with chronic medical conditions may be vaccinated unless their condition constitutes a contraindication, such as pregnancy or severe immunodeficiency. - Although zoster vaccination is not specifically recommended for HCP, they should receive the vaccine if they are in the recommended age group.\n\n# Measles, mumps, rubella (MMR) vaccination\n- Adults born before 1957 generally are considered immune to measles and mumps. dose should be administered 1 month after the first dose; the third dose should be given at least 2 months after the second dose (and at least 4 months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, give 3 doses at 0, 1, and 6 months; alternatively, a 4-dose Twinrix schedule, administered on days 0, 7, and 21-30 followed by a booster dose at month 12 may be used. - Adult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose o f 40 pg/mL (Recombivax HB) adminis tered on a 3-dose schedule at 0, 1, and 6 months or 2 doses o f 20 ^g/m L (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months. Recent (within 11 months) receipt o f antibody-containing blood product (specific interval depends on product).6,7\n\n# Selected conditions for which\nModerate or severe acute illness with or w ithout fever.\nReceipt o f specific antivirals (i.e., acyclovir, famciclovir, or valacyclovir) 24 hours before vaccination; avoid use o f these antiviral drugs for 14 days after vaccination.\n\n# Human papillomavirus (HPV)\nSevere allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever. Pregnancy.\n\n# Zoster\nSevere allergic reaction (e.g., anaphylaxis) to a vaccine component. Known severe im munodeficiency (e.g., from hematologic and solid tumors, receipt o f chemotherapy, or long-term immunosuppressive therapy5 or patients with HIV infection who are severely immunocompromised). Pregnancy.\nModerate or severe acute illness with or w ithout fever.\nReceipt o f specific antivirals (i.e., acyclovir, famciclovir, or valacyclovir) 24 hours before vaccination; avoid use o f these antiviral drugs for 14 days after vaccination.\nMeasles, mumps, rubella (MMR)3 Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component. Known severe im munodeficiency (e.g., from hematologic and solid tumors, receipt of chemotherapy, congenital immunodeficiency, or long-term immunosuppressive therapy5 or patients with HIV infection who are severely immunocompromised). Pregnancy.\nModerate or severe acute illness with or w ithout fever. Recent (within 11 months) receipt o f antibody-containing blood product (specific interval depends on product).6,7\nHistory o f throm bocytopenia or throm bocytopenic purpura. Need for tuberculin skin testing.8\nSee footnotes on page 18.\n\n# Supplem ent TABLE. (Continued) Contraindications and precautions to commonly used vaccines in adults1*\"*\n\n# Vaccine Contraindications Precautions\nPneumococcal polysaccharide (PPSV) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\nPneumococcal conjugate (PCV13) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component, including to any vaccine containing diphtheria toxoid.\nModerate or severe acute illness with or w ithout fever.\nMeningococcal, conjugate, (MCV4); meningococcal, polysaccharide (MPSV4)\nSevere allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\nHepatitis A (HepA) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\nHepatitis B (HepB) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\n1. Vaccine package inserts and the full ACIP recommendations for these vaccines should be consulted for additional information on vaccine-related contraindications and precautions and for more information on vaccine excipients. Events or conditions listed as precautions should be reviewed carefully. Benefits o f and risks for administering a specific vaccine to a person under these circumstances should be considered. If the risk from the vaccine is believed to outweigh the benefit, the vaccine should not be administered. If the benefit o f vaccination is believed to outweigh the risk, the vaccine should be administered. A contraindication is a condition in a recipient that increases the chance o f a serious adverse reaction. Therefore, a vaccine should not be administered when a contraindication is present. 6. Vaccine should be deferred for the appropriate interval if replacement immune globulin products are being administered.\n\n# Supplem ent\nThese recommendations must be read w ith the footnotes that follow. ------------- I -------------- for use among and can be administered to persons aged 50 years and older, ACIP recommends PCV13 for adults aged 19 years and older with the specific medical conditions noted above.\n\n# Meningococcal vaccination\n- Administer 2 doses o f meningococcal conjugate vaccine quadrivalent (MCV4) at least 2 months apart to adults w ith functional asplenia or per sistent complement component deficiencies.\n- HIV-infected persons who are vaccinated also should receive 2 doses.\n- Administer a single dose o f meningococcal vaccine to microbiologists routinely exposed to isolates o f N eisseria m e n in g itid is , military recruits, and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic. - First-year college students up through age 21 years who are living in residence halls should be vaccinated if they have not received a dose on or after their 16th birthday. - MCV4 is preferred for adults w ith any o f the preceding indications who are aged 55 years and younger; meningococcal polysaccharide vaccine (MPSV4) is preferred for adults aged 56 years and older. - Revaccination w ith MCV4 every 5 years is recommended for adults previ ously vaccinated with MCV4 or MPSV4 who remain at increased risk for infection (e.g., adults w ith anatomic or functional asplenia or persistent complem ent component deficiencies).\n\n# Hepatitis A vaccination"},"raw_text":{"kind":"string","value":"# CONTENTS\nC D C encourages organizations that have previously relied on copying and posting PDFs o f the schedules to their websites to instead use a safer m ethod to consistently display current schedules. This form o f \"content syndication\" ensures that the most current and accurate immunization schedule information is on each organization's website. This one-time step assures that your website displays current yearly schedules as soon as they are published, or revised.\nTo place the schedules on a website, organizations simply include two lines o f CDC-furnished com puter code on their Web page. Each organization's Web developer places the code into their existing website; the code automatically loads the current C D C schedule and footnotes. T he schedule is visible within the organization's Web page, and all other images and Web navigation display unchanged. Any C D C revisions or updates will automatically and immediately be reflected on the organization's Web page.\nThis form o f content syndication also gives organizations the ability to offer a PDF o f each schedule on their website. Staff members and Web visitors can print as well as view im m unization schedules and be confident they have the most current versions. Instructions for copying and placing syndication code are available at http://www.cdc.gov/vaccines/ schedules/syndicate.html.\nC D C offers technical assistance for organizations implementing this form o f content syndication. For assistance, readers can complete the e-mail form on the N C IR D Web support page (http://www.cdc.gov/vaccines/web-support.html), and a N CIRD Web team staff member will contact them and provide assistance. Each year, the Advisory Committee on Immunization Practices (ACIP) reviews the current recom m ended im m unization schedules for persons aged 0 through 18 years to ensure that the schedule reflects current recommendations for licensed vaccines. In October 2012, ACIP approved the recommended immunization schedules for persons aged 0 through 18 years for 2013, which includes several changes from 2012.\n# Advisory C o m m itte e on Im m u n iza tio n Practices (ACIP) R ecom m ended Im m u n iza tio n Schedule fo r Persons\nHealth-care providers are advised to use both the recommended schedule and the catch-up schedule (Figures 1 and 2) in com bination w ith their footnotes (pages 6-8) and not as stand-alones. For guidance on the use o f all the vaccines in the schedules, including contraindications and precautions to use o f a vaccine, providers are referred to the respective ACIP vaccine recommendations.\nPrintable versions o f the regular and catch-up schedules are available at http://www.cdc.gov/vaccines/schedules in various formats, including landscape and pocket-sized, in regular paper or laminated versions. A \"parent friendly\" regular schedule is available at http://www.cdc.gov/vaccines/schedules/easy-toread/child.htm l#print.\nFor 2013, several new references and links to additional inform ation have been added, including one for travel vaccine requirements and recommendations (1). New references also are provided for vaccination o f persons w ith prim ary and secondary im m unodeficiencies. Changes to the previous schedules (2) include the following:\n• Figure 1, \"Recommended immunization schedule for persons aged 0 through 18 years\" replaces \"Recommended immunization schedule for persons aged 0 through 6 years\" and \"Recommended immunization schedule for persons aged 7 through 18 years.\" -W ording was added to bars to represent the respective vaccine dose numbers in the series.\n-T he meningococcal conjugate vaccine (MCV4) purple bar was extended to age 6 weeks, to reflect licensure of Hib-M enCY vaccine. These recom m endationsmu st be read with the footnotes that foilow. For those w h o fa ll behind or start late, provide catch-up va ccination at the earliest opportunity as indica ted by the greet bars in Figure 1. To determine minimum intesvals between doses,see the catch-up schedule (Figute 2). School entry and adolescent vaccine age groups are in bold. The figure below provides catch-up schedules and minimum intervals between doses for children whose vaccinations have? been delayed. A vaccine series does not need to be restarted, regfrdl ess o fth e tim e that has elapsed between doces. Use the sectior appropriate for thechild'sage. Alwcys use this table in co n ju n ition wieh Figure 1 and the footnotes that follow. \n# Footnotes: Recommended Immunization Schedule for Persons Aged 0 Through 18 Years -United States, 2013\n\n# Additional guidance for use o f the vaccines described in this publication is available at http://www.cdc.gov/vaccines/pubs/acip-list.htm\n\n# Hepatitis B (HepB) vaccine. (Minimum age: birth)\nRoutine vaccination: At birth • Administer monovalent HepB vaccine to all newborns before hospital discharge. • For infants born to hepatitis B surface antigen (HBsAg)-positive mothers, administer HepB vaccine and 0.5 mL o f hepatitis B im mune globulin (HBIG) w ithin 12 hours o f birth. These infants should be tested for HBsAg and antibody to HBsAg (anti-HBs) 1 to 2 months after completion o f the HepB series, at age 9 through 18 months (preferably at the next well-child visit). • If mother's HBsAg status is unknown, w ithin 12 hours o f birth administer HepB vaccine to all infants regardless o f birth weight. For infants weigh ing <2,000 grams, administer HBIG in addition to HepB within 12 hours of birth. Determine mother's HBsAg status as soon as possible and, if she is HBsAg-positive, also administer HBIG for infants weighing >2,000 grams (no later than age 1 week). \n# Doses following the birth dose\n\n# Rotavirus (RV) vaccines. (Minimum age: 6 weeks for both RV-1 [Rotarix] and RV-5 [RotaTeq]). Routine vaccination:\n• Administer a series of RV vaccine to all infants as follows:\n1. If RV-1 is used, administer a 2-dose series at 2 and 4 months o f age.\n2. If RV-5 is used, administer a 3-dose series at ages 2, 4, and 6 months.\n3. If any dose in series was RV-5 or vaccine product is unknown for any dose in the series, a total o f 3 doses o f RV vaccine should be administered.\n# Catch-up vaccination:\n• The maximum age for the first dose in the series is 14 weeks, 6 days. • Vaccination should not be initiated for infants aged 15 weeks 0 days or older. • The maximum age for the final dose in the series is 8 months, 0 days. • If RV-1(Rotarix) is administered for the first and second doses, a third dose is not indicated. • For other catch-up issues, see Figure 2. S u p p le m e n t Please note: An erratum has been published for this issue. To view the erratum, please click here. • Administer 2 doses o f MMR vaccine to children aged 12 months and older, before departure from the United States for international travel. The first dose should be administered on or after age 12 months and the second dose at least 4 weeks later.\n# Diphtheria and tetanus toxoids and acellular pertussis (\n\n# Catch-up vaccination:\n• Ensure that all school-aged children and adolescents have had 2 doses of MMR vaccine; the minimum interval between the 2 doses is 4 weeks. months to all adolescents aged 11-12 years. Either HPV4 or HPV2 may be used for females, and only HPV4 may be used for males. • The vaccine series can be started beginning at age 9 years. • Administer the second dose 1 to 2 months after the first dose and the third dose 6 months after the first dose (at least 24 weeks after the first dose).\n# Catch-up vaccination:\n• Administer the vaccine series to females (either HPV2 or HPV4) and males (HPV4) at age 13 through 18 years if not previously vaccinated. Please note: An erratum has been published for this issue. To view the erratum, please click here. The Advisory Committee on Immunization Practices (ACIP) annually reviews and updates the adult immunization schedule, which is designed to provide vaccine providers with a summary o f existing ACIP recommendations regarding the routine use o f vaccines for adults (Figures 1 and 2). The adult schedule also includes a table summarizing the primary contraindications and precautions for routinely recommended vaccines (Table ). In October 2012, ACIP approved the adult immunization schedule for 2013. This schedule also incorporates changes to vaccine recommendations voted on by ACIP at its October 24-25, 2012 meeting.\n# Additional Vaccine Information\nThe primary updates include adding information for the first time on the use o f 13-valent pneumococcal conjugate vaccine (PCV13) and the timing of administration ofPCV13 relative to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in adults (4). PCV13 is recommended for adults aged 19 years and older with immunocompromising conditions (including chronic renal failure and nephrotic syndrome), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants. The schedule also clarifies which adults need 1 or 2 doses of PPSV23 before age 65 years. O ther changes to the PPSV23 footnote include adding information regarding recommendations for vaccination when vaccination status is unknown.\nFor tetanus, diphtheria, and acellular pertussis (Tdap) vaccine, recom m endations have been expanded to include routine vaccination o f adults aged 65 years and older and for pregnant women to receive Tdap vaccine with each pregnancy. T he ideal tim ing o f Tdap vaccination during pregnancy is during 27-36 weeks' gestation. This recom m endation was made to increase the likelihood o f optimal protection for the pregnant woman and her infant during the first few m onths of the infant's life, when the child is too young for vaccination but at highest risk for severe illness and death from pertussis (5,6).\nM anufacturers o f the live, attenuated influenza vaccine (LAIV) have obtained Food and Drug Administration (FDA) approval for a quadrivalent influenza vaccine that contains one influenza A (H 3N 2), one influenza A (H 1N 1) and two influenza B vaccine virus strains, one from each lineage o f circulating influenza B viruses. In approxim ately h alf of the recent influenza seasons, the trivalent influenza vaccine has included an influenza B vaccine virus from the lineage different from the predom inant circulating influenza B strains (7). Inclusion o f both lineages o f influenza B virus is intended to increase the likelihood that the vaccine provides cross reactive antibody against a higher proportion o f circulating influenza B viruses. For LAIV, beginning with the 2013-14 season, it is expected that only the quadrivalent formulation will be available and manufacture o f the trivalent formulation will cease. It is possible that quadrivalent inactivated influenza vaccine formulations might be available for the 2013-14 season as well. Because a mix o f quadrivalent and trivalent influenza vaccines might be available in 2013-14, the abbreviation for inactivated influenza vaccine has been changed from trivalent inactivated influenza vaccine (TIV) to inactivated influenza vaccine (IIV). T he abbreviation for LAIV remains unchanged.\nM inor wording changes, clarifications, or simplifications have been made to footnotes for measles, m um ps, rubella vaccine (MMR), hum an papillomavirus vaccine (HPV), zoster vaccine, and hepatitis A and hepatitis B vaccines. A correction has been made to Figure 1 for M M R vaccine: the bar that indicated the vaccine might be used in certain situations by persons born before 1957 has been removed. Persons born before 1957 are considered im mune, and routine vaccination is not recommended. Considerations for the possible use of M M R vaccine in outbreak situations are included in the 2011 M M W R publication on vaccination o f health-care personnel (8). In addition, a correction was made to Figure 2 for PPSV23. This vaccine is indicated for men who have sex with men if they have another risk factor (e.g., age or underlying condition); the bar has been changed from yellow to purple to more accurately reflect the recommendation.\nVaccine providers are reminded to consult the full ACIP vaccine recommendations if they have questions and to bear in m ind that additional updates might be made for specific vaccines during the year between updates to the adult schedule. Printable versions o f the 2013 adult im m unization schedule and other inform ation is available at http://www.cdc.gov/ vaccines/schedules/hcp/adult.html. Inform ation about adult vaccination is available at http://www.cdc.gov/vaccines/default. h tm . ACIP statements and inform ation for specific vaccines is available at http://www .cdc.gov/vaccines/pubs/acip-list. h tm . Adverse events from vaccination should be reported at http://www.vaers.hhs.gov or by telephone, 800-822-7967. This schedule has been approved by the American Academy o f Family Physicians, the American College o f Physicians, the American College o f Obstetricians and Gynecologists, and the American College o f Nurse-Midwives. T he adult im m unization schedule is published in the Annals o f Internal Medicine at the same time that it is published in M M W R.\n# Changes for 2013\n\n# Footnotes\n• Inform ation was added to footnote #1 to direct readers to additional inform ation regarding recommendations for vaccination when vaccination status is unknown. • T he influenza vaccination footnote (#2) now uses the abbreviation IIV for inactivated influenza vaccine and drops the abbreviation T IV for trivalent inactivated vaccine (TIV). For the 2013-14 influenza season, it is expected that the LAIV will be available only in a quadrivalent formulation; IIV might be available in both trivalent and quadrivalent formulations. • The tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination footnote (#3) is updated to include the recommendation to vaccinate pregnant women with Tdap during each pregnancy, regardless of the interval since prior Td/Tdap vaccination and to include the recommendation for all other adults, including persons aged 65 years and older, to receive 1 dose of Tdap vaccine.\n• T he varicella (#4) and H PV (#5) footnotes were simplified; no changes in recommendations were made. Additional inform ation was added to the H P V footnote regarding H PV vaccination and pregnancy. • T he zoster footnote (#6) was changed to clarify that ACIP recommends vaccination o f persons beginning at age 60 years both for persons with and w ithout underlying health conditions for whom the vaccine is not contraindicated. • The measles, mumps, rubella (MMR) vaccine footnote (#7) was modified to reflect the new recommendation that a provider diagnosis of measles, mumps, or rubella is not considered acceptable evidence of immunity. Previously, a provider diagnosis of measles or mumps, but not rubella, was considered acceptable evidence of immunity. • Inform ation was added to the pneumococcal polysaccharide (PPSV23) vaccination footnote (#8) and PPSV23 revaccination footnote (#9) to clarify that persons with certain medical conditions are recommended to receive 2 doses o f PPSV23 before age 65 years. In addition, even those who receive 2 doses of PPSV23 before age 65 years are recommended to receive PPSV23 at age 65 years, as long as it has been 5 years since the most recent dose. T he PPSV23 footnote refers to footnote #10 for pneumococcal conjugate 13-valent vaccine (PCV13) regarding the timing of PCV13 vaccine relative to PPSV23 for those persons recommended to be vaccinated with both pneumococcal vaccines. • A new footnote (#10) was added for PCV13 vaccine.\nThis vaccine is recommended for adults aged 19 years and older with im m unocomprom ising conditions (including chronic renal failure and nephrotic syndrome), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants. Those not previously vaccinated with PCV13 or PPSV23 should receive a single dose o f PCV13, followed by a dose o f PPSV23 at least 8 weeks later. Those previously vaccinated with PPSV23 should be vaccinated with PCV13 one year or more after PPSV23 vaccination (4). • The hepatitis A vaccine footnote (#12) was updated to clarify that vaccination is recommended for persons with a history o f either injection or noninjection illicit drug use.\n• The hepatitis B vaccine footnote (#13) includes minor wording changes and adds information on the vaccine schedule for hepatitis B vaccine series for the Recombivax HB vaccine. The dosing schedules for other hepatitis B vaccines were included in prior years' schedules.\n# Figures\n• For figure 1, the bar for T dap/T d for persons aged 65 years and older has been changed to solid yellow because all adults, including those 65 years and older, are now recommended to receive one dose of Tdap vaccine (5). • T he bar for M M R vaccine for persons born before 1957 has been removed. M M R vaccine is not recommended routinely for persons born before 1957. Considerations for vaccination in measles or mumps outbreak settings are discussed in the ACIP recommendations for health care personnel (8).\n• A new row for PCV13 vaccine has been added.\n• For Figure 2, the recom m endation for Tdap vaccination with each pregnancy is included, with a single dose of Tdap recommended for all other groups (6). • A correction was made to change the color for PPSV23 from yellow to purple for men who have sex with men (MSM). PPSV23 is recommended for M SM who have another risk factor such as age group or medical condition. • A row for PCV13 was added (4).\n# Contraindications and Precautions Table\n• T he inactivated influenza vaccine precautions were updated to indicate that persons who experience only hives with exposure to eggs should receive IIV rather than LAIV.\n• Pregnancy was removed as a precaution for hepatitis A vaccine. This is an inactivated vaccine, and similar to hepatitis B vaccines, is recommended if another high risk condition or other indication is present. • Language was clarified regarding the precaution for use o f antiviral medications and vaccination with varicella or zoster vaccines. \n# ACIP Adult Immunization Work Group\nWork\n# Human papillomavirus (HPV) vaccination\n• Two vaccines are licensed for use in females, bivalent HPV vaccine (HPV2) and quadrivalent HPV vaccine (HPV4), and one HPV vaccine for use in males (HPV4). • For females, either HPV4 or HPV2 is recommended in a 3-dose series for routine vaccination at age 11 or 12 years, and for those aged 13 through 26 years, if not previously vaccinated. • For males, HPV4 is recommended in a 3-dose series for routine vaccination at age 11 or 12 years, and for those aged 13 through 21 years, if not previ ously vaccinated. Males aged 22 through 26 years may be vaccinated. • HPV4 is recommended for men who have sex with men (MSM) through age 26 years for those who did not get any or all doses when they were younger. • Vaccination is recommended for immunocompromised persons (including those with HIV infection) through age 26 years for those who did not get any or all doses when they were younger. • A complete series for either HPV4 or HPV2 consists o f 3 doses. The second dose should be administered 1-2 months after the first dose; the third dose should be administered 6 months after the first dose (at least 24 weeks after the first dose). • HPV vaccines are not recommended for use in pregnant women. However, pregnancy testing is not needed before vaccination. If a woman is found to be pregnant after initiating the vaccination series, no intervention is needed; the remainder o f the 3-dose series should be delayed until completion o f pregnancy. • Although HPV vaccination is not specifically recommended for health-care personnel (HCP) based on their occupation, HCP should receive the HPV vaccine as recommended (see above).\n# Zoster vaccination\n• A single dose o f zoster vaccine is recommended for adults aged 60 years and older regardless o f whether they report a prior episode o f herpes zoster.\nAlthough the vaccine is licensed by the Food and Drug Administration (FDA) for use among and can be administered to persons aged 50 years and older, ACIP recommends that vaccination begins at age 60 years. • Persons aged 60 years and older with chronic medical conditions may be vaccinated unless their condition constitutes a contraindication, such as pregnancy or severe immunodeficiency. • Although zoster vaccination is not specifically recommended for HCP, they should receive the vaccine if they are in the recommended age group.\n# Measles, mumps, rubella (MMR) vaccination\n• Adults born before 1957 generally are considered immune to measles and mumps. dose should be administered 1 month after the first dose; the third dose should be given at least 2 months after the second dose (and at least 4 months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, give 3 doses at 0, 1, and 6 months; alternatively, a 4-dose Twinrix schedule, administered on days 0, 7, and 21-30 followed by a booster dose at month 12 may be used. • Adult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose o f 40 pg/mL (Recombivax HB) adminis tered on a 3-dose schedule at 0, 1, and 6 months or 2 doses o f 20 ^g/m L (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months. Recent (within 11 months) receipt o f antibody-containing blood product (specific interval depends on product).6,7\n# Selected conditions for which\nModerate or severe acute illness with or w ithout fever.\nReceipt o f specific antivirals (i.e., acyclovir, famciclovir, or valacyclovir) 24 hours before vaccination; avoid use o f these antiviral drugs for 14 days after vaccination.\n# Human papillomavirus (HPV)\nSevere allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever. Pregnancy.\n# Zoster\nSevere allergic reaction (e.g., anaphylaxis) to a vaccine component. Known severe im munodeficiency (e.g., from hematologic and solid tumors, receipt o f chemotherapy, or long-term immunosuppressive therapy5 or patients with HIV infection who are severely immunocompromised). Pregnancy.\nModerate or severe acute illness with or w ithout fever.\nReceipt o f specific antivirals (i.e., acyclovir, famciclovir, or valacyclovir) 24 hours before vaccination; avoid use o f these antiviral drugs for 14 days after vaccination.\nMeasles, mumps, rubella (MMR)3 Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component. Known severe im munodeficiency (e.g., from hematologic and solid tumors, receipt of chemotherapy, congenital immunodeficiency, or long-term immunosuppressive therapy5 or patients with HIV infection who are severely immunocompromised). Pregnancy.\nModerate or severe acute illness with or w ithout fever. Recent (within 11 months) receipt o f antibody-containing blood product (specific interval depends on product).6,7\nHistory o f throm bocytopenia or throm bocytopenic purpura. Need for tuberculin skin testing.8\nSee footnotes on page 18.\n# Supplem ent TABLE. (Continued) Contraindications and precautions to commonly used vaccines in adults1*\"*\n\n# Vaccine Contraindications Precautions\nPneumococcal polysaccharide (PPSV) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\nPneumococcal conjugate (PCV13) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component, including to any vaccine containing diphtheria toxoid.\nModerate or severe acute illness with or w ithout fever.\nMeningococcal, conjugate, (MCV4); meningococcal, polysaccharide (MPSV4)\nSevere allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\nHepatitis A (HepA) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\nHepatitis B (HepB) Severe allergic reaction (e.g., anaphylaxis) after a previous dose or to a vaccine component.\nModerate or severe acute illness with or w ithout fever.\n1. Vaccine package inserts and the full ACIP recommendations for these vaccines should be consulted for additional information on vaccine-related contraindications and precautions and for more information on vaccine excipients. Events or conditions listed as precautions should be reviewed carefully. Benefits o f and risks for administering a specific vaccine to a person under these circumstances should be considered. If the risk from the vaccine is believed to outweigh the benefit, the vaccine should not be administered. If the benefit o f vaccination is believed to outweigh the risk, the vaccine should be administered. A contraindication is a condition in a recipient that increases the chance o f a serious adverse reaction. Therefore, a vaccine should not be administered when a contraindication is present. 6. Vaccine should be deferred for the appropriate interval if replacement immune globulin products are being administered. \n# Supplem ent\nThese recommendations must be read w ith the footnotes that follow. ------------- I -------------- for use among and can be administered to persons aged 50 years and older, ACIP recommends PCV13 for adults aged 19 years and older with the specific medical conditions noted above.\n# Meningococcal vaccination\n• Administer 2 doses o f meningococcal conjugate vaccine quadrivalent (MCV4) at least 2 months apart to adults w ith functional asplenia or per sistent complement component deficiencies.\n• HIV-infected persons who are vaccinated also should receive 2 doses.\n• Administer a single dose o f meningococcal vaccine to microbiologists routinely exposed to isolates o f N eisseria m e n in g itid is , military recruits, and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic. • First-year college students up through age 21 years who are living in residence halls should be vaccinated if they have not received a dose on or after their 16th birthday. • MCV4 is preferred for adults w ith any o f the preceding indications who are aged 55 years and younger; meningococcal polysaccharide vaccine (MPSV4) is preferred for adults aged 56 years and older. • Revaccination w ith MCV4 every 5 years is recommended for adults previ ously vaccinated with MCV4 or MPSV4 who remain at increased risk for infection (e.g., adults w ith anatomic or functional asplenia or persistent complem ent component deficiencies).\n# Hepatitis A vaccination\n• "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":292,"cells":{"id":{"kind":"string","value":"f124c3c87ab6fa1003527cff1c175d12f286f9c9"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction\nPublic health surveillance is the ongoing, systematic collection, analysis, interpretation, and dissemination of data about a health-related event for use in public health action to reduce morbidity and mortality and to improve health (1). Surveillance serves at least eight public health functions. These include supporting case detection and public health interventions, estimating the impact of a disease or injury, portraying the natural history of a health condition, determining the distribution and spread of illness, generating hypotheses and stimulating research, evaluating prevention and control measures, and facilitating planning (2). Another important public health function of surveillance is outbreak detection (i.e., identifying an increase in frequency of disease above the background occurrence of the disease).\nOutbreaks typically have been recognized either based on accumulated case reports of reportable diseases or by clinicians and laboratorians who alert public health officials about clusters of diseases. Because of the threat of terrorism and the increasing availability of electronic health data, enhancements are being made to existing surveillance systems, and new surveillance systems have been developed and implemented in public health jurisdictions with the goal of early and complete detection of outbreaks (3). The usefulness of surveillance systems for early detection and response to outbreaks has not been established, and substantial costs can be incurred in developing or enhancing and managing these surveillance systems and investigating false alarms (4). The measurement of the performance of public health surveillance systems for outbreak detection is needed to establish the relative value of different approaches and to provide information needed to improve their efficacy for detection of outbreaks at the earliest stages. This report supplements existing CDC guidelines for evaluating public health surveillance systems (1). Specifically, the report provides a framework to evaluate timeliness for outbreak detection and the balance among sensitivity, predictive value positive (PVP), and predictive value negative (PVN) for detecting outbreaks. This framework also encourages detailed description of system design and operations and of their experience with outbreak detection.\nThe framework is best applied to systems that have data to demonstrate the attributes of the system under consideration. Nonetheless, this framework also can be applied to systems that are in early stages of development or in the planning phase by using citations from the published literature to support conclusions. Ideally, the evaluation should compare the performance of the surveillance system under scrutiny to alternative surveillance systems and produce an assessment of the relative usefulness for early detection of outbreaks.\n\n# Background\nEarly detection of outbreaks can be achieved in three ways: 1) by timely and complete receipt, review, and investigation of disease case reports, including the prompt recognition and reporting to or consultation with health departments by physicians, health-care facilities, and laboratories consistent with disease reporting laws or regulations; 2) by improving the ability to recognize patterns indicative of a possible outbreak early in its course, such as through analytic tools that improve the predictive value of data at an early stage of an outbreak or by lowering the threshold for investigating possible outbreaks; and 3) through receipt of new types of data that can signify an outbreak earlier in its course. These new types of data might include health-care product purchases, absences from work or school, presenting symptoms to a health-care provider, or laboratory test orders (5).\n\n# Disease Case Reports\nThe foundation of communicable disease surveillance in the United States is the state and local application of the reportable disease surveillance system known as the National Notifiable Disease Surveillance System (NNDSS), which includes the listing of diseases and laboratory findings of public health interest, the publication of case definitions for their surveillance, and a system for passing case reports from local to state to CDC. This process occurs best where two-way communication occurs between public health agencies and the clinical community: clinicians and laboratories report cases and clusters of reportable and unusual diseases, and health departments consult on case diagnosis and management, alerts, surveillance summaries, and clinical and public health recommendations and policies. Faster, more specific and affordable diagnostic methods and decision-support tools for diseases with substantial outbreak potential could improve the timely recognition of reportable diseases. On-going health-care provider and laboratory outreach, education, and 24-hour access to public health professionals are needed to enhance reporting of urgent health threats. Electronic laboratory reporting (i.e., the automated transfer of designated data from a laboratory database to a public health data repository using a defined message structure) also will improve the timeliness and completeness of reporting notifiable conditions (6)(7)(8) and can serve as a model for electronic reporting of a wider range of clinical information. A comprehensive surveillance effort supports timely investigation (i.e., tracking of cases once an outbreak has been recognized) and data needs for managing the public health response to an outbreak or terrorist event.\n\n# Pattern Recognition\nStatistical tools for pattern recognition and aberration detection can be applied to screen data for patterns warranting further public health investigation and to enhance recognition of subtle or obscure outbreak patterns (9). Automated analysis and visualization tools can lessen the need for frequent and intensive manual analysis of surveillance data.\n\n# New Data Types\nMany new surveillance systems, loosely termed syndromic surveillance systems, use data that are not diagnostic of a disease but that might indicate the early stages of an outbreak. The scope of this framework is broader than these novel systems, yet the wide-ranging definitions and expectations of syndromic surveillance require clarification. Syndromic surveillance for early outbreak detection is an investigational approach where health department staff, assisted by automated data acquisition and generation of statistical signals, monitor disease indicators continually (real-time) or at least daily (near real-time) to detect outbreaks of diseases earlier and more completely than might otherwise be possible with traditional public health methods (e.g., by reportable disease surveillance and telephone consultation). The distinguishing characteristic of syndromic surveillance is the use of indicator data types. For example, a laboratory is a data source that can support traditional disease case reporting by submitting reports of confirmatory laboratory results for notifiable conditions; however, test requests are a type of laboratory data that might be used as an outbreak indicator by tracking excess volume of test requests for diseases that typically cause outbreaks. New data types have been used by public health to enhance surveillance, reflecting events that might precede a clinical diagnosis (e.g., patient's chief complaints in emergency departments, clinical impressions on ambulance log sheets, prescriptions filled, retail drug and product purchases, school or work absenteeism, and constellations of medical signs and symptoms in persons seen in various clinical settings).\nOutbreak detection is the overriding purpose of syndromic surveillance for terrorism preparedness. Enhanced casefinding and monitoring the course and population characteristics of a recognized outbreak also are potential benefits of syndromic surveillance (4). A manual syndromic surveillance system was used to detect additional anthrax cases in the fall of 2001 when the outbreak was recognized (10). Complicating the understanding of syndromic surveillance is that syndromes have been used for case detection and management of diseases when the condition is infrequent and the syndrome is relatively specific for the condition of interest. Acute flaccid paralysis is a syndromic marker for poliomyelitis and is used to detect single cases of suspected polio in a timely way to initiate investigation and control measures. In this case, the syndrome is relatively uncommon and serious and serves as a proxy for polio (11). Syndromes also have been used effectively for surveillance in resource-poor settings for sexually transmitted disease detection and control where laboratory confirmation is not possible or practical (12). However, syndromic surveillance for terrorism is not intended for early detection of single cases or limited outbreaks because the early clinical manifestations of diseases that might be caused by terrorism are common and nonspecific (13).\n\n# Framework\nThis framework is intended to support the evaluation of all public health surveillance systems for the timely detection of outbreaks. The framework is organized into four categories: system description, outbreak detection, experience, and conclusions and recommendations. A comprehensive evaluation will address all four categories.\n\n# A. System Description\n1. Purpose. The purpose(s) of the system should be explicitly and clearly described and should include the intended uses of the system. The evaluation methods might be prioritized differently for different purposes. For example, if terrorism is expected to be rare, reassurance might be the primary purpose of the terrorism surveillance system. However, for reassurance to be credible, negative results must be accurate and the system should have a demonstrated ability to detect outbreaks of the kind and size being dismissed.\nThe description of purpose should include the indications for implementing the system; whether the system is designed for short-term, high-risk situations or long-term, continuous use; the context in which the system operates (whether it stands alone or augments data from other surveillance systems); what type of outbreaks the system is intended to detect; and what secondary functional value is desired. Designers of the system should specify the desired sensitivity and specificity of the system and whether it is intended to capture small or large events.\n2. Stakeholders. The stakeholders of the system should be listed. Stakeholders include those who provide data for the system and those who use the information generated by the system (e.g., public health practitioners; health-care providers; other health-related data providers; public safety officials; government officials at local, state, and federal levels; community residents; nongovernmental organizations; and commercial systems developers). The stakeholders might vary among different systems and might change as conditions change. Listing stakeholders helps define who the system is intended to serve and provides context for the evaluation results.\n3. Operation. All aspects of the operation of the syndromic surveillance system should be described in detail to allow stakeholders to validate the description of the system and for other interested parties to understand the complexity and resources needed to operate such a system. Detailed system description also will facilitate evaluation by highlighting variations in system operation that are relevant to variations in system performance (Figure 1). Such a conceptual model can facilitate the description of the system. The description of the surveillance process should address 1) systemwide characteristics (data flow ), including data and transmission standards to facilitate interoperability and data sharing between information systems, security, privacy, and confidentiality; 2) data sources (used broadly in this framework to include the dataproducing facility , the data type , and the data format ); 3) data processing before analysis (the data collation, filtering, transformation, and routing functions required for public health to use the data, including the classification and assigning of syndromes); 4) statistical analysis (tools for automated screening of data for potential outbreaks); and 5) epidemiologic analysis, interpretation, and investigation (the rules, procedures, and tools that support decision-making in response to a system signal, including adequate staffing with trained epidemiologists who can review, explore, and interpret the data in a timely manner).\n\n# B. Outbreak Detection\nThe ability of a system to reliably detect an outbreak at the earliest possible stage depends on the timely capture and processing of the data produced by transactions of health behaviors (e.g., over-the-counter pharmaceutical sales, emergency department visits, and nurse call-line volume) or health-care activities (e.g., laboratory test volume and triage categorization of chief complaint) that might indicate an outbreak; the validity of the data for measuring the conditions of interest at the earliest stage of illness and the quality of those data; and the detection methods applied to these processed surveillance data to distinguish expected events from those indicative of an outbreak.\n1. Timeliness. The timeliness of surveillance approaches for outbreak detection is measured by the lapse of time from exposure to the disease agent to the initiation of a public health intervention. A timeline with interim milestones is proposed to improve the specificity of timeliness measures (Figure 3). Although measuring all of the time points that define the intervals might be impractical or inexact in an applied outbreak setting, measuring intervals in a consistent way can be used to compare alternative outbreak-detection approaches and specific surveillance systems.\n- Onset of exposure: By anchoring the timeline on exposure, the timeliness advantage of different data sources can be assessed and compared. Exposure can most easily be estimated in a pointsource outbreak. Time of exposure is often inferred from knowledge of the agent (e.g., incubation period) and the epidemiology of the outbreak.\n- Onset of symptoms: The interval to symptom onset in each case is defined by the incubation period for the agent. Time of symptom onset might be estimated using case interviews or existing knowledge of the agent and the time of exposure. The incubation period might vary according to host factors and the route and dose of the exposure.\n- Onset of behavior: Following symptom onset, several health behaviors can occur (e.g., purchasing over-thecounter medication from a store, calling in sick to work, or visiting an urgent-care center). When an affected person interacts with the health-care system, a variety of health-care provider behaviors might be performed (e.g., order of a laboratory test and admission to a hospital).\nThe selection of data sources for a system has a strong influence on timeliness. Some of those experiencing symptoms will initiate a health behavior or stimulate a healthcare provider behavior that is a necessary step to being captured in the surveillance system. - Capture of data: The timing of the capture of a behavior by the data-providing facility varies by data type and can be influenced by system design. A retail purchase might be entered in an electronic database at the moment the transaction is completed, or a record might not be generated in a clinical setting until hours after health care was sought. - Completion of data processing: Time is required for the facility providing the data to process the data and produce the files needed for public health. Records might be transmitted to a central repository only periodically (e.g., weekly). Data form can influence processing time (e.g., transcription from paper to electronic form and coding text-based data), and data manipulations needed to de-identify data and prepare necessary files can affect processing time. - Capture of data in public health surveillance system:\nThe time required to transfer data from the data providing facility to the public health entity varies according to the frequency established for routine data transmission and by the data transmission method (e.g., Internet, mail, or courier).\n\n# Application of pattern recognition tools/algorithms:\nBefore analytic tools can be applied to the data in the surveillance system, certain processing steps are necessary (e.g., categorization into syndrome categories, application of case definition, and data transformations). - Generation of automated alert: The detection algorithm's alerting interval is a product of how often the algorithm is run and a report generated and the capacity of the algorithm to filter noise and detect an aberration as early as possible in the course of the outbreak. - Initiation of public health investigation: The initiation of a public health investigation occurs when a decision is made to acquire additional data. Analysis and judgment are applied by public health-care providers to the processed surveillance data and other available information to decide whether new data collection is warranted to confirm the existence of an outbreak. The challenge of interpreting data from multiple surveillance systems could diminish potential advantages in timeliness. The focus on outbreak detection allows for investigations of potential outbreaks to proceed before a specific clinical diagnosis is obtained.\n- Initiation of public health intervention: When an outbreak of public health significance is confirmed, interventions can be implemented to control the severity of disease and prevent further spread. Interventions might be of a general nature directed to the recognition of an outbreak (e.g., apply respiratory infection precautions and obtain clinical specimens for diagnosis) or can be specific to the diagnosis (e.g., antibiotic prophylaxis or vaccination).\n\n# Validity.\nMeasuring the validity of a system for outbreak detection requires an operational definition of an outbreak. Although a statistical deviation from a baseline rate can be useful for triggering further investigation, it is not sufficient for defining an outbreak. In practice, the confirmation of an outbreak is a judgment that depends on past experience with the condition, the severity of the condition, the communicability of the condition, confidence in the diagnosis of the condition, public health concern about outbreaks at the time, having options for effective prevention or control, and the resources required and available to respond. Operationally, an outbreak is defined by the affected public health jurisdiction when the occurrence of a condition has changed sufficiently to warrant public health attention.\nThe validity of a surveillance system for outbreak detection varies according to the outbreak scenario and surveillance system factors. These factors can confound the comparison of systems and must be carefully described in the evaluation. For example, the minimum size of an outbreak that can be detected by a system cannot be objectively compared among systems unless they are identical or differences are accounted for in several ways.\n- Case definitions: Establish the specificity and sensitivity for the condition of interest on the basis of the data source, data type, and response criteria. - Baseline estimation: Determine the stability of the background occurrence of cases. Estimations are affected by factors such as population size and geographic distribution. The performance of detection algorithms will vary by the quality and duration and inherent variability of baseline data. - Reporting delays: Result in incomplete data, introducing bias that will diminish the performance of detection algorithms. - Data characteristics: Includes underlying patterns in the data (e.g., seasonal variation) and systematic errors inherent in the data (e.g., product sales that influence purchasing behaviors unrelated to illness). - Outbreak characteristics: Results from agent, host, and environmental factors that affect the epidemiology of the outbreak. For example, a large aerosol exposure with an agent causing serious disease in a highly susceptible population will have different detection potential than an outbreak of similar size spread person-to-person over a longer time and dispersed distribution. - Statistical analysis: Defines how data are screened for outbreak detection. Detection algorithms have different performance characteristics under different outbreak conditions. - Epidemiologic analysis, interpretation, and investigation: The procedures, resources, and tools for analysis, interpretation, and response that can substantially affect the ability to detect and respond to outbreaks.\n\n# Validation Approaches\nDifferent approaches to outbreak detection need to be evaluated under the same conditions to isolate the unique features of the system (e.g., data type) from the outbreak characteristics and the health department capacity. The data needed to evaluate and compare the performance of surveillance systems for early outbreak detection can be obtained from naturally occurring outbreaks or through simulation.\nControlled comparisons of surveillance systems for detection of deliberately induced outbreaks will be difficult because of the infrequency of such outbreaks and the diversity of systems and outbreak settings. However, understanding the value of different surveillance approaches to early detection will increase as descriptions of their experience with detecting and missing naturally occurring outbreaks accumulate. Accumulation of experience descriptions is made more difficult by not having standard methods for measuring outbreak detection successes and failures across systems and by the diversity of surveillance system and outbreak factors that influence performance. Standardized classification of system and outbreak factors will enable comparison of experiences across systems. Pending the development of classification standards, descriptive evaluation should include as much detail as possible. Proxy outbreak scenarios reflect the types of naturally occurring outbreaks that should not be missed to instill confidence in the ability of these systems to detect outbreaks caused by terrorism. Examples of proxy events or outbreaks include seasonal events (e.g., increases in influenza, norovirus gastroenteritis, and other infectious respiratory agents) and community outbreaks (e.g., foodborne, waterborne, hepatitis A, child-care-associated shigellosis, legionellosis, and coccidioidomycosis and histoplasmosis in areas where the diseases are endemic).\nThe measurement of outbreaks detected, false alarms, and outbreaks missed or detected late should be designed as a routine part any system workflow and conducted with minimal effort or complexity. Routine reporting should be automated where possible. Relevant information needs include: the number of statistical aberrations detected at a set threshold in a defined period of time (e.g., frequency per month at a given p-value); the action taken as a result of the signals (e.g., review for data errors, in-depth follow-up analysis of the specific conditions within the syndrome category, manual epidemiologic analysis to characterize a signal, examining data from other systems, and increasing the frequency of reporting from affected sites); resources directed to the follow-up of the alert; public health response that resulted (e.g., an alert to clinicians, timely dissemination of information to other health entities, a vaccination campaign, or no further Generation of a response); documentation of how every recognized outbreak in the jurisdiction was detected; an assessment of the value of the follow-up effort (e.g., the effort was an appropriate application of public health resources); a detailed description of the agent, host, and environmental conditions of the outbreak; and the number of outbreaks detected only late in their course or in retrospect.\nTo evaluate the relative value of different methods for outbreak detection, a direct comparison approach is needed. For example, if a health department detects a substantial number of its outbreaks through telephone consultations, then a phone call tracking system might produce the data needed to compare telephone consults with other approaches for early detection of outbreaks.\nAs an alternative to naturally occurring outbreaks, simulations can allow for the control and modification of agent, host, and environmental factors to study system performance across a range of common scenarios. However, simulations are limited in their ability to mimic the diversity and unpredictability of real-life events. Whenever possible, simulated outbreaks should be superimposed on historical trend data. To evaluate detection algorithms comparatively, a shared challenge problem and data set would be helpful. Simulation is limited by the availability of well-documented outbreak scenarios (e.g., organism or agent characteristics, transmission characteristics, and population characteristics). Simulations should incorporate data for each of the factors described previously. Multiple simulation runs should be used to test algorithm performance in different outbreak scenarios, allowing for generation of operating characteristic curves that reflect performance in a range of conditions.\nFocused studies to validate the performance of limited aspects of systems (e.g., data sources, case definitions, statistical methods, and timeliness of reporting) can provide indirect evidence of system performance. Component studies also can test assumptions about outbreak scenarios and support better data simulation. Syndrome case definitions for certain specific data sources need to be validated. Component validation studies should emphasize outbreak detection over case detection. These studies contain explicit hypotheses and research questions and should be shared in a manner to advance the development of outbreak detection systems without unnecessary duplication.\n\n# Statistical Assessment of Validity\nSurveillance systems must balance the risk for an outbreak, the value of early intervention, and the finite resources for investigation. Perceived high risk and high value of timely detection support high sensitivity and low thresholds for investigation. A low threshold can prompt resource-intensive investigations and occupy vital staff, and a high threshold might delay detection and intervention. The perceived threat of an outbreak, the community value attached to early detection, and the investigation resources available might vary over time. As a result, specifying a fixed relation between optimal sensitivity and predictive value for purposes of evaluation might be difficult.\nThe sensitivity and PVP and PVN are closely linked and considered together in this framework. Sensitivity is the percentage of outbreaks occurring in the jurisdiction detected by the system. PVP reflects the probability of a system signal being an outbreak. PVN reflects the probability that no outbreak is occurring when the system does not yield a signal. The calculation of sensitivity and predictive value is described in detail in the updated guidelines for evaluating public health surveillance systems (1). Measurement of sensitivity requires an alternative data source of high quality (e.g., \"gold\" standard) to confirm outbreaks in the population that were missed by the surveillance system. Sensitivity for outbreak detection could be assessed through capture-recapture techniques with two independent data sources (14). The high costs associated with responding to false alarms and with delayed response to outbreaks demand efforts to quantify and limit the impact of both. As long as the likelihood of terrorism is extremely low, PVP will remain near zero and a certain level of nonterrorism signals will be a necessary part of conducting surveillance for the detection of terrorism. Better performance can be achieved in one attribute (e.g., sensitivity) without a performance decrement in another (e.g., PVP) by changing the system (e.g., adding a data type or applying a better detection algorithm). Improving sensitivity by lowering the cut-off for signaling an outbreak will reduce PVP. Sensitivity and PVP for these surveillance systems will ultimately be calibrated in each system to balance the secondary benefits (e.g., detection of naturally occurring outbreaks, disease case finding and management, reassurance of no outbreak during periods of heightened risk, and a stronger reporting and consultation relation between public health and clinical medicine) with the locally acceptable level of false alarms.\n\n# Data Quality\nThe validity of syndromic surveillance system data is dependent on data quality. Error-prone systems and data prone to inaccurate measurement can negatively affect detection of unusual trends. Although data quality might be a less critical problem for screening common, nonspecific indicators for statistical aberrations, quality should be evaluated and improved to the extent possible. Measuring data quality is dependent on a standard (e.g., medical record review or fabricated test data with values known to the evaluator). The updated May 7, guidelines for evaluating public health surveillance systems (1) describe data quality in additional detail.\n- Representativeness: When case ascertainment within a population is incomplete (e.g., in a sentinel system or a statistically based sample), representativeness reflects whether a system accurately describes the distribution of cases by time, place, and person. Geographic representativeness is particularly important for detecting outbreaks of infectious diseases. - Completeness of data: The frequency of unknown or blank responses to data items in the system can be used to measure the level of completeness. For systems that update data from previous transmissions, time should be factored into measurement by indicating the percentage of records that are complete (i.e., all variables are captured for a record) on initial report and within an appropriate interval (e.g., 48 hours) of submission. Sites with substantial reporting delays can be flagged for reliability concerns and targeted for improvement. Incomplete data can require follow-up before analysis, with associated decreases in timeliness and increase in cost. When multiple data providers contribute to a common data store for statistical analysis, the percentage of reporting sources that submit their data on a routine interval (e.g., every 24 hours) conveys the completeness of the aggregate database for routine analysis. Evaluation of completeness should include a description of the problems experienced with manual data management (e.g., coding errors or loss of data) and the problems with automated data management (e.g., programming errors or inappropriate filtering of data).\n\n# C. System Experience\nThe performance attributes described in this section convey the experience that has accrued in using the system.\n1. System usefulness. A surveillance system is useful for outbreak detection depending on its contribution to the early detection of outbreaks of public health significance that leads to an effective intervention. An assessment of usefulness goes beyond detection to address the impact or value added by its application. Measurement of usefulness is inexact. As with validity, measurement will benefit from common terminology and standard data elements. In the interim, detailed efforts to describe and illustrate the consequences of early detection efforts will improve understanding of their usefulness.\nEvaluation should begin with a review of the objectives of the system and should consider the priorities. To the extent possible, usefulness should be described by the disease prevention and control actions taken as a result of the analysis and interpretation of the data from the system.\nThe impact of the surveillance system should be contrasted with other mechanisms available for outbreak detection. An assessment of usefulness should list the outbreaks detected and the role that different methods played in the identification of each one. Examples of how the system has been used to detect or track health problems other than outbreaks in the community should be included. The public health response to the outbreaks and health problems detected should be described as well as how data from new or modified surveillance systems support inferences about disease patterns that would not be possible without them.\nSurveillance systems for early outbreak detection are sometimes justified for the reassurance they provide when aberrant patterns are not apparent during a heightened risk period or when the incidence of cases declines during an outbreak. When community reassurance is claimed as a benefit of the surveillance system, reassurance should be defined and the measurement quantified (e.g., number of phone calls from the public on a health department hotline, successful press conferences, satisfaction of public health decision-makers, or resources to institutionalize the new surveillance system). A description should include who is reassured and of what they are reassured, and reassurance should be evaluated for validity by estimating the PVN.\n2. Flexibility. The flexibility of a surveillance system refers to the system's ability to change as needs change. The adaptation to changing detection needs or operating conditions should occur with minimal additional time, personnel, or other resources. Flexibility generally improves the more data processing is handled centrally rather than distributed to individual data-providing facilities because fewer system and operator behavior changes are needed. Flexibility should address the ability of the system to apply evolving data standards and code sets as reflected in Public Health Information Network (PHIN) standards (). Flexibility includes the adaptability of the system to shift from outbreak detection to outbreak management. The flexibility of the system to meet changing detection needs can include the ability to add unique data to refine signal detection, to capture exposure and other data relevant to managing an outbreak, to add data providers to increase population coverage and detect or track low frequency events, to modify case definitions (the aggregation of codes into syndrome groupings), to improve the detection algorithm to filter random variations in trends more efficiently, and to adjust the detection threshold. Flexibility also can be reflected by the ability of the system to detect and monitor naturally occurring outbreaks in the absence of terrorism. System flexibility is needed to balance the risk for an outbreak, the value of early intervention, and the resources for investigation as understanding of these factors changes.\n3. System acceptability. As with the routine evaluation of public health surveillance systems (1), the acceptability of a surveillance system for early outbreak detection is reflected by the willingness of participants and stakeholders to contribute to the data collection and analysis. This concept includes the authority and willingness to share electronic health data and should include an assessment of the legal basis for the collection of prediagnosis data and the implications of privacy laws (e.g., Health Insurance Portability and Accountability Act Privacy Rule) (15). All states have broad disease-reporting laws that require reporting of diseases of public health importance, and many of these laws appear compatible with the authority to receive syndromic surveillance data (16). The authority to require reporting of indicator data for persons who lack evidence of a reportable condition and in the absence of an emergency is less clear and needs to be verified by jurisdictions. Acceptability can vary over time as the threat level, perceived value of early detection, support for the methods of surveillance, and resources fluctuate.\nAcceptability of a system can be inferred from the extent of its adoption. Acceptability is reflected by the participation rate of potential reporting sources, by the completeness of data reporting, and by the timeliness of person-dependent steps in the system (e.g., manual data entry from emergency department logs as distinguished from electronic data from the normal clinical workflow).\n4. Portability. The portability of a surveillance system addresses how well the system could be duplicated in another setting. Adherence to the PHIN standards can enhance portability by reducing variability in the application of information technology between sites. Reliance on person-dependent steps, including judgment and action criteria (e.g., for analysis and interpretation) should be fully documented to improve system portability. Portability also is influenced by the simplicity of the system. Examples should be provided of the deployment of similar systems in other settings, and the experience of those efforts should be described. In the absence of examples, features of the system that might support or detract from portability should be described.\n5. System stability. The stability of a surveillance system refers to its resilience to system changes (e.g., change in coding from International Classifications of Disease, Ninth Revision to ICD-10). Stability can be demonstrated by the duration and consistent operation of the system. System stability is distinguished from the reliability of data elements within the system. The consistent representation of the condition under surveillance (reliability) is an aspect of data quality. Stability can be measured by the frequency of system outages or downtime for servicing during periods of need, including downtime of data providers, the frequency of personnel deficiencies from staff turnover, and budget constraints. Ongoing support by system designers and evolving software updates might improve system stability. Stability also can be reflected in the extent of control over costs and system changes that the sponsoring agency maintains.\n6. System costs. Cost is a vital factor in assessing the relative value of surveillance for terrorism preparedness. Costeffectiveness analyses and data modeling are needed under a range of scenarios to estimate the value of innovations in surveillance for outbreak detection and terrorism preparedness (17). Improved methods of measuring cost and impact are needed. Costs borne by data providers should be noted; however, the cost perspective should be that of the community (societal perspective) to account for costs of prevention and treatment born by the community.\nDirect costs include the fees paid for software and data, the personnel salary and support expenses (e.g., training, equipment support, and travel), and other resources needed to operate the system and produce information for public health decisions (e.g. office supplies, Internet and telephone lines, and other communication equipment). Fixed costs for running the system should be differentiated from the variable costs of responding to system alarms. Variable costs include the cost of follow-up activities (e.g., for diagnosis, case-management, or community interventions). The cost of responding to false alarms represents a variable but inherent inefficiency of an early detection system that should be accounted for in the evaluation. Similarly, variable costs include the financial and public health costs of missing outbreaks entirely or recognizing them late. Costs vary because the sensitivity and timeliness of the detection methods can be modified according to changes in tolerance for missing outbreaks and for responding to false alarms. Similarly, the threshold and methods for investigating system alarms can vary with the perceived risk and need to respond. Costs from public health response to false alarms with traditional surveillance systems need to be measured in a comparable way when assessing the relative value of new surveillance methods. Cost savings should be estimated by assessing the impact of prevention and control efforts (e.g., health-care costs and productivity losses averted) Questions to answer include the following:\n- How many investigations were initiated as a result of these data?\n\n# D. Conclusions and Recommendations for Use and Improvement of Systems for Early Outbreak Detection\nThe evaluation should be summarized to convey the strengths and weaknesses of the system under scrutiny. Summarizing and reporting evaluation findings should facilitate the comparison of systems for those making decisions about new or existing surveillance methods. These conclusions should be validated among stakeholders of the system and modified accordingly. Recommendations should address adoption, continuation, or modification of the surveillance system so that it can better achieve its intended purposes. Recommendations should be disseminated widely and actively interpreted for all appropriate audiences.\nAn Institute of Medicine study concluded that although innovative surveillance methods might be increasingly helpful in the detection and monitoring of outbreaks, a balance is needed between strengthening proven approaches (e.g., diagnosis of infectious illness and strengthening the liaison between clinical-care providers and health departments) and the exploration and evaluation of new approaches (17). Guidance for the evaluation of surveillance systems for outbreak detection is on-going. Many advances are needed in understanding of systems and outbreak characteristics to improve performance metrics. For example, research is needed to understand the personal health and clinical health care behaviors that might serve as early indicators of priority diseases; analytic methods are needed to improve pattern recognition and to integrate multiple streams of data; a shared vocabulary is needed for describing outbreak conditions, managing text-based information, and supporting case definitions; and evaluation research is needed, including costeffectiveness of different surveillance models for early detection, both in real-life comparisons and in simulated data environments, to characterize the size and nature of epidemics that can be detected through innovative surveillance approaches. Pending more robust measures of system performance, the goal of this framework is to improve public health surveillance systems for early outbreak detection by providing practical guidance for evaluation.\n❑ Indicate the frequency of editing and updating the electronic file ❑ Indicate how incomplete records are handled in analysis and reports ❑ Describe how data archiving and disposal is managed ❑ Describe how new data sources or necessary changes in data sources are identified and incorporated in the system.\n\n# D. Statistical Analysis\n❑ Describe how the health outcome baseline is established: ❑ Describe the population under surveillance ❑ Describe the source, the criteria, and the methods for establishing the background frequencies used to detect aberrations ❑ How much baseline data are managed in the analysis database ❑ Describe analytic methods used in automated analyses (i.e., aberration detection): ❑ Describe in mathematical and statistical detail the algorithms intended to signal an event requiring further investigation ❑ Describe adaptations in analytic methods to account for different outbreak patterns that might be anticipated in different data sources and types and for different outbreak scenarios ❑ Indicate how reporting delays are corrected for in the analysis. ❑ Describe the method of adjusting results for potential confounding factors ❑ Describe how the system adapts over time and the empirical basis for modifications in the methods ❑ Describe the detection process:\n❑ The frequency of data analysis ❑ How an alarm is generated ❑ Where the alarm goes ❑ The type of alarms generated by the system ❑ What is done to ensure that signals are not being missed ❑ Describe the report generation process:\n❑ What routine reports are generated ❑ Whether data are presented graphically or in tables ❑ Whether data can be manipulated to get a specific\n\n# E. Epidemiologic Analysis, Interpretation, and Investigation\n❑ Describe the process for managing system alarms:\n❑ Describe the special procedures instituted when the alarm is generated (e.g., review for data errors, in-depth manual analysis of the specific conditions within the syndrome category, manual epidemiological analysis to identify subgroups responsible for an alarm, examining data from other systems, increasing the frequency of reporting from affected sites) ❑ Estimate the person-hours that are devoted to review and analysis each day and the interval at which data are analyzed ❑ Indicate documented procedures for managing system alarms. ❑ Indicate communication method that staff is alerted of alarms (e.g., whether they get paged at home, receive an automated e-mail, etc.?) ❑ Indicate the expectations and schedule of staff to actively check the system and schedule, including nights and weekends ❑ Indicate the response options to an alarm and the factors that influence the choice (e.g., wait for an alarm in another system, initiate an onsite investigation, alert clinicians to gather information) ❑ Describe the process for identifying cases for investigation when the data analyzed routinely are unidentified ❑ Describe how independent data types are integrated in the analysis for improved decision making ❑ Describe the rules, procedures, and tools for communication ❑ Indicate the mechanisms used and content guidance provided for sharing results with 1) reporting sources, 2) response community, and 3) the public; ❑ Describe how decisions are made for sending urgent communications and the methods for sending urgent communications ❑ Indicate whether receipt of a communication is acknowledged and how unacknowledged receipt is managed ❑ Indicate how often urgent communications and routine reports are sent ❑ Describe the protocol for conducting surveillance during outbreak management, if one exists ❑ Indicate how often data will be updated and analyzed ❑ Describe how the system can be modified or customized to meet special data needs ❑ Describe how the system will monitor the impact of prevention and control measures ❑ Describe how and how often system components are tested for operational readiness (e.g., 'spiked' data or modeling exercises)\n\n# A. System-wide Issues\n❑ Describe the political, administrative, and geographic context for the system ❑ Provide a process model that describes the data flow of the system:\n\n# Appendix. Operations Checklist\nVol. / RR-5"},"raw_text":{"kind":"string","value":"depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction\nPublic health surveillance is the ongoing, systematic collection, analysis, interpretation, and dissemination of data about a health-related event for use in public health action to reduce morbidity and mortality and to improve health (1). Surveillance serves at least eight public health functions. These include supporting case detection and public health interventions, estimating the impact of a disease or injury, portraying the natural history of a health condition, determining the distribution and spread of illness, generating hypotheses and stimulating research, evaluating prevention and control measures, and facilitating planning (2). Another important public health function of surveillance is outbreak detection (i.e., identifying an increase in frequency of disease above the background occurrence of the disease).\nOutbreaks typically have been recognized either based on accumulated case reports of reportable diseases or by clinicians and laboratorians who alert public health officials about clusters of diseases. Because of the threat of terrorism and the increasing availability of electronic health data, enhancements are being made to existing surveillance systems, and new surveillance systems have been developed and implemented in public health jurisdictions with the goal of early and complete detection of outbreaks (3). The usefulness of surveillance systems for early detection and response to outbreaks has not been established, and substantial costs can be incurred in developing or enhancing and managing these surveillance systems and investigating false alarms (4). The measurement of the performance of public health surveillance systems for outbreak detection is needed to establish the relative value of different approaches and to provide information needed to improve their efficacy for detection of outbreaks at the earliest stages. This report supplements existing CDC guidelines for evaluating public health surveillance systems (1). Specifically, the report provides a framework to evaluate timeliness for outbreak detection and the balance among sensitivity, predictive value positive (PVP), and predictive value negative (PVN) for detecting outbreaks. This framework also encourages detailed description of system design and operations and of their experience with outbreak detection.\nThe framework is best applied to systems that have data to demonstrate the attributes of the system under consideration. Nonetheless, this framework also can be applied to systems that are in early stages of development or in the planning phase by using citations from the published literature to support conclusions. Ideally, the evaluation should compare the performance of the surveillance system under scrutiny to alternative surveillance systems and produce an assessment of the relative usefulness for early detection of outbreaks.\n# Background\nEarly detection of outbreaks can be achieved in three ways: 1) by timely and complete receipt, review, and investigation of disease case reports, including the prompt recognition and reporting to or consultation with health departments by physicians, health-care facilities, and laboratories consistent with disease reporting laws or regulations; 2) by improving the ability to recognize patterns indicative of a possible outbreak early in its course, such as through analytic tools that improve the predictive value of data at an early stage of an outbreak or by lowering the threshold for investigating possible outbreaks; and 3) through receipt of new types of data that can signify an outbreak earlier in its course. These new types of data might include health-care product purchases, absences from work or school, presenting symptoms to a health-care provider, or laboratory test orders (5).\n# Disease Case Reports\nThe foundation of communicable disease surveillance in the United States is the state and local application of the reportable disease surveillance system known as the National Notifiable Disease Surveillance System (NNDSS), which includes the listing of diseases and laboratory findings of public health interest, the publication of case definitions for their surveillance, and a system for passing case reports from local to state to CDC. This process occurs best where two-way communication occurs between public health agencies and the clinical community: clinicians and laboratories report cases and clusters of reportable and unusual diseases, and health departments consult on case diagnosis and management, alerts, surveillance summaries, and clinical and public health recommendations and policies. Faster, more specific and affordable diagnostic methods and decision-support tools for diseases with substantial outbreak potential could improve the timely recognition of reportable diseases. On-going health-care provider and laboratory outreach, education, and 24-hour access to public health professionals are needed to enhance reporting of urgent health threats. Electronic laboratory reporting (i.e., the automated transfer of designated data from a laboratory database to a public health data repository using a defined message structure) also will improve the timeliness and completeness of reporting notifiable conditions (6)(7)(8) and can serve as a model for electronic reporting of a wider range of clinical information. A comprehensive surveillance effort supports timely investigation (i.e., tracking of cases once an outbreak has been recognized) and data needs for managing the public health response to an outbreak or terrorist event.\n# Pattern Recognition\nStatistical tools for pattern recognition and aberration detection can be applied to screen data for patterns warranting further public health investigation and to enhance recognition of subtle or obscure outbreak patterns (9). Automated analysis and visualization tools can lessen the need for frequent and intensive manual analysis of surveillance data.\n# New Data Types\nMany new surveillance systems, loosely termed syndromic surveillance systems, use data that are not diagnostic of a disease but that might indicate the early stages of an outbreak. The scope of this framework is broader than these novel systems, yet the wide-ranging definitions and expectations of syndromic surveillance require clarification. Syndromic surveillance for early outbreak detection is an investigational approach where health department staff, assisted by automated data acquisition and generation of statistical signals, monitor disease indicators continually (real-time) or at least daily (near real-time) to detect outbreaks of diseases earlier and more completely than might otherwise be possible with traditional public health methods (e.g., by reportable disease surveillance and telephone consultation). The distinguishing characteristic of syndromic surveillance is the use of indicator data types. For example, a laboratory is a data source that can support traditional disease case reporting by submitting reports of confirmatory laboratory results for notifiable conditions; however, test requests are a type of laboratory data that might be used as an outbreak indicator by tracking excess volume of test requests for diseases that typically cause outbreaks. New data types have been used by public health to enhance surveillance, reflecting events that might precede a clinical diagnosis (e.g., patient's chief complaints in emergency departments, clinical impressions on ambulance log sheets, prescriptions filled, retail drug and product purchases, school or work absenteeism, and constellations of medical signs and symptoms in persons seen in various clinical settings).\nOutbreak detection is the overriding purpose of syndromic surveillance for terrorism preparedness. Enhanced casefinding and monitoring the course and population characteristics of a recognized outbreak also are potential benefits of syndromic surveillance (4). A manual syndromic surveillance system was used to detect additional anthrax cases in the fall of 2001 when the outbreak was recognized (10). Complicating the understanding of syndromic surveillance is that syndromes have been used for case detection and management of diseases when the condition is infrequent and the syndrome is relatively specific for the condition of interest. Acute flaccid paralysis is a syndromic marker for poliomyelitis and is used to detect single cases of suspected polio in a timely way to initiate investigation and control measures. In this case, the syndrome is relatively uncommon and serious and serves as a proxy for polio (11). Syndromes also have been used effectively for surveillance in resource-poor settings for sexually transmitted disease detection and control where laboratory confirmation is not possible or practical (12). However, syndromic surveillance for terrorism is not intended for early detection of single cases or limited outbreaks because the early clinical manifestations of diseases that might be caused by terrorism are common and nonspecific (13).\n# Framework\nThis framework is intended to support the evaluation of all public health surveillance systems for the timely detection of outbreaks. The framework is organized into four categories: system description, outbreak detection, experience, and conclusions and recommendations. A comprehensive evaluation will address all four categories.\n# A. System Description\n1. Purpose. The purpose(s) of the system should be explicitly and clearly described and should include the intended uses of the system. The evaluation methods might be prioritized differently for different purposes. For example, if terrorism is expected to be rare, reassurance might be the primary purpose of the terrorism surveillance system. However, for reassurance to be credible, negative results must be accurate and the system should have a demonstrated ability to detect outbreaks of the kind and size being dismissed.\nThe description of purpose should include the indications for implementing the system; whether the system is designed for short-term, high-risk situations or long-term, continuous use; the context in which the system operates (whether it stands alone or augments data from other surveillance systems); what type of outbreaks the system is intended to detect; and what secondary functional value is desired. Designers of the system should specify the desired sensitivity and specificity of the system and whether it is intended to capture small or large events.\n2. Stakeholders. The stakeholders of the system should be listed. Stakeholders include those who provide data for the system and those who use the information generated by the system (e.g., public health practitioners; health-care providers; other health-related data providers; public safety officials; government officials at local, state, and federal levels; community residents; nongovernmental organizations; and commercial systems developers). The stakeholders might vary among different systems and might change as conditions change. Listing stakeholders helps define who the system is intended to serve and provides context for the evaluation results.\n3. Operation. All aspects of the operation of the syndromic surveillance system should be described in detail to allow stakeholders to validate the description of the system and for other interested parties to understand the complexity and resources needed to operate such a system. Detailed system description also will facilitate evaluation by highlighting variations in system operation that are relevant to variations in system performance (Figure 1). Such a conceptual model can facilitate the description of the system. The description of the surveillance process should address 1) systemwide characteristics (data flow [Figure 2]), including data and transmission standards to facilitate interoperability and data sharing between information systems, security, privacy, and confidentiality; 2) data sources (used broadly in this framework to include the dataproducing facility [i.e., the entity sharing data with the public health surveillance system], the data type [e.g., chief complaint, discharge diagnosis, laboratory test order], and the data format [e.g., electronic or paper, text descriptions of events or illnesses, or structured data reworded or stored in standardized format]); 3) data processing before analysis (the data collation, filtering, transformation, and routing functions required for public health to use the data, including the classification and assigning of syndromes); 4) statistical analysis (tools for automated screening of data for potential outbreaks); and 5) epidemiologic analysis, interpretation, and investigation (the rules, procedures, and tools that support decision-making in response to a system signal, including adequate staffing with trained epidemiologists who can review, explore, and interpret the data in a timely manner).\n# B. Outbreak Detection\nThe ability of a system to reliably detect an outbreak at the earliest possible stage depends on the timely capture and processing of the data produced by transactions of health behaviors (e.g., over-the-counter pharmaceutical sales, emergency department visits, and nurse call-line volume) or health-care activities (e.g., laboratory test volume and triage categorization of chief complaint) that might indicate an outbreak; the validity of the data for measuring the conditions of interest at the earliest stage of illness and the quality of those data; and the detection methods applied to these processed surveillance data to distinguish expected events from those indicative of an outbreak.\n1. Timeliness. The timeliness of surveillance approaches for outbreak detection is measured by the lapse of time from exposure to the disease agent to the initiation of a public health intervention. A timeline with interim milestones is proposed to improve the specificity of timeliness measures (Figure 3). Although measuring all of the time points that define the intervals might be impractical or inexact in an applied outbreak setting, measuring intervals in a consistent way can be used to compare alternative outbreak-detection approaches and specific surveillance systems.\n• Onset of exposure: By anchoring the timeline on exposure, the timeliness advantage of different data sources can be assessed and compared. Exposure can most easily be estimated in a pointsource outbreak. Time of exposure is often inferred from knowledge of the agent (e.g., incubation period) and the epidemiology of the outbreak.\n• Onset of symptoms: The interval to symptom onset in each case is defined by the incubation period for the agent. Time of symptom onset might be estimated using case interviews or existing knowledge of the agent and the time of exposure. The incubation period might vary according to host factors and the route and dose of the exposure.\n• Onset of behavior: Following symptom onset, several health behaviors can occur (e.g., purchasing over-thecounter medication from a store, calling in sick to work, or visiting an urgent-care center). When an affected person interacts with the health-care system, a variety of health-care provider behaviors might be performed (e.g., order of a laboratory test and admission to a hospital).\nThe selection of data sources for a system has a strong influence on timeliness. Some of those experiencing symptoms will initiate a health behavior or stimulate a healthcare provider behavior that is a necessary step to being captured in the surveillance system. • Capture of data: The timing of the capture of a behavior by the data-providing facility varies by data type and can be influenced by system design. A retail purchase might be entered in an electronic database at the moment the transaction is completed, or a record might not be generated in a clinical setting until hours after health care was sought. • Completion of data processing: Time is required for the facility providing the data to process the data and produce the files needed for public health. Records might be transmitted to a central repository only periodically (e.g., weekly). Data form can influence processing time (e.g., transcription from paper to electronic form and coding text-based data), and data manipulations needed to de-identify data and prepare necessary files can affect processing time. • Capture of data in public health surveillance system:\nThe time required to transfer data from the data providing facility to the public health entity varies according to the frequency established for routine data transmission and by the data transmission method (e.g., Internet, mail, or courier).\n# • Application of pattern recognition tools/algorithms:\nBefore analytic tools can be applied to the data in the surveillance system, certain processing steps are necessary (e.g., categorization into syndrome categories, application of case definition, and data transformations). • Generation of automated alert: The detection algorithm's alerting interval is a product of how often the algorithm is run and a report generated and the capacity of the algorithm to filter noise and detect an aberration as early as possible in the course of the outbreak. • Initiation of public health investigation: The initiation of a public health investigation occurs when a decision is made to acquire additional data. Analysis and judgment are applied by public health-care providers to the processed surveillance data and other available information to decide whether new data collection is warranted to confirm the existence of an outbreak. The challenge of interpreting data from multiple surveillance systems could diminish potential advantages in timeliness. The focus on outbreak detection allows for investigations of potential outbreaks to proceed before a specific clinical diagnosis is obtained.\n• Initiation of public health intervention: When an outbreak of public health significance is confirmed, interventions can be implemented to control the severity of disease and prevent further spread. Interventions might be of a general nature directed to the recognition of an outbreak (e.g., apply respiratory infection precautions and obtain clinical specimens for diagnosis) or can be specific to the diagnosis (e.g., antibiotic prophylaxis or vaccination).\n# Validity.\nMeasuring the validity of a system for outbreak detection requires an operational definition of an outbreak. Although a statistical deviation from a baseline rate can be useful for triggering further investigation, it is not sufficient for defining an outbreak. In practice, the confirmation of an outbreak is a judgment that depends on past experience with the condition, the severity of the condition, the communicability of the condition, confidence in the diagnosis of the condition, public health concern about outbreaks at the time, having options for effective prevention or control, and the resources required and available to respond. Operationally, an outbreak is defined by the affected public health jurisdiction when the occurrence of a condition has changed sufficiently to warrant public health attention.\nThe validity of a surveillance system for outbreak detection varies according to the outbreak scenario and surveillance system factors. These factors can confound the comparison of systems and must be carefully described in the evaluation. For example, the minimum size of an outbreak that can be detected by a system cannot be objectively compared among systems unless they are identical or differences are accounted for in several ways.\n• Case definitions: Establish the specificity and sensitivity for the condition of interest on the basis of the data source, data type, and response criteria. • Baseline estimation: Determine the stability of the background occurrence of cases. Estimations are affected by factors such as population size and geographic distribution. The performance of detection algorithms will vary by the quality and duration and inherent variability of baseline data. • Reporting delays: Result in incomplete data, introducing bias that will diminish the performance of detection algorithms. • Data characteristics: Includes underlying patterns in the data (e.g., seasonal variation) and systematic errors inherent in the data (e.g., product sales that influence purchasing behaviors unrelated to illness). • Outbreak characteristics: Results from agent, host, and environmental factors that affect the epidemiology of the outbreak. For example, a large aerosol exposure with an agent causing serious disease in a highly susceptible population will have different detection potential than an outbreak of similar size spread person-to-person over a longer time and dispersed distribution. • Statistical analysis: Defines how data are screened for outbreak detection. Detection algorithms have different performance characteristics under different outbreak conditions. • Epidemiologic analysis, interpretation, and investigation: The procedures, resources, and tools for analysis, interpretation, and response that can substantially affect the ability to detect and respond to outbreaks.\n# Validation Approaches\nDifferent approaches to outbreak detection need to be evaluated under the same conditions to isolate the unique features of the system (e.g., data type) from the outbreak characteristics and the health department capacity. The data needed to evaluate and compare the performance of surveillance systems for early outbreak detection can be obtained from naturally occurring outbreaks or through simulation.\nControlled comparisons of surveillance systems for detection of deliberately induced outbreaks will be difficult because of the infrequency of such outbreaks and the diversity of systems and outbreak settings. However, understanding the value of different surveillance approaches to early detection will increase as descriptions of their experience with detecting and missing naturally occurring outbreaks accumulate. Accumulation of experience descriptions is made more difficult by not having standard methods for measuring outbreak detection successes and failures across systems and by the diversity of surveillance system and outbreak factors that influence performance. Standardized classification of system and outbreak factors will enable comparison of experiences across systems. Pending the development of classification standards, descriptive evaluation should include as much detail as possible. Proxy outbreak scenarios reflect the types of naturally occurring outbreaks that should not be missed to instill confidence in the ability of these systems to detect outbreaks caused by terrorism. Examples of proxy events or outbreaks include seasonal events (e.g., increases in influenza, norovirus gastroenteritis, and other infectious respiratory agents) and community outbreaks (e.g., foodborne, waterborne, hepatitis A, child-care-associated shigellosis, legionellosis, and coccidioidomycosis and histoplasmosis in areas where the diseases are endemic).\nThe measurement of outbreaks detected, false alarms, and outbreaks missed or detected late should be designed as a routine part any system workflow and conducted with minimal effort or complexity. Routine reporting should be automated where possible. Relevant information needs include: the number of statistical aberrations detected at a set threshold in a defined period of time (e.g., frequency per month at a given p-value); the action taken as a result of the signals (e.g., review for data errors, in-depth follow-up analysis of the specific conditions within the syndrome category, manual epidemiologic analysis to characterize a signal, examining data from other systems, and increasing the frequency of reporting from affected sites); resources directed to the follow-up of the alert; public health response that resulted (e.g., an alert to clinicians, timely dissemination of information to other health entities, a vaccination campaign, or no further Generation of a response); documentation of how every recognized outbreak in the jurisdiction was detected; an assessment of the value of the follow-up effort (e.g., the effort was an appropriate application of public health resources); a detailed description of the agent, host, and environmental conditions of the outbreak; and the number of outbreaks detected only late in their course or in retrospect.\nTo evaluate the relative value of different methods for outbreak detection, a direct comparison approach is needed. For example, if a health department detects a substantial number of its outbreaks through telephone consultations, then a phone call tracking system might produce the data needed to compare telephone consults with other approaches for early detection of outbreaks.\nAs an alternative to naturally occurring outbreaks, simulations can allow for the control and modification of agent, host, and environmental factors to study system performance across a range of common scenarios. However, simulations are limited in their ability to mimic the diversity and unpredictability of real-life events. Whenever possible, simulated outbreaks should be superimposed on historical trend data. To evaluate detection algorithms comparatively, a shared challenge problem and data set would be helpful. Simulation is limited by the availability of well-documented outbreak scenarios (e.g., organism or agent characteristics, transmission characteristics, and population characteristics). Simulations should incorporate data for each of the factors described previously. Multiple simulation runs should be used to test algorithm performance in different outbreak scenarios, allowing for generation of operating characteristic curves that reflect performance in a range of conditions.\nFocused studies to validate the performance of limited aspects of systems (e.g., data sources, case definitions, statistical methods, and timeliness of reporting) can provide indirect evidence of system performance. Component studies also can test assumptions about outbreak scenarios and support better data simulation. Syndrome case definitions for certain specific data sources need to be validated. Component validation studies should emphasize outbreak detection over case detection. These studies contain explicit hypotheses and research questions and should be shared in a manner to advance the development of outbreak detection systems without unnecessary duplication.\n# Statistical Assessment of Validity\nSurveillance systems must balance the risk for an outbreak, the value of early intervention, and the finite resources for investigation. Perceived high risk and high value of timely detection support high sensitivity and low thresholds for investigation. A low threshold can prompt resource-intensive investigations and occupy vital staff, and a high threshold might delay detection and intervention. The perceived threat of an outbreak, the community value attached to early detection, and the investigation resources available might vary over time. As a result, specifying a fixed relation between optimal sensitivity and predictive value for purposes of evaluation might be difficult.\nThe sensitivity and PVP and PVN are closely linked and considered together in this framework. Sensitivity is the percentage of outbreaks occurring in the jurisdiction detected by the system. PVP reflects the probability of a system signal being an outbreak. PVN reflects the probability that no outbreak is occurring when the system does not yield a signal. The calculation of sensitivity and predictive value is described in detail in the updated guidelines for evaluating public health surveillance systems (1). Measurement of sensitivity requires an alternative data source of high quality (e.g., \"gold\" standard) to confirm outbreaks in the population that were missed by the surveillance system. Sensitivity for outbreak detection could be assessed through capture-recapture techniques with two independent data sources (14). The high costs associated with responding to false alarms and with delayed response to outbreaks demand efforts to quantify and limit the impact of both. As long as the likelihood of terrorism is extremely low, PVP will remain near zero and a certain level of nonterrorism signals will be a necessary part of conducting surveillance for the detection of terrorism. Better performance can be achieved in one attribute (e.g., sensitivity) without a performance decrement in another (e.g., PVP) by changing the system (e.g., adding a data type or applying a better detection algorithm). Improving sensitivity by lowering the cut-off for signaling an outbreak will reduce PVP. Sensitivity and PVP for these surveillance systems will ultimately be calibrated in each system to balance the secondary benefits (e.g., detection of naturally occurring outbreaks, disease case finding and management, reassurance of no outbreak during periods of heightened risk, and a stronger reporting and consultation relation between public health and clinical medicine) with the locally acceptable level of false alarms.\n# Data Quality\nThe validity of syndromic surveillance system data is dependent on data quality. Error-prone systems and data prone to inaccurate measurement can negatively affect detection of unusual trends. Although data quality might be a less critical problem for screening common, nonspecific indicators for statistical aberrations, quality should be evaluated and improved to the extent possible. Measuring data quality is dependent on a standard (e.g., medical record review or fabricated test data with values known to the evaluator). The updated May 7, guidelines for evaluating public health surveillance systems (1) describe data quality in additional detail.\n• Representativeness: When case ascertainment within a population is incomplete (e.g., in a sentinel system or a statistically based sample), representativeness reflects whether a system accurately describes the distribution of cases by time, place, and person. Geographic representativeness is particularly important for detecting outbreaks of infectious diseases. • Completeness of data: The frequency of unknown or blank responses to data items in the system can be used to measure the level of completeness. For systems that update data from previous transmissions, time should be factored into measurement by indicating the percentage of records that are complete (i.e., all variables are captured for a record) on initial report and within an appropriate interval (e.g., 48 hours) of submission. Sites with substantial reporting delays can be flagged for reliability concerns and targeted for improvement. Incomplete data can require follow-up before analysis, with associated decreases in timeliness and increase in cost. When multiple data providers contribute to a common data store for statistical analysis, the percentage of reporting sources that submit their data on a routine interval (e.g., every 24 hours) conveys the completeness of the aggregate database for routine analysis. Evaluation of completeness should include a description of the problems experienced with manual data management (e.g., coding errors or loss of data) and the problems with automated data management (e.g., programming errors or inappropriate filtering of data).\n# C. System Experience\nThe performance attributes described in this section convey the experience that has accrued in using the system.\n1. System usefulness. A surveillance system is useful for outbreak detection depending on its contribution to the early detection of outbreaks of public health significance that leads to an effective intervention. An assessment of usefulness goes beyond detection to address the impact or value added by its application. Measurement of usefulness is inexact. As with validity, measurement will benefit from common terminology and standard data elements. In the interim, detailed efforts to describe and illustrate the consequences of early detection efforts will improve understanding of their usefulness.\nEvaluation should begin with a review of the objectives of the system and should consider the priorities. To the extent possible, usefulness should be described by the disease prevention and control actions taken as a result of the analysis and interpretation of the data from the system.\nThe impact of the surveillance system should be contrasted with other mechanisms available for outbreak detection. An assessment of usefulness should list the outbreaks detected and the role that different methods played in the identification of each one. Examples of how the system has been used to detect or track health problems other than outbreaks in the community should be included. The public health response to the outbreaks and health problems detected should be described as well as how data from new or modified surveillance systems support inferences about disease patterns that would not be possible without them.\nSurveillance systems for early outbreak detection are sometimes justified for the reassurance they provide when aberrant patterns are not apparent during a heightened risk period or when the incidence of cases declines during an outbreak. When community reassurance is claimed as a benefit of the surveillance system, reassurance should be defined and the measurement quantified (e.g., number of phone calls from the public on a health department hotline, successful press conferences, satisfaction of public health decision-makers, or resources to institutionalize the new surveillance system). A description should include who is reassured and of what they are reassured, and reassurance should be evaluated for validity by estimating the PVN.\n2. Flexibility. The flexibility of a surveillance system refers to the system's ability to change as needs change. The adaptation to changing detection needs or operating conditions should occur with minimal additional time, personnel, or other resources. Flexibility generally improves the more data processing is handled centrally rather than distributed to individual data-providing facilities because fewer system and operator behavior changes are needed. Flexibility should address the ability of the system to apply evolving data standards and code sets as reflected in Public Health Information Network (PHIN) standards (http://www.cdc.gov/phin). Flexibility includes the adaptability of the system to shift from outbreak detection to outbreak management. The flexibility of the system to meet changing detection needs can include the ability to add unique data to refine signal detection, to capture exposure and other data relevant to managing an outbreak, to add data providers to increase population coverage and detect or track low frequency events, to modify case definitions (the aggregation of codes into syndrome groupings), to improve the detection algorithm to filter random variations in trends more efficiently, and to adjust the detection threshold. Flexibility also can be reflected by the ability of the system to detect and monitor naturally occurring outbreaks in the absence of terrorism. System flexibility is needed to balance the risk for an outbreak, the value of early intervention, and the resources for investigation as understanding of these factors changes.\n3. System acceptability. As with the routine evaluation of public health surveillance systems (1), the acceptability of a surveillance system for early outbreak detection is reflected by the willingness of participants and stakeholders to contribute to the data collection and analysis. This concept includes the authority and willingness to share electronic health data and should include an assessment of the legal basis for the collection of prediagnosis data and the implications of privacy laws (e.g., Health Insurance Portability and Accountability Act Privacy Rule) (15). All states have broad disease-reporting laws that require reporting of diseases of public health importance, and many of these laws appear compatible with the authority to receive syndromic surveillance data (16). The authority to require reporting of indicator data for persons who lack evidence of a reportable condition and in the absence of an emergency is less clear and needs to be verified by jurisdictions. Acceptability can vary over time as the threat level, perceived value of early detection, support for the methods of surveillance, and resources fluctuate.\nAcceptability of a system can be inferred from the extent of its adoption. Acceptability is reflected by the participation rate of potential reporting sources, by the completeness of data reporting, and by the timeliness of person-dependent steps in the system (e.g., manual data entry from emergency department logs as distinguished from electronic data from the normal clinical workflow).\n4. Portability. The portability of a surveillance system addresses how well the system could be duplicated in another setting. Adherence to the PHIN standards can enhance portability by reducing variability in the application of information technology between sites. Reliance on person-dependent steps, including judgment and action criteria (e.g., for analysis and interpretation) should be fully documented to improve system portability. Portability also is influenced by the simplicity of the system. Examples should be provided of the deployment of similar systems in other settings, and the experience of those efforts should be described. In the absence of examples, features of the system that might support or detract from portability should be described.\n5. System stability. The stability of a surveillance system refers to its resilience to system changes (e.g., change in coding from International Classifications of Disease, Ninth Revision to ICD-10). Stability can be demonstrated by the duration and consistent operation of the system. System stability is distinguished from the reliability of data elements within the system. The consistent representation of the condition under surveillance (reliability) is an aspect of data quality. Stability can be measured by the frequency of system outages or downtime for servicing during periods of need, including downtime of data providers, the frequency of personnel deficiencies from staff turnover, and budget constraints. Ongoing support by system designers and evolving software updates might improve system stability. Stability also can be reflected in the extent of control over costs and system changes that the sponsoring agency maintains.\n6. System costs. Cost is a vital factor in assessing the relative value of surveillance for terrorism preparedness. Costeffectiveness analyses and data modeling are needed under a range of scenarios to estimate the value of innovations in surveillance for outbreak detection and terrorism preparedness (17). Improved methods of measuring cost and impact are needed. Costs borne by data providers should be noted; however, the cost perspective should be that of the community (societal perspective) to account for costs of prevention and treatment born by the community.\nDirect costs include the fees paid for software and data, the personnel salary and support expenses (e.g., training, equipment support, and travel), and other resources needed to operate the system and produce information for public health decisions (e.g. office supplies, Internet and telephone lines, and other communication equipment). Fixed costs for running the system should be differentiated from the variable costs of responding to system alarms. Variable costs include the cost of follow-up activities (e.g., for diagnosis, case-management, or community interventions). The cost of responding to false alarms represents a variable but inherent inefficiency of an early detection system that should be accounted for in the evaluation. Similarly, variable costs include the financial and public health costs of missing outbreaks entirely or recognizing them late. Costs vary because the sensitivity and timeliness of the detection methods can be modified according to changes in tolerance for missing outbreaks and for responding to false alarms. Similarly, the threshold and methods for investigating system alarms can vary with the perceived risk and need to respond. Costs from public health response to false alarms with traditional surveillance systems need to be measured in a comparable way when assessing the relative value of new surveillance methods. Cost savings should be estimated by assessing the impact of prevention and control efforts (e.g., health-care costs and productivity losses averted) Questions to answer include the following:\n• How many investigations were initiated as a result of these data? \n•\n# D. Conclusions and Recommendations for Use and Improvement of Systems for Early Outbreak Detection\nThe evaluation should be summarized to convey the strengths and weaknesses of the system under scrutiny. Summarizing and reporting evaluation findings should facilitate the comparison of systems for those making decisions about new or existing surveillance methods. These conclusions should be validated among stakeholders of the system and modified accordingly. Recommendations should address adoption, continuation, or modification of the surveillance system so that it can better achieve its intended purposes. Recommendations should be disseminated widely and actively interpreted for all appropriate audiences.\nAn Institute of Medicine study concluded that although innovative surveillance methods might be increasingly helpful in the detection and monitoring of outbreaks, a balance is needed between strengthening proven approaches (e.g., diagnosis of infectious illness and strengthening the liaison between clinical-care providers and health departments) and the exploration and evaluation of new approaches (17). Guidance for the evaluation of surveillance systems for outbreak detection is on-going. Many advances are needed in understanding of systems and outbreak characteristics to improve performance metrics. For example, research is needed to understand the personal health and clinical health care behaviors that might serve as early indicators of priority diseases; analytic methods are needed to improve pattern recognition and to integrate multiple streams of data; a shared vocabulary is needed for describing outbreak conditions, managing text-based information, and supporting case definitions; and evaluation research is needed, including costeffectiveness of different surveillance models for early detection, both in real-life comparisons and in simulated data environments, to characterize the size and nature of epidemics that can be detected through innovative surveillance approaches. Pending more robust measures of system performance, the goal of this framework is to improve public health surveillance systems for early outbreak detection by providing practical guidance for evaluation.\n❑ Indicate the frequency of editing and updating the electronic file ❑ Indicate how incomplete records are handled in analysis and reports ❑ Describe how data archiving and disposal is managed ❑ Describe how new data sources or necessary changes in data sources are identified and incorporated in the system.\n# D. Statistical Analysis\n❑ Describe how the health outcome baseline is established: ❑ Describe the population under surveillance ❑ Describe the source, the criteria, and the methods for establishing the background frequencies used to detect aberrations ❑ How much baseline data are managed in the analysis database ❑ Describe analytic methods used in automated analyses (i.e., aberration detection): ❑ Describe in mathematical and statistical detail the algorithms intended to signal an event requiring further investigation ❑ Describe adaptations in analytic methods to account for different outbreak patterns that might be anticipated in different data sources and types and for different outbreak scenarios ❑ Indicate how reporting delays are corrected for in the analysis. ❑ Describe the method of adjusting results for potential confounding factors ❑ Describe how the system adapts over time and the empirical basis for modifications in the methods ❑ Describe the detection process:\n❑ The frequency of data analysis ❑ How an alarm is generated ❑ Where the alarm goes ❑ The type of alarms generated by the system ❑ What is done to ensure that signals are not being missed ❑ Describe the report generation process:\n❑ What routine reports are generated ❑ Whether data are presented graphically or in tables ❑ Whether data can be manipulated to get a specific \n# E. Epidemiologic Analysis, Interpretation, and Investigation\n❑ Describe the process for managing system alarms:\n❑ Describe the special procedures instituted when the alarm is generated (e.g., review for data errors, in-depth manual analysis of the specific conditions within the syndrome category, manual epidemiological analysis to identify subgroups responsible for an alarm, examining data from other systems, increasing the frequency of reporting from affected sites) ❑ Estimate the person-hours that are devoted to review and analysis each day and the interval at which data are analyzed ❑ Indicate documented procedures for managing system alarms. ❑ Indicate communication method that staff is alerted of alarms (e.g., whether they get paged at home, receive an automated e-mail, etc.?) ❑ Indicate the expectations and schedule of staff to actively check the system and schedule, including nights and weekends ❑ Indicate the response options to an alarm and the factors that influence the choice (e.g., wait for an alarm in another system, initiate an onsite investigation, alert clinicians to gather information) ❑ Describe the process for identifying cases for investigation when the data analyzed routinely are unidentified ❑ Describe how independent data types are integrated in the analysis for improved decision making ❑ Describe the rules, procedures, and tools for communication ❑ Indicate the mechanisms used and content guidance provided for sharing results with 1) reporting sources, 2) response community, and 3) the public; ❑ Describe how decisions are made for sending urgent communications and the methods for sending urgent communications ❑ Indicate whether receipt of a communication is acknowledged and how unacknowledged receipt is managed ❑ Indicate how often urgent communications and routine reports are sent ❑ Describe the protocol for conducting surveillance during outbreak management, if one exists ❑ Indicate how often data will be updated and analyzed ❑ Describe how the system can be modified or customized to meet special data needs ❑ Describe how the system will monitor the impact of prevention and control measures ❑ Describe how and how often system components are tested for operational readiness (e.g., 'spiked' data or modeling exercises)\n# A. System-wide Issues\n❑ Describe the political, administrative, and geographic context for the system ❑ Provide a process model that describes the data flow of the system: \n# Appendix. Operations Checklist\nVol. / RR-5"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":293,"cells":{"id":{"kind":"string","value":"c3a0023064dec976d499d10a4f817f805180e6de"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampinresistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided. Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.# Overview\nTreatment of tuberculosis (TB), regardless of the results of drug susceptibility testing (DST), is focused on both curing the individual patient and minimizing the transmission of Mycobacterium tuberculosis to other persons. Thus, effective treatment of TB has benefits for both the individual patient and the community in which the patient resides. However, notable complexities need to be addressed to successfully treat disease resulting from drug-resistant M. tuberculosis isolates compared with treatment of drugsusceptible TB disease, including additional molecular and phenotypic diagnostic tests to determine drug susceptibility; the use of second-line drugs, which have toxicities that increase harms that must be balanced with their benefits; and prolonged treatment durations. The new recommendations provided in this guideline are for the treatment of drug-resistant TB (DR-TB), including multidrug-resistant TB (MDR-TB) and isoniazid-resistant TB, and are intended to help providers identify the therapeutic options associated with improved outcomes (i.e., greater treatment success, fewer adverse events, and fewer deaths) and in the context of individual patient values and preferences. Worthy of emphasis, the committee recommends that only drugs to which the patient's M. tuberculosis isolate has documented, or high likelihood of, susceptibility be included in an effective treatment regimen, noted as an ungraded good practice statement, and consistent with ongoing stewardship efforts for the optimal use of antibiotics (1). Drugs known to be ineffective on the basis of in vitro growth-based or molecular DST should not be used. The following alphabetically listed drugs and drug classes were considered for inclusion in treatment regimens: amoxicillin/clavulanate, bedaquiline, carbapenem with clavulanic acid, clofazimine, cycloserine, delamanid, ethambutol, ethionamide, fluoroquinolones, injectable agents, linezolid, macrolides, p-aminosalicylic acid, and pyrazinamide. Of note, pretomanid in combination with bedaquiline and linezolid was recently approved by U.S. Food and Drug Administration (FDA) for the treatment of a specific limited population of adults with pulmonary extensively drugresistant (XDR-TB) or treatment-intolerant or nonresponsive MDR-TB; however, the preparation and completion of these guidelines predated this approval (2). For each drug or drug class, the following Population, Intervention, Comparator, and Outcomes (PICO) question was addressed: In patients with MDR-TB, are outcomes safely improved when regimens include the following individual drugs or drug classes compared with regimens that do not include them?\nThe recommendations in this practice guideline were supported by scientific evidence, including results of a propensity score (PS)-matched individual patient data meta-analyses (IPDMA) conducted using a database of more than 12,000 patient records from 25 countries in support of these guidelines (see APPENDIX A: METHODOLOGY in the online supplement) (3). We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to appraise the quality of evidence and to formulate, write, and grade most recommendations (4,5).\nAlthough published data on costs are noted in these guidelines, the committee did not conduct formal cost-effectiveness analyses of the treatments reviewed to determine a recommendation. The treatment of DR-TB can be complicated and thus is necessarily preceded and accompanied by important components of care relating to the access to TB experts, microbiological and molecular diagnosis, education, monitoring and followup, and global patient-centered strategies. The writing committee considered that these topics are crucial but do not require formal and extensive evidence appraisal in the context of the present guidelines. Following GRADE guidance, it was thus decided that these practices would be addressed in good practice statements. Below, six ungraded good practice statements as well as 25 GRADE-based recommendations addressing 21 PICO questions (Table 1) are listed. Questions were selected according to their importance to clinical practice, as determined by the guideline panel, expert advisors, and patient advocates. The implications of the strength of recommendation, conditional or strong, for patients, clinicians, and policy makers are described in APPENDIX A and shown in Table 2. Detailed and referenced information on treatment of MDR-TB is available below, including a summary of the evidence, and the benefits, harms, and additional considerations of each practice or recommendation.\n\n# Summary of Good Practices\nFor patients being evaluated and treated for any form of drug-resistant TB, the following six ungraded good practice statements are emphasized, as the writing committee had high confidence in their net benefit:\n1. Consultation should be requested with a TB expert when there is suspicion of or confirmation of DR-TB. In the United States, TB experts can be found through CDC-supported TB Centers of Excellence for Training, Education, and Medical Consultation (. cdc.gov/tb/education/rtmc/default.htm), through local health department TB control programs (. gov/tb/links/tboffices.htm), and through international MDR-TB expert groups such as the Global TB Network (6). 2. Molecular DSTs should be obtained for rapid detection of mutations associated with resistance. When rifampin resistance is detected, additional DST should be performed immediately for first-line drugs, fluoroquinolones, and aminoglycosides. Resistance to fluoroquinolones should be excluded whenever isoniazid resistance is found. 3. Regimens should include only drugs to which the patient's M. tuberculosis isolate has documented or high Table 1. Questions Regarding the Treatment of Drug-Resistant Tuberculosis Selected by the Guideline Writing Committee Number of effective drugs in a regimen for MDR-TB 1. Should patients with MDR-TB be prescribed five effective drugs vs. more or fewer agents during the intensive and continuation phases of treatment? Duration of intensive and continuation phases of treatment for MDR-TB 2. Should patients with MDR-TB undergoing intensive-phase treatment be treated for >6 mo after culture conversion or ,6 mo after culture conversion? 3. Should patients with MDR-TB undergoing continuation-phase treatment be treated for >18 mo after culture conversion or ,18 mo after culture conversion? Drug and drug classes for the treatment of MDR-TB 4. In patients with MDR-TB, are outcomes safely improved when regimens include amoxicillin/clavulanate compared with regimens that do not include amoxicillin/clavulanate? 5. In patients with MDR-TB, are outcomes safely improved when regimens include bedaquiline compared with regimens that do not include bedaquiline? 6. In patients with MDR-TB, are outcomes safely improved when regimens include carbapenems with clavulanic acid compared with regimens that do not include them? 7. In patients with MDR-TB, are outcomes safely improved when regimens include clofazimine compared with regimens that do not include clofazimine? 8. In patients with MDR-TB, are outcomes safely improved when regimens include cycloserine compared with regimens that do not include cycloserine? 9. In patients with MDR-TB, are outcomes safely improved when regimens include delamanid compared with regimens that do not include delamanid? 10. In patients with MDR-TB, are outcomes safely improved when regimens include ethambutol compared with regimens that do not include ethambutol? 11. In patients with MDR-TB, are outcomes safely improved when regimens include ethionamide/prothionamide compared with regimens that do not include ethionamide/prothionamide? 12. In patients with MDR-TB, are outcomes safely improved when regimens include fluoroquinolones compared with regimens that do not include fluoroquinolones? 13. In patients with MDR-TB, are outcomes safely improved when regimens include an injectable compared with regimens that do not include an injectable? 14. In patients with MDR-TB, are outcomes safely improved when regimens include linezolid compared with regimens that do not include linezolid? 15. In patients with MDR-TB, are outcomes safely improved when regimens include macrolides compared with regimens that do not include macrolides? 16. In patients with MDR-TB, are outcomes safely improved when regimens include p-aminosalicylic acid compared with regimens that do not include p-aminosalicylic acid? 17. In patients with MDR-TB, are outcomes safely improved when regimens include pyrazinamide compared with regimens that do not include pyrazinamide? Use of a standardized, shorter-course regimen of <12 mo for the treatment of MDR-TB 18. In patients with MDR-TB, does treatment with a standardized MDR-TB regimen for <12 mo lead to better outcomes than treatment with an MDR-TB regimen for 18-24 mo? Treatment of isoniazid-resistant, rifampin-susceptible TB:\n19a. Should patients with isoniazid-resistant TB be treated with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 mo compared with rifampin, ethambutol, and pyrazinamide (without a fluoroquinolone) for 6 mo? 19b. Should patients with isoniazid-resistant TB be treated with a regimen composed of fluoroquinolone, rifampin, and ethambutol for 6 mo and pyrazinamide for the first 2 mo compared with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 mo? Surgery as adjunctive therapy for MDR-TB:\n20. Among patients with MDR/XDR TB receiving antimicrobial therapy, does lung resection surgery (i.e., lobectomy or pneumonectomy) lead to better outcomes than no surgery? Management of contacts exposed to an infectious patient with MDR-TB:\n21. Should contacts exposed to an infectious patient with MDR-TB be offered LTBI treatment vs. followed with observation alone?\nlikelihood of susceptibility (hereafter defined as effective). Drugs known to be ineffective based on in vitro growthbased or molecular resistance should NOT be used. This recommendation applies to all drugs and treatment regimens discussed in this practice guideline, unless reliable methods of testing susceptibility for a drug have yet to be developed. 4. Treatment response should be monitored clinically, radiographically, and bacteriologically, with cultures obtained at least monthly for pulmonary TB. When cultures remain positive after 3 months of treatment, susceptibility tests for drugs should be repeated.\nWeight and other measures of clinical response should be recorded monthly. 5. Patients should be educated and asked about adverse effects at each visit. Adverse effects should be investigated and ameliorated. 6. Patient-centered case management helps patients understand their diagnoses, understand and participate in their treatment, and discuss potential barriers to treatment. Patient-centered strategies and interventions should be used to minimize barriers to treatment.\n\n# Summary of Recommendations\nFor the selection of an effective MDR-TB treatment regimen and duration of MDR-TB treatment:\n1. We suggest using at least five drugs in the intensive phase of treatment and four drugs in the continuation phase of treatment (conditional recommendation, very low certainty in the evidence). 2. We suggest an intensive-phase duration of treatment of between 5 and 7 months after culture conversion (conditional recommendation, very low certainty in the evidence). 3. We suggest a total treatment duration of between 15 and 21 months after culture conversion (conditional recommendations, very low certainty in the evidence). 4. In patients with pre-XDR-TB and XDR-TB, which are both subsets of MDR-TB, we suggest a total treatment duration of between 15 and 24 months after culture conversion (conditional recommendations, very low certainty in the evidence).\nFor the selection of oral drugs for MDR-TB treatment (in order of strength of recommendation):\n5. We recommend including a latergeneration fluoroquinolone (levofloxacin or moxifloxacin) (strong recommendation, low certainty of evidence). 6. We recommend including bedaquiline (strong recommendation, very low certainty in the evidence). 7. We suggest including linezolid (conditional recommendation, very low certainty in the evidence).\n8. We suggest including clofazimine (conditional recommendation, very low certainty of evidence). 9. We suggest including cycloserine (conditional recommendation, very low certainty in the evidence). 10. We suggest including ethambutol only when other more effective drugs cannot be assembled to achieve a total of five drugs in the regimen (conditional recommendation, very low certainty in the evidence). 11. We suggest including pyrazinamide in a regimen for treatment of patients with MDR-TB or with isoniazidresistant TB, when the M. tuberculosis isolate has not been found resistant to pyrazinamide (conditional recommendation, very low certainty in the evidence). 12. The guideline panel was unable to make a clinical recommendation for or against delamanid because of the absence of data in the PS-matched IPDMA conducted for this practice guideline. We make a research recommendation for the conduct of randomized clinical trials and cohort studies evaluating the efficacy, safety, and tolerability of delamanid in combination with other oral agents. Until additional data are available, the guideline panel concurs with the conditional recommendation of the 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis\n\n# For patients\nThe overwhelming majority of individuals in this situation would want the recommended course of action, and only a small minority would not.\nThe majority of individuals in this situation would want the suggested course of action, but a sizeable minority would not.\n\n# For clinicians\nThe overwhelming majority of individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.\nDifferent choices will be appropriate for different patients, and you must help each patient arrive at a management decision consistent with her or his values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences.\nClinicians should expect to spend more time with patients when working toward a decision.\nFor policy makers The recommendation can be adapted as policy in most situations, including for the use as performance indicators.\nTreatment that delamanid may be included in the treatment of patients with MDR/rifampin-resistant (RR)-TB aged >3 years on longer regimens (7).\nFor selected oral drugs previously included in regimens for the treatment of MDR-TB: 13. We recommend NOT including amoxicillin-clavulanate, with the exception of when the patient is receiving a carbapenem wherein the inclusion of clavulanate is necessary (strong recommendation, very low certainty in the evidence). 14. We recommend NOT including the macrolides azithromycin and clarithromycin (strong recommendation, very low certainty in the evidence). 15. We suggest NOT including ethionamide/prothionamide if more effective drugs are available to construct a regimen with at least five effective drugs (conditional recommendation, very low certainty in the evidence). 16. We suggest NOT including p-aminosalicylic acid in a regimen if more effective drugs are available to construct a regimen with at least five effective drugs (conditional recommendation, very low certainty in the evidence).\nFor the selection of drugs administered through injection when needed to compose an effective treatment regimen for MDR-TB: 17. We suggest including amikacin or streptomycin when susceptibility to these drugs is confirmed (conditional recommendation, very low certainty of evidence). 18. We suggest including a carbapenem (always to be used with amoxicillinclavulanic acid) (conditional recommendation, very low certainty of evidence). 19. We suggest NOT including kanamycin or capreomycin (conditional recommendation, very low certainty in the evidence).\nA summary of the recommendations on drugs, the certainty in the evidence, and the relative risks of success and death is provided in Figure 1. Additional details and other outcomes of interest are provided in the section on Drugs and Drug Classes and For the use of the WHO-recommended standardized shorter-course 9-to 12-month regimen for MDR-TB: 20. The shorter-course regimen is standardized with the use of kanamycin (which the committee recommends against using) and includes drugs for which there is documented or high likelihood of resistance (e.g., isoniazid, ethionamide, pyrazinamide). Although the STREAM (Standard Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB) Stage 1 randomized trial found the shorter-course regimen to be noninferior to longer injectablecontaining regimens with respect to the primary efficacy outcome (8), the guideline committee cannot make a recommendation either for or against this standardized shorter-course regimen, compared with longer individualized all-oral regimens that can be composed in accordance with the recommendations in this practice guideline. We make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is documented or highly likely.\nFor the role of surgery in the treatment of MDR-TB: 21. We suggest elective partial lung resection (e.g., lobectomy or wedge resection), rather than medical therapy alone, for adults with MDR-TB receiving antimicrobial-based therapy (conditional recommendation, very low certainty in the evidence). The writing committee believes this option would be beneficial for patients for whom clinical judgement, supported by bacteriological and radiographic data, suggest a strong risk of treatment failure or relapse with medical therapy alone. 22. We suggest medical therapy alone, rather than including elective total lung resection (pneumonectomy), for adults with MDR-TB receiving antimicrobial therapy (conditional recommendation, very low certainty in the evidence).\nFor the treatment of isoniazid-resistant TB: 23. We suggest adding a later-generation fluoroquinolone to a 6-month regimen of daily rifampin, ethambutol, and pyrazinamide for patients with isoniazid-resistant TB (conditional recommendation, very low certainty in the evidence). 24. In patients with isoniazid-resistant TB treated with a daily regimen of a latergeneration fluoroquinolone, rifampin, ethambutol, and pyrazinamide, we suggest that the duration of pyrazinamide can be shortened to 2 months in selected situations (i.e., noncavitary and lower burden disease or toxicity from pyrazinamide) (conditional recommendation, very low certainty in the evidence).\nFor the management of contacts to patients with MDR-TB: 25. We suggest offering treatment for latent TB infection (LTBI) for contacts to patients with MDR-TB versus following with observation alone (conditional recommendation, very low certainty in the evidence). We suggest 6 to 12 months of treatment with a later-generation fluoroquinolone alone or with a second drug, on the basis of drug susceptibility of the source-case M. tuberculosis isolate. On the basis of evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug.\nIn this guideline, we provide new recommendations for treatment of MDR-TB and for treatment of isoniazid-resistant TB. On the basis of the evidence review conducted for this guideline, a clinical strategy tool for building a treatment regimen for MDR-TB is provided.\n\n# Introduction\nThe American Thoracic Society (ATS), U.S. Centers for Disease Control and Prevention, European Respiratory Society (ERS), and Infectious Diseases Society of America (IDSA) have jointly developed these Drug-Resistant Tuberculosis guidelines. These new recommendations are based on the certainty in the evidence (also known as the quality of evidence) and developed based on the evidence that was appraised using GRADE methodology, which incorporates patient values and costs as well as judgments about trade-offs between benefits and harms (4,5). A carefully selected panel of experts, screened for conflicts of interest, including specialists in pulmonary medicine, infectious diseases, pediatrics, primary care, public health, epidemiology, economics, pharmacokinetics, microbiology, systematic review methodology, and patient advocacy, was assembled to assess the evidence supporting each recommendation. In contrast to prior analytic approaches, wherein systematic reviews of aggregate data were used for decision-making, a new PS-matched meta-analysis of IPDMA from 12,030 patients, in 50 studies, from 25 countries with confirmed pulmonary RR-TB was conducted for this guideline (3). Given the paucity of high-quality randomized controlled trials conducted in DR-TB, individual data from observational studies represent the next best level of evidence for analyses. Nonetheless, the writing committee noted that observational data are prone to bias and confounding. The 21 PICO questions and associated recommendations are summarized below, all appraised using GRADE methodology (see APPENDIX B). Questions were selected according to their importance to clinical practice, as determined by the guideline panel, expert advisors, and patient advocates. The implications of the strength of recommendation, conditional or strong, for patients, clinicians, and policy makers are described in APPENDIX A. On the basis of the GRADE methodology framework, all recommendations in these guidelines are based on very low certainty in the evidence. The writing committee selected death, treatment success, and serious adverse effects as the endpoints of critical importance on which to generate recommendations. Our meta-analytic approaches included PS matching to AMERICAN THORACIC SOCIETY DOCUMENTS e98 reduce confounding (on the basis of individual-level covariates of age, sex, HIV coinfection, acid-fast bacilli smear results, cavitation on chest radiographs, history of TB treatment with first-line or second-line TB drugs, and number of possibly effective drugs in the regimen, among other variables), described in detail in the publication of the PS-matched IPDMA publication and in APPENDIX A (3). However, the risk of bias remained serious, because the average loss to follow-up across included studies was 10% to 20%. In addition, despite the efforts, there was a large residual imbalance in background regimens used in experimental and control groups.\nThese guidelines are intended for settings in which treatment is individualized and where mycobacterial cultures, molecular (genotypic) and culture-based (phenotypic) DSTs, and radiographic facilities are available (9,10). Of note, published data on costs are referenced in these guidelines, but the committee did not conduct formal costeffectiveness analyses of the treatments and interventions reviewed in relation to determining a recommendation.\nIn these guidelines, MDR-TB is defined specifically as resistance to at least isoniazid and rifampin, the two most important first-line drugs. XDR-TB is a subset of MDR-TB with additional resistance to a fluoroquinolone and a second-line injectable agent. Because XDR-TB evolves from MDR-TB in two steps, the term \"pre-XDR-TB\" was introduced to identify MDR-TB with additional resistance to either one but not both of these classes of drugs. In these guidelines, we also provide recommendations for the treatment of isoniazid-resistant TB.\n\n# Good Practices for Treating DR-TB\nThe fundamentals of TB care, regardless of the treatment selected, rest on ensuring timely diagnosis and initiation of appropriate therapy, with ongoing support and management to achieve successful treatment completion and cure. The responsibility for successful treatment of TB is placed primarily on the provider or program initiating therapy rather than on the patient (11). Nevertheless, a patientcentered approach, described more fully in the section on case management below, requires the involvement of the patient in decision-making. We recommend seeking consultation with an expert in TB when there is suspicion for or confirmation of DR-TB (ungraded good practice statement). In the United States, DR-TB experts can be found through CDCsupported TB Centers of Excellence for Training, Education, and Medical Consultation (/ tb/education/rtmc/default.htm), through local health department TB Control Programs (/ links/tboffices.htm), and through international MDR-TB expert groups such as the British Thoracic Society MDR-TB Clinical Advisory Service (. brit-thoracic.org.uk/) and the Global TB Network (6). Additional good practices in the treatment of patients in need of evaluation for DR-TB include the following:\n\n# Diagnosing TB and Identification of Drug Resistance\nThe potential for drug resistance is considered in every patient. An aggressive effort is made to collect biological specimens for detection of M. tuberculosis and for drug resistance. A rapid test for a least rifampin resistance should ideally be done for every patient, but especially for those at risk of drug resistance. The concern for possible resistance is heightened for patients from areas of the world with at least a moderate incidence of TB in general (>20/100,000) and a high primary MDR-TB prevalence (>2%) (12). Individuals who have or recently had close contact with a patient with infectious DR-TB, especially when the contact is a young child or has HIV infection, are at risk of developing DR-TB. Molecular methods, and more recently whole-genome sequencing (WGS), are increasingly available and can provide information on resistance to all first-line and many second-line drugs. Many public health laboratories provide molecular tests, and WGS is available in selected laboratories. These tests can be used to guide initial therapeutic decisions and contribute to population-level control of DR-TB. Providers should be familiar with phenotypic and genotypic laboratory services available in their locale. In the United States, CDC's Division of Tuberculosis Elimination Laboratory Branch provides testing services for both clinical specimens and isolates of M. tuberculosis (. gov/tb/topic/laboratory/default.htm). CDC's Molecular Detection of Drug Resistance (MDDR) service serves to rapidly identify DR-TB. This service uses DNA sequencing for detection of mutations most frequently associated with resistance to both first-line (e.g., rifampin, isoniazid, ethambutol, and pyrazinamide) as well as second-line drugs (MDDR Service Request Form is available here: https:// www.cdc.gov/tb/topic/laboratory/ MDDRsubmissionform.pdf). Recently published ATS/CDC/IDSA Official Practice Guidelines for the diagnosis of TB provide additional details on the optimal use of diagnostic tools and algorithms (13).\n\n# Treatment and Monitoring of DR-TB\nRegimens should only include drugs to which the patient's isolate has documented or high likelihood of susceptibility. Drugs known to be ineffective, on the basis of in vitro resistance or clinical and epidemiological information (i.e., resistance in the index case or high population prevalence of resistance), should not be used, even when resistance is present in only a small percentage of the mycobacteria in the population. If at least 1% of organisms in a solid media culture exhibit resistance to a drug (the current standard laboratory definition of drug resistance) (14), using that drug in a regimen will increase the risk for poor treatment outcomes, and the isolate will eventually exhibit 100% resistance to the drug. Drugs should be selected based on their efficacy and the likelihood that patients will be able to tolerate them without significant toxicity. Treatment response is monitored clinically (decrease in cough and systemic symptoms and increase in weight), radiographically, and bacteriologically (15)(16)(17)(18). If sputum cultures remain positive after 3 months of treatment, or if there is bacteriological reversion from negative to positive at any time, DST should be repeated (11). Patients should be asked about the clinical response at each visit and weight recorded monthly. Monthly cultures help to identify early evidence of failure (19). Most persons have difficulty taking one or more of the drugs used to treat MDR-TB. Patients should be educated about adverse effects, and all adverse effects should be investigated and ameliorated. Some adverse effects are difficult to tolerate but do not put patients at risk for serious short-or long-term damage to organ systems and can be managed with symptom-specific ancillary medication and supportive care. Nausea\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS\nwith vomiting is common and is not always an indication to discontinue therapy permanently. New-onset vomiting may indicate liver toxicity or, in children especially, increased intracranial pressure. If drug-induced liver toxicity (and increased intracranial pressure) is excluded, vomiting can be managed by changing dosing schedule, giving medications with a small snack (noting that this may affect plasma concentrations of the drug), or premedicating adult patients with an antiemetic (noting that some prolong the QT interval) before the dose. Patients may note fatigue or describe myalgia or arthralgia, but these symptoms are not typically treatment limiting. Although low-grade adverse effects can resolve gradually over time, recognizing the negative impact on patient's quality of life, all adverse effects must be addressed diligently. The Curry International TB Center's guides, Drug Resistant TB: Clinician's Survival Guide and the Nursing Guide for Managing Side Effects to Drug-Resistant TB Treatment, in addition to the World Health Organization (WHO) companion handbook, are good resources to assist in evaluation and management of patients (15,16,18).\n\n# Infection Control and DR-TB\nThree main strategies will reduce the transmission of DR-TB: rapid diagnosis, prompt appropriate treatment, and improved airborne infection control (11,13,20,21). Rapid molecular DST and conventional phenotypic culture-based DST are almost universally available in the United States, Europe, and low-incidence, high-resource countries (22). Targeted active case finding combined with rapid diagnostics leading to effective therapy is a strategy endorsed by WHO (13,23,24).\nTreatment delays have been associated with increased transmission. A systematic review and meta-analysis looking at patientrelated risk factors for transmission of M. tuberculosis found that treatment initiation delays of 28 to 30 days were significantly associated with increased transmission to contacts (25). Effective therapy renders patients with TB, even those with DR-TB, rapidly noninfectious (24,26). The rapid reduction in infectiousness even in the setting of MDR-TB makes outpatient therapy possible, but directly observed therapy (DOT) applied through patientcentered approaches plays an important role in this regard (11,23). Infection control measures such as administrative and environmental controls, and personal protective equipment, listed in order of priority, are important for preventing the transmission of M. tuberculosis regardless of drug susceptibility. Every healthcare facility should have these measures in place per CDC guidelines (27). Furthermore, patients should be educated about the importance of infection control measures, such as the value of good ventilation, open windows, and the risks of exposure for children ,5 years of age and immunocompromised individuals (21).\nCase Management for DR-TB Case management is a collaborative process that entails engaging with patients; comprehensively assessing, monitoring, and attending to patients' physical, psychological, social, material, and informational needs; care planning; medication management; facilitating access to services; and functioning as patient advocate/agent (28)(29)(30). Commonly, case management is used in community and public health settings to coordinate services for patients with chronic and complex health conditions and to attain good, quality, cost-effective outcomes. The practice of case management has long been considered an important component of care for patients with TB (20,31,32), and a patient-centered (or family-centered in case of children) approach is preferred (7,11,33). Patient-centered case management helps patients understand their diagnosis and treatment and participate in treatment selection and promotes communication about factors that matter to the patient (33)(34)(35). Importantly, a patient-centered approach includes discussions with the patient to identify potential barriers to care and the selection of strategies and interventions to address and minimize these barriers (7,11,33,(35)(36)(37).\nCase management tools for drugresistant TB include a drug-o-gram, which organizes clinical details in a format that aligns test results with treatment, as well as laboratory, bacteriology, and other toxicity monitoring flow sheets. This format is a visible representation of pertinent clinical parameters being tracked (16,38). A monitoring checklist or care plan can also help the case manager ensure timely drug toxicity monitoring and provision of examinations required to assess a patient's response to treatment. Case management interventions that have demonstrated favorable outcomes include the provision of patient education and counseling related to diagnosis, treatment, and adherence, as well as the use of treatment adherence interventions alongside suitable patientcentered administration options. For example, home or community-based DOT is shown to be preferred and associated with greater likelihood of treatment success compared with health facility-based DOT or self-administered therapy (11,39). Enhancing treatment completion through the use of patient-centered case management strategies, including DOT, also aims to reduce risk of acquisition of drug resistance, which aligns with international efforts in antibiotic stewardship (1). Recent WHO guidelines evaluated various adherence interventions and outcomes of TB treatment through a systematic review of clinical trials and observational studies, identifying data from 129 studies for quantitative analysis published through 2018 (39). Another meta-analysis of 22 randomized controlled trials of DOT and other interventions to improve adherence reported significant increases in cure with DOT (18%) and with patient education and counseling (16%). Compared with the complementary groups, loss to follow-up was 49% lower with DOT, 26% lower with financial incentives, and 13% lower with patient education and counseling. However, there was no significant reduction in mortality (40).\nThe use of video-enabled electronic devices to conduct DOT is expanding rapidly (41,42). Electronic methods for DOT have the potential to improve TB treatment outcomes and extend public health support to patients with TB when face-to-face DOT is not feasible. Pilot studies have reported that patients find electronic methods for DOT to be both acceptable and more convenient than traditional in-person DOT. These studies also reported good adherence, fewer unobserved doses, and high satisfaction among study participants (43)(44)(45)(46). Further evidence is needed to validate electronically observed therapy under more diverse conditions, with larger cross-sections of patient subgroups, including children, and to determine to what degree these methods impact treatment outcomes for patients with DR-TB (39,(47)(48)(49).\n\n# Treatment of MDR-TB, Number of Drugs, and Duration of Treatment Phases\n\n# Number of Drugs in the Regimen\nUp until the recent 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment (7), WHO has recommended at least five drugs in the intensive phase of treatment, defined by the use of a second-line injectable agent (23). The recent WHO change to recommending at least four effective drugs at initiation of treatment is graded as a conditional recommendation with very low certainty in the estimates of effect (7). Of note, both our guideline committee and the 2019 WHO guidelines promote the use of newer or repurposed oral agents with greater efficacy and deemphasize the use of injectable agents (7). Given these changes and that an injectable drug is no longer obligatory, the intensive phase can no longer be defined by the inclusion of injectables. In this guideline, we define the intensive phase to be the initiation phase of treatment with at least five effective drugs. These recommendations do not apply to the WHO-endorsed shorter-course 9-to 12-month (Bangladesh) regimen, which combines seven drugs for 4 months or until sputum smear conversion, whichever is the longer period, followed by four drugs in the continuation phase (23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. For the analysis of number of effective drugs, we counted drugs with published evidence from randomized trials of effectiveness (3). Hence, we counted ethambutol, pyrazinamide, all injectables and fluoroquinolones, ethionamide/prothionamide, cycloserine/terizidone, and p-aminosalicylic acid on the basis of DST showing susceptibility and counted clofazimine, linezolid, carbapenems, bedaquiline, and delamanid-if susceptible, or no DST for that drug. We did not count amoxicillin/clavulanate (in the absence of a carbapenem) and macrolides as effective drugs (see PICO Questions 4 and 15). The intensive phase was defined by the use of an injectable agent (other than imipenem-cilastatin or meropenem). Culture conversion was not an outcome measure. Instead, the analysis assessed the association of the number of possibly effective drugs included in the first 2 weeks of the intensive phase with the two final treatment outcomes: 1) \"treatment success,\" which includes both cure and treatment completed; and 2) mortality. For the intensive phase of treatment, final treatment outcomes were compared between those treated with five or more (n = 2,527) effective drugs and those treated with three or four effective drugs (n = 5,923).\nBenefits. In our PS-matched IPDMA, using zero to two effective drugs as the reference value, treatment success was most likely with regimens for MDR-TB containing five effective drugs in the intensive phase (Table 3). Mortality was also significantly reduced for those taking five or six effective drugs.\nThe number of drugs used in the continuation phase was also evaluated (Table 4). In the continuation phase, four Definition of abbreviations: aOR = adjusted odds ratio; CI = confidence interval. *World Health Organization definitions: fail = treatment terminated or need for permanent regimen change of at least two antituberculosis drugs because of: lack of conversion by the end of the intensive phase, bacteriological reversion in the continuation phase after conversion to negative, evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs or adverse drug reactions. † Relapse was defined as a positive bacteriological culture in the 12 months after treatment completion.\nPICO Question 1: Should patients with MDR-TB be prescribed five effective drugs versus more or fewer agents during the intensive and continuation phases of treatment?\nRecommendation 1a: We suggest using at least five drugs in the intensive phase of treatment of MDR-TB (conditional recommendation, very low certainty of evidence).\n\n# Recommendation 1b:\nWe suggest using at least four drugs in the continuation phase of treatment of MDR-TB (conditional recommendation, very low certainty of evidence).\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS\ndrugs gave the greatest success (adjusted odds ratio , 2.3) and four or more drugs the greatest reduction in mortality. Few significant differences were found in patients with pre-XDR-TB or XDR-TB. Subgroup analyses in pre-XDR-TB and XDR-TB did not suggest that a different number of effective drugs for the intensive and continuation phases was required to achieve good outcomes.\nHarms. The recommendation places a higher value on reduced morbidity and greater treatment success than on the as yet unmeasured avoidance of the summative or synergistic toxicity across drugs in the treatment regimen.\nAdditional considerations. Each drug was counted as equivalent in effectiveness, representing the average effectiveness of the most widely used MDR-TB drugs, for the purpose of adjusting for the number of other effective drugs in the regimen. A regimen composition approach with suggested ranking of drugs is provided in the section BUILDING A TREATMENT REGIMEN FOR MDR-TB. The smallest number of drugs to achieve sputum conversion and ensure a cure without relapse minimizes problems with drug-drug interactions, reduces adverse effects, and is cost effective. Injectable drugs are problematic in terms of route of administration, patient preference, significant adverse effects such as hearing loss or vertigo, and costs of administration and monitoring blood levels. On the basis of these limitations, combined with evidence of low efficacy for injectable agents, the use of injectables in defining the intensive phase of treatment is no longer appropriate. WHO has recategorized injectables to a lower grouping and recommended that the injectables only be used when oral medicines from higher categories cannot be used (7). The South African National Department of Health also has endorsed replacing the injectable agents in the shorter-course MDR-TB treatment regimen in adults and children .12 years of age with bedaquiline, on the basis of a retrospective observational study of improved mortality with adding bedaquiline (50). In conjunction, experts from the Sentinel Project on Pediatric Drug-Resistant Tuberculosis () have also called for replacing the injectable drug in children ,12 years of age with an alternative effective drug (51).\nConclusions. At least five drugs should be used in the intensive phase of treatment and four drugs in the continuation phase of treatment of MDR-TB (conditional recommendation, very low certainty of evidence). Drugs of poor or doubtful efficacy should not be added to a regimen purely to ensure that the recommended number of drugs is obtained.\nResearch needs. Randomized controlled trials with fewer but more effective and safer drugs should be undertaken (e.g., TB-PRACTECAL, ClinicalTrials.gov identifier NCT02589782). Randomized trials comparing regimens with and without injectable agents are underway (e.g., STREAM-stage 2, NCT02409290; Evaluating Newly Approved Drugs for Multidrug-resistant TB: endTB, NCT02754765). The effect of duration of individual drugs in the intensive phase on culture conversion as well as treatment cure without relapse should be explored (52).\n\n# Duration of Intensive and Continuation Phases in Treating MDR-TB\nTreatment of both drug-susceptible and MDR-TB has typically been divided across PICO Question 2: Should patients with MDR-TB undergoing intensive-phase treatment be treated for >6 months after culture conversion or ,6 months after culture conversion? Recommendation 2: In patients with MDR-TB, we suggest an intensivephase duration of treatment of between 5 and 7 months after culture conversion (conditional recommendation, very low certainty of evidence). two phases, with an initial \"intensive\" phase that contains more drugs than the subsequent \"continuation\" phase. For MDR-TB, this intensive phase has historically been characterized by the use of an aminoglycoside (amikacin or kanamycin) or a polypeptide (capreomycin) delivered parenterally (53). This approach has been intended to provide greater bactericidal activity during the time when the bacillary burden is highest and reducing the number of drugs in the continuation phase to reduce risk of toxicity and intolerability caused by the multidrug regimen at a phase when the microbial burden has diminished. The 6-month duration of bedaquiline treatment, in part, was developed by analogy, and clinical trials are underway to determine whether this drug may replace aminoglycosides in terms of an initial intensive phase of treatment. The duration of the intensive phase has never been examined through a randomized, controlled clinical trial. Rather, it has been defined by a combination of practicality, the clinical experiences of MDR-TB experts, and, most recently, an IPDMA that resulted in the WHO practice guideline recommendations of 2011 that an intensive phase of at least 8 months' duration be used (54). This represented a departure from the prior recommendations in 2008 that the injectable agent should be continued for at least 6 months and at least 4 months after the patient first becomes and remains smear or culture negative (55). This is similar to current expert guidance provided by the Curry International TB Center Drug Resistant TB: Clinician's Survival Guide, namely \"Intensive phase: recommend at least 6 months beyond culture conversion for the use of injectable agent\" (16). The PS-matched IPDMA completed as part of the present guideline development process includes cohorts that were treated according to this range of durations of the intensive phase and represents the available evidence base for our recommendation. Our analyses and recommendations for the duration of intensive and continuation phases of therapy are anchored to the timing of culture conversion, as this approach factors in that treatment response may vary by patient, resistance patterns, and regimen composition and potency, among other factors. Summary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. The association between treatment duration of the intensive phase (defined by the use of an injectable agent) after culture conversion and outcomes (success, failure, relapse) was examined among 4,122 (49.3%) subjects from 29 studies who had sufficient information to be included in this analysis (3). This total reflected exclusion of studies without a reported intensive-phase duration (n = 942 patients) or time to culture conversion (n = 1,880 patients), as well as 955 (11.4%) patients in the included studies but for whom intensive-phase duration or time to conversion was not known. Patients taking the 9-to 12-month standardized shorter-course regimen were excluded (see PICO Question 18). An additional 464 (5.0%) patients were excluded for conversion after the end of the intensive phase or after 14.3 months, or for an intensive phase exceeding 24.3 months. Among the 4,122 patients included, 3,303 (80.1%) had MDR-TB without resistance to fluoroquinolone or second-line injectable. The remainder had pre-or XDR-TB. To reflect meaningful variations in the duration of the intensive regimen after conversion, stratified analyses were conducted: strata were 0 to 1.0 months, 1.01 to 3.0 months, 3.01 to 5.0 months, 5.01 to 7.0 months, and 7.1 to 15.0 months (see Table 5). The largest proportion (28.6% ) received treatment for 5.01 to 7 (mean, 5.9) months after conversion. Time to conversion was roughly inversely proportional to duration of intensive phase, suggesting that the tendency in the included studies was to treat for a total intensive-phase duration of 5 to 8 months.\nBenefits. The patients who received treatment for 5.01 to 7 months after conversion experienced a 3.3-fold increase in adjusted odds of treatment success (95% confidence interval , 2.1-5.2) compared with the reference group (0-1.0 months of intensive phase after conversion). Some variability was observed in distribution of intensive-phase duration after culture conversion by baseline characteristics: ,10.0% of patients who received longer durations of intensive phase were HIVcoinfected, compared with .15% in the 0.0 to 3.0 month interval groups. Number of (effective) drugs was greater in longer durations than in shorter.\nPatients with MDR-TB who received 5.01 to 7.0 months of intensive-phase treatment after conversion had the highest odds of success in adjusted PS-matched analysis; although other, shorter intervals showed improvement over the reference, <1.0 month of postconversion treatment, the benefits of 5 to 7 months of treatment after conversion were more pronounced (Table 6). The effect estimates were also better for subgroups of MDR only (aOR, 2.0; 95% CI, 1.1-3.4) and pre-XDR (aOR, 1.5; 95% CI, 0.6-3.7) subgroups.\n\n# Harms\nDetailed data on duration-related toxicities were not available through our PS-matched IPDMA. On the basis of the clinical observations and experiences of the MDR-TB experts on the guideline committee, the intensive phase should not be prolonged beyond that considered necessary to optimize treatment outcomes.\nAdditional considerations. No information is available in the datasets on AMERICAN THORACIC SOCIETY DOCUMENTS how duration was selected. Duration selected may reflect interim response to treatment or may reflect a planned duration that is not conditioned on treatment response; the latter is suggested by the observation that duration was inversely related to time to conversion except in the 7.01-to 15-month interval. Analyses were adjusted for possible baseline confounders, relying on PS matching, to reduce the bias introduced. However, the possibility of unmeasured confounding by indication, in particular by time-varying characteristics (such as toxicity, microbiological, radiographic, or clinical results), cannot be ruled out. Such confounding by indication would likely result in an underestimate of the benefit of a longer intensive phase after conversion: patients in the 7.01-to 15-month interval had slower conversion and more poor outcomes than those in the 5.01-to 7.0month interval. Last, the optimal total duration of treatment for MDR-TB using injectable-free, all-oral regimens cannot be determined from these datasets, but clinical trials evaluating newer drugs and all-oral regimens for MDR-TB are underway (56).\nConclusions. We suggest an intensivephase treatment of between 5 and 7 months after culture conversion in patients with MDR-TB (conditional recommendation, very low certainty in the evidence). The clinical context, extent of disease, and response to treatment, among other factors, will play a role in choosing a final duration from within the recommended range. There were limited data in pre-XDR-TB and XDR-TB. Subgroup analyses in pre-XDR and XDR-TB did not suggest that a different duration for the intensive phase would be required to achieve good outcomes. This intensive-phase duration recommendation does not apply to the 9-to 12-month shortercourse regimen addressed in PICO 18.\nResearch needs. Further research is urgently needed to define the optimal durations of treatment using newer drugs and all-oral regimens. Research in defining optimal duration that prevents death or loss to follow-up is also needed. In the short term, further research on datasets that include longitudinal observations that can inform choice of regimen duration would be important to reducing the uncertainty around the present recommendations. In the long term, randomized controlled trials evaluating various intensive phases and durations are needed. Research on stratified medicine approaches that use measures of burden of disease and consider subgroups in the selection of the optimal duration may allow for greater precision and better inform decision-making around the balance of benefits and harms of durations for individual patients (57).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. The association between total duration of treatment after culture conversion and outcomes (success, failure, relapse) was performed on 4,691 observations from 32 studies (3). We excluded 18 studies (n = 2,615) that did not report time to culture conversion and 798 patients from included studies because endpoints were missing. Last, 259 patients were excluded for outlier values in total duration or culture conversion; patients whose outcome was loss to follow-up or death were excluded. Among the 4,691 included, 3,034 had MDR-TB. The remainder had pre-XDR or XDR-TB. To reflect meaningful variations in the duration of treatment after conversion, stratified analyses were conducted: Time to conversion was inversely related to duration of treatment after conversion (Table 7).\nBenefits. Among all resistance groups, durations of 15.01 to 21 months after conversion outperformed the reference (12.01-15 mo); intervals of 15.01 to 18 (aOR, 2.1; 95% CI, 1.4-3.1), 18.01 to 21 (aOR, 1.6; 95% CI, 1.1-2.3), and 21.01 to 24 (aOR, 1.2; 95% CI, 0.9-1.8) months were indistinguishable from each other (Table 8). In the MDR-only subgroup, the duration of 15.01 to 18.0 months was associated with similar to slightly improved outcomes compared with reference (aOR, 1.8; 95% CI, 1.0-3.0) (data not shown). Results for the pre-XDR-TB subgroup supported the notion that longer intervals were associated with success; effects were statistically significant, with confidence intervals that were wide and overlapping across durations of 15.01 to 24 months (data not shown). PICO Question 3: Should patients with MDR-TB undergoing continuation-phase treatment be treated for >18 months after culture conversion or ,18 months after culture conversion?\nRecommendation 3a: In patients with MDR-TB, we suggest a total treatment duration of between 15 and 21 months after culture conversion (conditional recommendations, very low certainty in the evidence).\n\n# Recommendation 3b:\nIn patients with pre-XDR-TB and XDR-TB, we suggest a total treatment duration of between 15 and 24 months after culture conversion (conditional recommendations, very low certainty in the evidence).\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS e104\nHarms. Extending treatment longer than necessary can engender additional toxicity and costs to patients and health systems. For this reason, recommendations are for the minimum duration found to have a significant treatment advantage, and different recommendations are made for the MDR only and XDR/pre-XDR subgroups.\nAdditional considerations. No information on how duration was selected is available from the data. Duration selection may reflect interim response to treatment or may reflect a planned duration that is not conditioned on treatment response; the latter is suggested by the observation that duration was inversely related to time to conversion except in the longest interval. Analyses were adjusted for all possible baseline confounders, relying on PS matching, to minimize the bias introduced. Nevertheless, the possibility of unmeasured confounding by indication, in particular by time-varying characteristics, cannot be ruled out. Such confounding by indication would likely result in an underestimate of the benefit of a longer treatment duration after conversion. No significant difference in outcomes was observed across durations for the XDR-TB subgroup, likely because of small numbers and the aforementioned potential bias.\nConclusions. We suggest a total treatment duration of at least 15 and up to 21 months after culture conversion for patients with MDR-TB only. In patients with pre-XDR-TB and XDR-TB, we suggest a total treatment duration of between 15 and 24 months after culture conversion (conditional recommendations, very low certainty in the evidence). The clinical context and extent of disease will be relevant for choosing a final duration from within the recommended range.\nResearch needs. The optimal total duration of regimens composed of only oral drugs urgently needs further research. Defining optimal total durations that prevent death or loss to follow-up also needs study. In the short term, further research on datasets that include longitudinal observations that can inform choice of regimen duration would be very important to reducing the uncertainty around the present recommendation. In the long term, randomized controlled trials comparing different intensive phases and durations are needed. As with the duration of the intensive phase, research is needed in stratified medicine approaches that consider measures of burden of disease, and subgroups in the selection of the optimal total duration will allow for greater precision in selecting and individualizing regimen duration (57).\n\n# Drugs and Drug Classes\nThese guidelines are intended for settings in which treatment is individualized based on DST results and clinical and epidemiological factors. Individualized treatment regimens should only include drugs to which the patient's isolate has documented or high likelihood of susceptibility. Treatment regimens should favor medications that are associated with improved outcomes, as identified in our PS-matched IPDMA, that limit toxicity and that incorporate patient preferences. The following alphabetically listed drugs and drug classes were considered for inclusion in treatment regimens: amoxicillin/clavulanate, bedaquiline, carbapenem with clavulanic acid, clofazimine, cycloserine, delamanid, ethambutol, ethionamide, fluoroquinolones, injectable agents, linezolid, macrolides, p-aminosalicylic acid, and pyrazinamide. For each drug or drug class, the following PICO was addressed: In patients with MDR-TB, are outcomes safely improved when regimens include the following individual drugs or drug classes compared with regimens that do not include them? Amoxicillin/Clavulanate Amoxicillin-clavulanate, consisting of the b-lactam antibiotic amoxicillin and the b-lactamase inhibitor potassium clavulanate, is considered safe and effective for numerous bacterial infections. Although M. tuberculosis has an impenetrable cell wall and produces a b-lactamase inhibitor (58), amoxicillin-clavulanate has been used to treat TB. It is viewed as a \"salvage\" agent when few other PICO Question 4-Amoxicillin/Clavulanate: In patients with MDR-TB, are outcomes safely improved when regimens include amoxicillin/clavulanate compared with regimens that do not include amoxicillin/clavulanate? Recommendation 4: We recommend NOT including amoxicillin-clavulanate in a treatment regimen for patients with MDR-TB, with the exception of when the patient is receiving a carbapenem, wherein the inclusion of clavulanate is necessary (strong recommendation, very low certainty in the evidence). Our recommendation against the use of amoxicillin-clavulanate (except to provide clavulanate when using a carbapenem) in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug as having a notably unfavorable balance of benefits to potential harms. (63,64), and the combination has been reported to be efficacious, safe, and tolerable when added to linezolid and other drugs (65)(66)(67)(68)(69). See PICO Question 6 for the evaluation of carbapenems with amoxicillin-clavulanate.\nSummary of the evidence. Procedures and methodology to assemble and the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA showed that patients who received amoxicillinclavulanate were more likely to have been treated with second-line drugs and to be resistant to fluoroquinolones or any second-line injectable (3). They were more likely to have received a later-generation fluoroquinolone (72%), capreomycin (58%), linezolid (25%), and bedaquiline (8%). In adjusted analyses, patients who received amoxicillin-clavulanate were less likely to have treatment success (aOR, 0.6; 95% CI, 0.5-0.8) and more likely to die (aOR, 1.7; 95% CI, 1.3-2.1) compared with patients who did not receive amoxicillin-clavulanate.\nBenefits. The addition of amoxicillinclavulanate (without coadministration with carbapenems) to a regimen for MDR-TB does not appear to provide benefit.\nHarms. Patients who received amoxicillin-clavulanate were less likely to have treatment success and more likely to die than patients who did not receive amoxicillin-clavulanate. Data on adverse effects were not collected systematically across studies in our PS-matched IPDMA or in most trials. A published systematic review identified diarrhea and candidiasis as key adverse effects associated with amoxicillin-clavulanic acid use (70).\nAdditional considerations. Clavulanic acid is only available as a coformulation with amoxicillin. Therefore, amoxicillin-clavulanate must be given whenever carbapenems are included in an MDR-TB regimen (see PICO Question 6 on carbapenems with clavulanate).\nConclusions. Patients who received amoxicillin-clavulanate were less likely to achieve treatment success and more likely to die than patients who did not receive amoxicillin-clavulanate. These data suggest amoxicillin-clavulanate should not be used in MDR-TB treatment, except to provide clavulanate when using a carbapenem (see PICO Question 6 on carbapenems with clavulanate). Our recommendation against the use of amoxicillin-clavulanate (except to provide clavulanate when using a carbapenem) in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug as having a notably unfavorable balance of benefits to potential harms.\nResearch needs. The development of a clavulanic acid formulation without amoxicillin, for use in combination with carbapenems, would be helpful and would avoid unnecessary toxicities from amoxicillin as well as adhere to international efforts in promoting antimicrobial stewardship (1).\n\n# Bedaquiline\nBedaquiline, a diarylquinoline, approved by FDA in 2013, is the first drug with a novel mechanism of action against M. tuberculosis to have been approved by FDA in .40 years (71,72). Bedaquiline is bactericidal to nonreplicating and actively replicating mycobacteria, through ATP synthase inhibition, and has bactericidal and sterilizing activity in the murine model of TB infection (73). No cross-resistance has been found between bedaquiline and the following: isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin, amikacin, or moxifloxacin. There have been a few reports of cross-resistance with clofazimine PICO Question 5-Bedaquiline: In patients with MDR-TB, are outcomes safely improved when regimens include bedaquiline compared with regimens that do not include bedaquiline? Recommendation 5: We recommend including bedaquiline in a regimen for the treatment of patients with MDR-TB (strong recommendation, very low certainty in the evidence). Our recommendation for the use of bedaquiline is strong despite very low certainty in the evidence because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment including bedaquiline (compared with no bedaquiline) as having a particularly favorable balance of benefits over harms. AMERICAN THORACIC SOCIETY DOCUMENTS e106 (74,75). Bedaquiline is customarily used as part of combination therapy (minimum four-drug therapy) for adults aged >18 years with a diagnosis of pulmonary MDR-TB when an effective treatment regimen cannot otherwise be provided (e.g., mycobacterial isolates show a complicated drug resistance pattern, drug intolerance, or drug-drug interactions) (76). The recommended dose of bedaquiline for the treatment of pulmonary MDR-TB in adults is 400 mg administered orally once daily for 2 weeks, followed by 200 mg administered orally three times weekly, for an entire treatment duration of 24 weeks (72,(76)(77)(78).\nBedaquiline has recently has been identified as the key drug in assembling an all-oral, injectable-free drug regimen in South Africa (79).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PSmatched IPDMA included 411 patients who received bedaquiline-containing regimens, for whom it was assumed that there was no bedaquiline resistance, and 10,932 patients who did not receive bedaquiline (3). Patients who received bedaquiline-containing regimens were more likely to have cavitary disease (82% vs. 62%), to have been treated with second-line drugs (34% vs. 14%), to be infected with an organism resistant to fluoroquinolones (57% vs. 21%) or to any second-line injectable (58% vs. 23%), and to have XDR-TB (29% vs. 13%). They were also more likely to have received a latergeneration fluoroquinolone (69% vs. 54%), linezolid (64% vs. 4%), or clofazimine (48% vs. 4%). Treatment success (cure and completion) was slightly greater (70% vs. 60%; P = 0.001) with bedaquiline, whereas failure/relapse (6% vs. 9%), death (10% vs. 15%), and loss to follow-up (14% vs. 16%) were less frequent in PS-adjusted analyses.\nBenefits. Our PS-matched IPDMA showed that patients treated with bedaquiline-containing regimens were more likely to have treatment success (aOR, 2.0; 95% CI, 1.4-2.9), less likely to experience failure/relapse, and less likely to die (aOR, 0.4; 95% CI, 0.3-0.5; absolute risk reduction, 7.2%). Results were similar when only patients from high-income countries treated with bedaquiline-containing regimens were included and when comparing only patients with XDR-TB who were and were not treated with bedaquiline.\nA recent large program-based observational multinational study confirmed a high treatment success rate (76.9%) with bedaquiline-containing regimens, with a low proportion (5.8%) of interruptions owing to adverse events (80). In our IPDMA, using PS-matched pairs comparing the effects of bedaquiline to those of clofazimine, statistically significant differences for success versus failure/relapse favoring bedaquiline use were observed (aOR, 2.1; 95% CI, 1.1-4.1) (using .170 PS-matched pairs), but statistically significant findings were not observed in mortality or when restricting analyses to high-income countries. PS-matched pairs analyses comparing the effects of various combinations of drugs used with bedaquiline all noted improved outcomes. When comparisons of effects of bedaquiline and linezolid with those of no bedaquiline or linezolid were performed, combination of bedaquiline and linezolid was associated with an aOR of 2.7 (95% CI, 1.5-4.9) for success versus failure/relapse and with an aOR of 0.3 (95% CI, 0.2-0.4) for death versus success/failure/relapse. Similarly, when PS-matched pair analyses comparing the effects of bedaquiline and clofazimine to those of no bedaquiline or clofazimine were performed, combination of bedaquiline and clofazimine was associated with an aOR of 5.0 (95% CI, 2.4-10.6) for success versus failure/relapse, and with an aOR of 0.3 (95% CI, 0.2-0.5) for death versus success/failure/relapse. Of note, patients to whom bedaquiline was administered tended to have more cavitary disease or to have pre-XDR or XDR-TB. Prescription of bedaquiline was associated with greater success and less death than clofazimine, but the greatest success and least mortality was found when bedaquiline was administered together with linezolid or clofazimine.\nFinally, a recent retrospective routinecare observational study in South Africa showed that a bedaquiline-containing regimen was associated with significantly lower mortality (128 deaths among 1,016 patients receiving bedaquiline compared with 4,612 deaths among 18,601 patients on the standard regimens). Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with MDR-or RR-TB (hazard ratio , 0.35; 95% CI, 0.28-0.46) and XDR-TB (HR, 0.26; 95% CI, 0.18-0.38) compared with standard regimens (50).\nHarms. In a review of cases treated with bedaquiline, only 44 of 1,266 (3.5%) cases with information available discontinued bedaquiline because of adverse events. Only 8 of 875 (0.9%) discontinued bedaquiline because of QT interval prolongation (two restarted the drug after resolution of the acute episode without further problems) (81).\nAdditional considerations. When bedaquiline is included in the regimen, most experts obtain ECGs after the initial 2 weeks of therapy and then at monthly intervals to monitor for QT interval prolongation. Serum electrolytes, including calcium, magnesium, and potassium, are also monitored.\nThe 2013 CDC guidelines on the use of bedaquiline note that there is insufficient evidence to provide guidance on the use of bedaquiline in children but that its use can be considered on a case-by-case basis given the high mortality and limited treatment options for MDR-TB (71). More recently, adolescents .10 years old and weight .34 kg have been safely treated off-label with the recommended adult dose of bedaquiline (82). The Sentinel Project on Pediatric Drug-Resistant Tuberculosis has recommended that children >12 years of age and >31 kg body weight receive bedaquiline at the same dose as adults, and children >6 years with 16 to 30 kg body weight could receive half the adult bedaquiline dose for the same indications (7,17,83).\nConclusions. In our PS-matched IPDMA, bedaquiline-containing regimens were more likely to achieve treatment success and to have a lower rate of death than those that did not include bedaquiline. Bedaquiline should be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB. Our recommendation for the use of bedaquiline is strong despite very low certainty in the evidence because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment including bedaquiline (compared with no bedaquiline) as having a particularly favorable balance of benefits over harms.\nResearch needs. Further research is needed to elucidate the potential synergy of bedaquiline with other agents. Studies underway are evaluating the use of bedaquiline together with linezolid, clofazimine, or nitroimidazoles AMERICAN THORACIC SOCIETY DOCUMENTS (i.e., pretomanid and delamanid). Research is also needed on the safety, tolerability, and efficacy of bedaquiline-based shorter-course regimens as well as on the use of bedaquiline for durations .24 weeks, an approach currently considered when effective treatment cannot otherwise be provided (71,84). Finally, research is urgently needed on the risk factors and any interventions (e.g., the selection of companion drugs) that influence acquisition of bedaquiline resistance.\n\n# Carbapenems with Clavulanic Acid\nThe combination of carbapenems and clavulanate, a b-lactamase inhibitor, has been shown to have in vitro bactericidal activity (65,85,86). As clavulanate is not available by itself, the combination drug amoxicillin-clavulanate must be given with the carbapenems. Carbapenems have been used primarily for MDR and XDR TB, and a recent systematic review found that carbapenems are safe and likely to be effective (65). Carbapenem drugs have been recently included in WHO guidelines for the treatment of DR-TB (23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA compared death, treatment success, and culture conversion among 169 individuals who received carbapenems to 9,535 individuals from centers that did not use any of the drugs previously classified by WHO as \"Group 5\" drugs (3). In addition, we considered adverse events reported in a recent review (65), IPDMA, and systematic review that summarize the available evidence on carbapenems from five primary studies (all observational studies) (23,(65)(66)(67)(87)(88)(89)(90)(91)(92). The reviewed evidence showed that there was concomitant use of linezolid and bedaquiline in large proportions of the patient population receiving carbapenems, suggestive of confounding, which was considered in the review of the efficacy results.\nBenefits. In our PS-matched IPDMA, inclusion of carbapenems in the treatment regimen had no effect on the risk of death (aOR, 1.0; 95% CI, 0.5-1.7) or culture conversion (aOR, 2.3; 95% CI, 0.8-6.9). However, treatment success was more likely among patients treated with regimens including a carbapenem compared with those treated with regimens not including a carbapenem (aOR, 4.0; 95% CI, 1.7-9.1).\nHarms. In our meta-analysis, the rate of treatment discontinuation due to an adverse event was lower among patients treated with regimens including a carbapenem than those treated with regimens not including a carbapenem, although this difference was not statistically significant (relative risk, 0.82; 95% CI, 0.23-2.94). In the published literature, treatment discontinuation due to adverse events has been reported in 0 to 3% of patients, with minor adverse events occurring in 5% to 6% of patients (65).\nAdditional considerations. Of note, clavulanic acid is only available as a coformulation with amoxicillin. Therefore, amoxicillin-clavulanate must be given to achieve a dose of 125 mg of the clavulanate with each dose of carbapenem daily, whenever carbapenems are included in an MDR-TB regimen. DST is currently not available for carbapenems. When used, imipenem-cilastatin/clavulanate or meropenem/clavulanate have been administered intravenously in a hospital setting, with multiple injections required daily (67). There is no clear evidence of whether imipenem-cilastatin or meropenem is more efficacious (66). Ertapenem belongs to the same family (65,93); because of its longer half-life and the possibility to administer it once a day intramuscularly or intravenously, ertapenem may be useful when a patient treated with meropenem or imipenem-cilastatin intravenously during hospitalization is discharged and needs to continue carbapenem-based treatment outpatient (92). Long-term intravenous administration requires long-term venous access through an indwelling catheter, which carries risks of infection, thrombosis, and thromboembolism. Data on the use of a carbapenem combined with amoxicillin-clavulanate in children are lacking-only two adolescents are included in one review (65). However, efficacy has been shown in adults, and both carbapenems and amoxicillinclavulanate have been used safely in children for other purposes (although there are no long-term treatment safety data in young children); therefore, this combination could be used in children with MDR-TB where there is no other option to build an effective regimen.\nConclusions. In our PS-matched IPDMA, inclusion of carbapenems with clavulanic acid was associated with an increase in treatment success when compared with the control group not receiving carbapenems with clavulanic acid. Carbapenems with clavulanic acid can be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB.\nResearch needs. Randomized, controlled clinical trials that confirm the role of carbapenems used for different durations of time within different regimens are needed. A comparative evaluation of the safety, tolerability, and efficacy of the different agents is also necessary. Because of the high cost of these drugs, economic analyses will also be useful (65). The development of oral formulations of carbapenems is underway, which, if proven safe and effective, would enhance feasibility of using these agents significantly. Additional advances in rapid DST for carbapenems would enhance potential scale-up of use for this class of drugs.\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS e108\nClofazimine Clofazimine, a fat-soluble riminophenazine dye, has shown in vitro and in vivo activity as a sterilizing drug to treat MDR-TB (94)(95)(96).\nClofazimine has been used as a leprosy drug and was first developed in the 1950s because of in vitro and in vivo activity against M. tuberculosis (94, 95, 97). Although the exact mechanism of action is not known, it is a prodrug that appears to have both antimycobacterial and antiinflammatory properties (98). The published clinical evidence on the safety and efficacy of clofazimine for treatment of TB is modest (99). However, interest in the drug has increased since WHO endorsed the new shorter-course regimen (23, 100), which includes clofazimine (101)(102)(103)(104)(105)(106)(107)(108).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PSmatched IPDMA compared death, treatment success, and culture conversion among 639 individuals who received clofazimine to 7,398 individuals from centers that did not use any of the drugs previously classified by WHO as \"Group 5\" drugs (3). In addition, we considered adverse events reported in a published systematic review of nine observational studies (six MDR-TB and three XDR-TB) including 599 patients treated with clofazimine (427 from a single cohort study from Bangladesh) (95) and two studies published after the systematic review. They include a trial at six specialty hospitals in China that randomized 105 patients to 21 months of treatment with an optimized background regimen with or without clofazimine (100 mg/d) ( 94) and a retrospective cohort study from Brazil that compared outcomes in patients with MDR-TB treated with clofazimine (100 mg/d)-containing regimens versus pyrazinamide-containing regimens (109).\nBenefits. Our PS-matched IPDMA showed that treatment success was more likely with regimens containing clofazimine compared with regimens that did not (aOR, 1.5; 95% CI, 1.1-2.1). Addition of clofazimine was associated with an aOR of 0.8 (95% CI, 0.6-1.0) for the outcome of death and with an aOR of 1.1 (95% CI, 0.6-1.8) for culture conversion within 6 months. As noted in PICO Question 5 on bedaquiline, when PSmatched pair analyses were performed comparing the effects of bedaquiline and clofazimine to those of no bedaquiline or clofazimine, the combination of bedaquiline and clofazimine was associated with an aOR of 5.0 (95% CI, 2.4-10.6) for success versus failure/relapse and with an aOR of 0.3 (95% CI, 0.2-0.5) for death versus success/failure/relapse.\nHarms. In our PS-matched IPDMA, 2 of 81 (2.5%) patients treated with regimens including clofazimine had treatment discontinued because of adverse events. Brownish skin pigmentation has been observed in 75% to 100%, ichthyosis in 8% to 20%, gastrointestinal intolerance in 40% to 50%, and neurological disturbances in up to 13% of patients (94,95,109). Clofazimine was judged to have small to moderate desirable effects (on treatment success, mortality, and culture conversions) and small undesirable effects (low risk of serious adverse events requiring treatment discontinuation). However, there is important uncertainty about how patients value skin discoloration. Some patients perceive skin discoloration as significant, which may become a key factor in the acceptability of this drug in some settings. Recent publications have noted the potential QT interval-prolonging effects of clofazimine when used in combination with bedaquiline and delamanid (110)(111)(112).\nAdditional considerations. Access is a limitation to expanded use of clofazimine for treatment of MDR-TB, especially in the United States and Europe, where clofazimine lacks a TB indication. In the United States, clofazimine is currently only available under an investigational new drug protocol administered by FDA, which can be a burdensome procedure. Significant improvements in the mechanisms for accessing clofazimine are necessary for more expanded use of this drug. Quality-assured clofazimine is available through the Global Drug Facility, although currently in limited quantities. Although our PS-matched IPDMA had limited pediatric data, the efficacy in children is believed by experts to be the same as in adults. A recent IPDMA in children with MDR-TB did not show a benefit using clofazimine, which might be related to selection of cases and very small numbers (23 of 641) receiving clofazimine (113). Moreover, children are included in the WHO shortercourse regimen for MDR-TB treatment, which includes clofazimine, albeit on the basis of limited data. Dosing clofazimine in children is challenging because of the lack of childfriendly formulations and lack of pharmacokinetic data. The currently recommended dose for clofazimine in children varies from 2 to 5 mg/kg daily. Skin discoloration is common; some improve during treatment and others resolve rapidly after discontinuation of treatment. Ichthyosis is less common and improves with intensive efforts at applying lubricants during treatment. As noted, QT interval prolongation may occur and is especially important to monitor by ECG if given together with other QT interval-prolonging medication (68, 83, 110-112, 114, 115). Clofazimine may have cross-resistance with bedaquiline, which may need to be considered when building a regimen for MDR-TB (75).\nConclusions. In our PS-matched IPDMA, inclusion of clofazimine was associated with increase in treatment success when compared with the control group not receiving clofazimine. Clofazimine can be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB.\nResearch needs. The value of using loading doses and the optimal dosing for clofazimine requires additional research. Pharmacokinetic data in adults and children are needed.\n\n# Cycloserine\nCycloserine is an oral bacteriostatic drug that has been part of the backbone regimen for MDR-TB treatment in the past. Cycloserine is a broad-spectrum antibiotic that inhibits cell wall synthesis (116,117). Terizidone is a structural analog that is a combination of two cycloserine molecules; it appears to be used interchangeably by experts, although it is currently not available in the United States (118). Although some advantages of cycloserine include the absence of crossresistance to other drugs and reasonable gastrointestinal tolerability, a significant drawback relates to psychological side effects, which occasionally necessitate discontinuation of the drug (16).\nSummary of the evidence. Previous studies showed an increase of the likelihood of treatment success when cycloserine was included in the MDR-TB regimen (marginally statistically significant) (96). Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B.\nBenefits. Our PS-matched IPDMA showed that inclusion of cycloserine was associated with an increase in treatment success (aOR, 1.5; 95% CI, 1.4-1.7) and a decrease in AMERICAN THORACIC SOCIETY DOCUMENTS mortality (aOR, 0.6; 95% CI, 0.5-0.6) when compared with the control group. A published IPDMA of children with successful treatment of MDR-TB showed that cycloserine as a single drug had an aOR of 1.7 (95% CI, 0.9-3.0; 641 children with MDR-TB, of whom 356 received cycloserine/terizidone) (113). Limited pharmacokinetic data are available on cycloserine (or terizidone) in children, but a recent study of 25 children (only 5 to ,12 yr of age) receiving a median of 14.3 mg/kg (range, 10.0-18.0 mg/kg) showed that the maximum concentration of the drug achieved in the plasma after dose administration was similar to the adult target maximum concentration of 20 to 35 mg/L (119). The recommended dose for children of 10 to 20 mg/kg/d seems adequate. An advantage of cycloserine in children, as in adults, with miliary and/or central nervous system (CNS) TB is that it penetrates the CNS well. Cycloserine may interfere with the pharmacokinetics and absorption of isoniazid and ethionamide/prothionamide; therefore, it may be advisable to give it separately from these drugs if used together in the same regimen (117).\nHarms. Cycloserine has CNS adverse effects, which are reported to occur in about 20% to 30% of adults (120). A meta-analysis of published articles identified adverse events in 201 of 2,164 patients across all studies (118). An average weighted proportion of patients receiving cycloserine who discontinued treatment owing to adverse effect pooled across the studies was 9.1% (95% CI, 6.4-11.7%). An average weighted proportion of patients with psychiatric adverse effects was 5.7% (95% CI, 3.7-7.6%) (118). Limited data exist on cycloserine adverse effects in children. In older pediatric studies, no adverse effects were reported with the use of cycloserine (121)(122)(123). In a systematic review of outcomes of MDR-TB in children, 6 of 182 (3.3%) children had adverse effects attributed to cycloserine, which included depression, anxiety, hallucinations, transitory psychosis, and blurred vision (124).\nAdditional considerations. Lowerthan-recommended serum cycloserine concentrations and delayed absorption have been reported (125). Some experts obtain peak concentrations within the first 1 to 2 weeks of therapy and continue to monitor serially. Because of specific technical challenges related to cycloserine DST, poor accuracy of testing in liquid media, and poor intrinsic reproducibility of results, few laboratories perform DST for cycloserine (16).\nConclusions. In our PS-matched IPDMA, inclusion of cycloserine was associated with a decrease in mortality and increase in treatment success when compared with the control group not receiving cycloserine. Cycloserine can be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB.\nResearch needs. Studies are needed to determine the effect of cycloserine on the absorption of isoniazid and ethionamide.\n\n# Delamanid\nDelamanid is a nitro-dihydro-imidazooxazole derivative, which was approved for the treatment of MDR-TB by the European Medicines Agency in 2013 but has not yet received FDA approval. In 2014, WHO issued interim policy guidance on the use of delamanid for the treatment of MDR-TB on the basis of phase 2b clinical trial data. The interim policy guidance stated that \"delamanid may be added to an MDR-TB regimen in adult patients with pulmonary TB conditional upon: i) careful selection of patients likely to benefit; ii) patient informed consent; iii) adherence to WHO recommendations in designing a longer MDR-TB regimen; iv) close monitoring of clinical treatment response; and v) active TB drug-safety monitoring and management (aDSM)\" (126). WHO issued an updated position statement on the use of delamanid for MDR-TB in 2018 on the basis of final results from the phase 3 randomized controlled trial, Trial 213 (127).\nSummary of the evidence. Delamanid data were not available as part of the PS-matched IPDMA completed for this guideline development process; however, the 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment, wherein individual-level data on delamanid were attained for analyses, provides practice guidance on the use of delamanid for treatment of MDR-TB (7,128). Several recent reports, clinical trials, and cohort studies report on delamanid-containing regimens achieving success rates of 77% to 84%, in absence of major adverse events (128)(129)(130)(131). In the United States, through a compassionate use program, delamanid has recently been successfully accessed and used in the care of patients with MDR-TB (132). Regarding use of delamanid in children, only a small number of children (.6 yr of age) have had documented access to the drug, also by compassionate use (133,134). On the basis of review of the data available in the IPDMA conducted by WHO, delamanid has been included in \"Group C\" in their guidelines, corresponding to drugs that can be added \"to complete the regimen and when medicines from Groups A and B cannot be used.\" WHO has recommended that \"delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more on longer regimens\" (7,135). The guideline writing committee concurs with the updated 2019 WHO guidance (7). As noted for other drugs discussed in this practice guideline, QT interval PICO Question 9-Delamanid: In patients with MDR-TB, are outcomes safely improved when regimens include delamanid compared with regimens that do not include delamanid?\nRecommendation 9: The guideline panel was unable to make a clinical recommendation for or against delamanid because of the absence of data in the PSmatched IPDMA conducted for this practice guideline. We make a research recommendation for the conduct of randomized clinical trials and cohort studies evaluating the efficacy, safety, and tolerability of delamanid in combination with other oral agents. Until additional data are available, the guideline panel concurs with the conditional recommendation of the 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment that delamanid may be included in the treatment of patients with MDR/RR-TB aged >3 years on longer regimens (7).\nPICO Question 8-Cycloserine: In patients with MDR-TB, are outcomes safely improved when regimens include cycloserine compared with regimens that do not include cycloserine?\nRecommendation 8: We suggest including cycloserine in a regimen for treatment of patients with MDR-TB (conditional recommendation, very low certainty in the evidence).\nprolongation may occur with delamanid use, and routine ECG monitoring is recommended. A recent evaluation of the cardiac safety of delamanid and bedaquiline given together as part of multidrug therapy for MDR-TB concluded that the combined effect on the corrected QT interval (QTc) using the Fridericia formula (QTcF) is clinically modest and no more than additive (ClinicalTrials.gov Identifier: NCT02583048), with mean change in QTcF from baseline at 11.9 milliseconds (95.1% CI, 7.4-16.5 ms) in the bedaquiline arm, 8.6 milliseconds (95.1% CI, 4.0-13.2 ms) in the delamanid arm, and 20.7 milliseconds (95.1% CI, 16.1-25.4 ms) in the combined bedaquiline and delamanid arm (136).\nConclusions. The guideline panel was unable to make a recommendation for or against delamanid because of the absence of data in the IPDMA conducted for this practice guideline. In 2018, WHO updated the IPDMA with additional data and recommended delamanid be included in the third tier of drugs, Group C, and for the drug to be used in the treatment of patients with MDR/RR-TB aged >3 years on longer regimens. The guideline writing committee agrees with the updated 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment that delamanid may be included in the treatment of patients with MDR/RR-TB aged >3 years on longer regimens (7). We make a research recommendation for the conduct of randomized clinical trials and cohort studies evaluating the efficacy, safety, and tolerability of all-oral, shortened regimens inclusive of delamanid in combination with other oral agents.\nResearch needs. The companion drugs with which to combine delamanid for optimal efficacy, safety, and tolerability remain uncertain. The conduct of randomized clinical trials and cohort studies evaluating all-oral, shortened regimens, inclusive of delamanid and in combination with other oral agents are urgently needed. The endTB trial is a phase 3 multicountry randomized clinical trial evaluating the efficacy and safety of five new, all-oral, shortened regimens including combinations of bedaquiline and delamanid (ClinicalTrials.gov Identifier: NCT02754765). Recent cohort data are also emerging on the use of delamanid and bedaquiline in combination, which to date has been generally reserved for severe cases with extensive resistance and when other options are not feasible (137)(138)(139)(140). The Nix-TB (A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects with Drug-Resistant Pulmonary Tuberculosis) trial (ClinicalTrials.gov Identifier: NCT02333799) evaluated an all-oral 6-month regimen comprising bedaquiline, pretomanid (member of the nitroimidazooxazines class of compounds), and linezolid for the treatment of either XDR-TB or treatment-intolerant or nonresponsive MDR-TB. FDA granted priority review of the new drug application for pretomanid in March 2019, the Antimicrobial Drugs Advisory Committee discussed pretomanid in June 2019, and in August 2019 FDA approved pretomanid in combination with bedaquiline and linezolid for the treatment of a specific limited population of adults with pulmonary XDR-TB or treatment-intolerant or nonresponsive MDR-TB (2,141). Given FDA approval, additional trials that include diverse patient populations will be essential to understand optimal use of the regimen, in addition to head-to-head comparisons of pretomanid with delamanid to determine if these drugs can be used interchangeably.\n\n# Ethambutol\nEthambutol is an ethylenediamine that inhibits arabinosyl transferases, which contribute to M. tuberculosis cell wall synthesis (142). The drug is included in standard regimens for treatment of drugsusceptible TB and commonly used in regimens for MDR-TB (11,16,23). The published evidence available on its safety and efficacy is modest, and its use as part of the first-line drug-susceptible TB regimen rests largely on its ability to prevent the emergence of resistance to the other drugs in the regimen rather than on its own sterilizing activity (143). Ethambutol has been demonstrated to have modest sterilizing activity as part of combination regimens when used against ethambutolsusceptible isolates for treatment of drugsusceptible TB. The drug is not effective when used for ethambutol-resistant isolates, and such use is not recommended (54,96).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA compared outcomes among 3,002 individuals with isolates susceptible to ethambutol who received the drug to 667 individuals with isolates susceptible to ethambutol who did not receive the drug (3). Receipt of ethambutol was associated with an aOR of 0.9 (95% CI, 0.7-1.1) for the outcome of treatment success; receipt of ethambutol was associated with an aOR of 1.0 (95% CI, 0.9-1.2) for the outcome of death. However, the groups were not balanced with regard to other effective drugs; in particular, the patients not receiving ethambutol were more likely to receive linezolid. Thus, the ability to detect an effect of ethambutol might have been obscured. In a previous IPDMA, before linezolid and bedaquiline use were common, administration of ethambutol among patients with susceptible isolates was associated with an aOR of 1.7 (95% CI, 1.2-2.4) for cure/complete versus failure/relapse and an aOR of 1.6 (95% CI, 1.1-2.4) for cure/complete versus failure/relapse/death, compared with patients receiving ethambutol whose isolates were resistant in vitro (144).\nBenefits. Our PS-matched IPDMA showed that treatment success was not significantly more likely with regimens containing ethambutol. However, a number of earlier studies indicate that ethambutol is associated with increased success when used to treat patients whose isolates are susceptible to the drug (143). Moreover, these earlier studies determined that the effectiveness of ethambutol is directly related to dose, and that a dose of 25 mg/kg was more effective than a dose of 15 mg/kg (143). Dosages were not available for analysis in our PS-matched IPDMA. Finally, our PS-matched IPDMA did not address a key attribute of ethambutol, the prevention of the emergence of resistance, which is a substantial concern among patients with MDR-TB (145).\nPICO Question 10-Ethambutol: In patients with MDR-TB, are outcomes safely improved when regimens include ethambutol compared with regimens that do not include ethambutol?\nRecommendation 10: We suggest including ethambutol in a regimen for treatment of patients with MDR-TB only when more effective drugs cannot be assembled to achieve a total of five effective drugs in the regimen (conditional recommendation, very low certainty in the evidence).\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS\nHarms. In a recent review of the tolerability of TB drugs, ethambutol was associated with serious adverse events in 6 of 1,325 (0.5%) patients (23). This is consistent with previous reports of ethambutol toxicity, in which optic neuropathy (including optic neuritis and retrobulbar neuritis) was attributed to ethambutol, manifesting as symptoms of decreased visual acuity, scotomata, color blindness, or visual defects. These toxic effects are dose dependent and, although serious, are generally reversible if recognized promptly and the drug is discontinued or the dose reduced.\nAdditional considerations. When ethambutol is used, some experts recommend using the higher dose of 25 mg/kg, which is associated with increased efficacy but also slightly greater ocular toxicity. Other experts recommend using 15 to 20 mg/kg, counting the drug predominantly as providing protection against the acquisition of additional resistance. All patients receiving ethambutol as part of an MDR-TB treatment regimen should be monitored monthly for signs of ocular toxicity, particularly visual impairment, and if this is detected, ethambutol should be discontinued. If optic neuritis occurs in patients taking both ethambutol and linezolid, both drugs must be stopped. Many patients may be rechallenged successfully with linezolid once vision normalizes, but rechallenge with ethambutol is not recommended. The efficacy of ethambutol is not expected to be different in children compared with adults. A dose of 25 mg/kg is recommended by experts for children with MDR-TB. Two reviews on safety of ethambutol relating to vision have shown low risk of ocular toxicity (143,146). However, other drugs, such as linezolid, may also cause optic neuritis, and this should be taken into consideration when treating MDR-TB in children, especially as screening for visual loss is difficult in young children.\nConclusions. We suggest including ethambutol in a regimen for treatment of patients with MDR-TB only when more effective drugs cannot be used to achieve a total of five effective drugs in the regimen (conditional recommendation, very low certainty in the evidence). The committee was divided on the value of recommending ethambutol, given the drug was not associated with any benefit in terms of treatment success or mortality. Concerns about the comparability of IPDMA patient groups treated with and without ethambutol were noted. Unlike ethionamide/prothionamide, where there are substantial undesirable effects, ethambutol had small undesirable effects (low risk of serious adverse events requiring treatment discontinuation). Finally, our PS-matched IPDMA did not address the prevention of emergence of resistance-a recognized attribute of ethambutol in the treatment of drug-susceptible TB-although the applicability of this attribute to MDR-TB regimens is unknown. Overall, the committee suggested that ethambutol can be used only when more effective drugs cannot be assembled to achieve the necessary five effective drugs in the regimen.\nResearch needs. More evidence is needed on the beneficial role that ethambutol may play in preventing emergence of drug resistance in MDR-TB, including to newer oral drugs. More research is also needed to improve on the reliability of DST for ethambutol in different settings.\n\n# Ethionamide and Prothionamide\nEthionamide and prothionamide are derivatives of isonicotinic acid, somewhat similar in structure to isoniazid. Ethionamide is a prodrug and requires activation, after which it inhibits mycobacterial fatty acid synthesis that is necessary for cell wall synthesis and repair. Clinical studies indicate efficacy of these drugs, and they have been included in regimens for treatment of MDR-TB and for treatment of TB meningitis in adults and children (16,23,147,148).\nSummary of evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA showed that ethionamide/prothionamide were not associated with any benefit, even if susceptible by phenotypic DST (3). Previous studies have shown, however, an increase in the likelihood of treatment success if ethionamide was included in the MDR-TB regimen (23,149). These different results can be explained by the inclusion of newer and more effective drugs, improving outcomes in the comparator groups, potentially biasing the observed effect against ethionamide; fewer patients in the ethionamide/prothionamide group, compared with control subjects, received newer-generation fluoroquinolone (51% vs. 76%), amikacin (17% vs. 35%), and linezolid (5% vs. 18%), and more patient in the ethionamide/prothionamide groups received kanamycin (51% vs. 12%) and capreomycin (27% vs. 16%).\nBenefits. No benefits were identified for inclusion of ethionamide/prothionamide in regimens, even if susceptible by phenotypic DST. A pediatric IPDMA of MDR-TB cases also did not show benefit using ethionamide/ prothionamide; however, the majority of children (590 of 641) in this study did receive ethionamide or prothionamide, potentially limiting the ability to discern a benefit (113).\nHarms. The potential of ethionamide to cause adverse events can also limit its tolerability (120). A review of studies comparing a regimen containing ethionamide or prothionamide (all studies before 1970) showed that adverse effects leading to discontinuation of treatment were equally frequent with ethionamide (11.3%; range 6-42%) and prothionamide (11.9%; range 6-40%). Adverse effects, when reported, included abnormal liver function tests, gastrointestinal intolerance, endocrine dysfunction, and hypothyroidism, the latter occasionally requiring treatment with thyroxine (147). Hypothyroidism is a common adverse effect of ethionamide (experienced by approximately 20%) (150,151) and is particularly noted if used with p-aminosalicylic acid and in HIV-infected children (152). Gastrointestinal disturbance is common but usually resolve within the first 2 weeks of treatment in children.\nAdditional considerations. When ethionamide/prothionamide is included in a regimen for which five other effective drugs cannot be assembled, experts recommend dose escalation (drug ramping) at time of treatment initiation, as well as monitoring of thyroid-stimulating hormone for evidence of hypothyroidism requiring replacement (16). Of note, in the presence of inhA mutation, many isolates will show PICO Question 11-Ethionamide/ prothionamide: In patients with MDR-TB, are outcomes safely improved when regimens include ethionamide/ prothionamide compared with regimens that do not include ethionamide/prothionamide? Recommendation 11: We suggest NOT including ethionamide/ prothionamide in a treatment regimen for patients with MDR-TB if newer and more effective drugs are available to construct a regimen with at least five effective drugs (conditional recommendation, very low certainty in the evidence). cross-resistance between isoniazid and ethionamide/prothionamide (153).\nConclusions. When the individualized treatment regimen for patients with MDR-TB contains newer-generation, moreeffective drugs, the addition of ethionamide/prothionamide does not appear to provide benefit.\nResearch needs. Research efforts are underway to identify potential boosters of potency for ethionamide, which, if successful when coadministered, may result in improved therapeutic index and overall better risk-benefit ratio for use (154).\n\n# Fluoroquinolones: Levofloxacin, Moxifloxacin, Ciprofloxacin, and Ofloxacin\nThe fluoroquinolones are a family of chemically related drugs characterized by a common core dual-ring structure (155). Ofloxacin, then levofloxacin, then moxifloxacin sequentially improved on earlier generation's spectrum of activity, including mycobacteria, and their antimycobacterial action increased as evidenced by lower minimum inhibitory concentrations (MICs) and increasing success in clinical use (156,157). Physicians began using these drugs to treat MDR-TB on the basis of in vitro data, with subsequent case series and observational studies showing efficacy (158), although none of the fluoroquinolones are currently indicated by regulatory authorities for the treatment of TB. In general, these drugs are well absorbed orally, have favorable pharmacological profiles for once-daily dosing, are generally well tolerated, and now are available in generic formulations (155).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PSmatched IPDMA, ofloxacin was used most commonly (n = 4,020), followed by levofloxacin (n = 3,872), moxifloxacin (n = 2,132), and ciprofloxacin (n = 431); 734 patients did not receive a fluoroquinolone, the comparison group for subsequent analyses, and 828 patients received two or more quinolones and were excluded (3). The groups were similar in age, sex, proportion AFB smear positive, proportion with cavitary disease on chest radiograph, and prior treatment with first-line drugs. However, the no-quinolone group had substantially more HIV coinfection (44% vs. 13-28%; proportion with HIV coinfection across different quinolones), more past treatment with secondline drugs (52% vs. 8-25%), more quinolone resistance (86% vs. 6-33%), more second line injectables resistance (74% vs.12-34%), and more XDR TB (73% vs. 4-19%). In terms of treatment, the no-fluoroquinolone group received less amikacin (7% vs. 18-43%) and kanamycin (13% vs, 26-65%) and more capreomycin (66% vs. 6-34%). Therefore, the median number of effective drugs (intensive phase) was lower in the no-fluoroquinolone group (2.1) than in the other groups (3.3-4.0). Thus, treatment success was lower in the nofluoroquinolone group (35% vs. 55-68%) and failure/relapse was higher than but not greatly different from the others (13% vs. 2-10%); mortality, however, was much higher (40% vs. 11-15%).\nBenefits. In our PS-matched IPDMA, among patients with susceptible isolates, levofloxacin-containing regimens compared with no quinolone were associated with significantly more treatment successes (aOR, 4.2; 95% CI, 3.3-5.4) and significantly fewer deaths (aOR, 0.6; 95% CI, 0.5-0.7). Moxifloxacin, compared with no quinolone, was also associated with significantly more treatment successes (aOR, 3.8; 95% CI, 2.8-5.2) and significantly fewer deaths (aOR, 0.5; 95% CI, 0.4-0.6). In the subgroup with resistance to an injectable drug(s), levofloxacin or moxifloxacin were associated with a significant improvement in treatment success (aOR, 1.8; 95% CI, 1.2-2.8) and reduction in death (aOR, 0.6; 95% CI, 0.4-0.8), although the corresponding adjusted risk differences were not statistically significant. In pairwise comparisons, both levofloxacin and moxifloxacin were associated with significantly better treatment outcomes than ofloxacin. The aORs of death were lower for the two later-generation quinolones when compared with ofloxacin (levofloxacin: aOR, 0.8; 95% CI, 0.6-0.9; moxifloxacin: aOR, 0.8; 95% CI, 0.6-1.0) (data not shown). Ofloxacin and ciprofloxacin are considered inferior quinolones against M. tuberculosis (144,149,159,160). Levofloxacin and moxifloxacin did not differ significantly from each other.\nIn a recent IPDMA describing treatment outcomes in children treated for MDR-TB (113), new and repurposed TB drugs, including late-generation fluoroquinolones, were not used enough to adequately evaluate efficacy, but most experts and emerging evidence suggest that the efficacy of fluoroquinolones noted in adults should be similar in children (83,161).\nHarms. In our PS-matched IPDMA, grade 3 adverse events were recorded systematically in a subset of 1,962 patients from a cohort study of MDR-TB at 27 sites in nine countries. Permanent discontinuation of fluoroquinolones due to adverse events was uncommon. Among 150 patients treated with levofloxacin, the drug was stopped permanently because of adverse events in 6 (4.0%). Among 398 patients treated with moxifloxacin, the drug was stopped permanently in 14 (3.5%) patients. Among 1,167 patients treated with ofloxacin, the drug was stopped permanently in 56 (4.8%) patients. An analysis of 56 clinical trials comparing quinolones against placebo or against other antimicrobial agents found generally similar adverse event profiles (3). Seven studies reported more frequent adverse events and six studies reported fewer adverse events in fluoroquinolone-treated patients. The most frequent adverse effects reported are those of the gastrointestinal tract in 3% to 17% and CNS in 0.9% to 11% of patients (155,162). Allergic and other hypersensitivity reactions and other skin reactions occur in 0.5% to 2.8% of patients. Other adverse effects that occur in .1% of patients are cardiac (QT interval prolongation) and endocrine (hypoglycemia). Recently, FDA strengthened warnings in the prescribing information for the entire class of fluoroquinolones on risks of severe hypoglycemia, certain mental health side effects, and tendonitis, as well as risks of ruptures or tears in the aorta (163). Safety concerns persist for long-term pediatric use of fluoroquinolones, especially regarding arthropathy. However, several long-term prospective and retrospective studies in children have confirmed that severe adverse effects with the fluoroquinolones are rare, including musculoskeletal, neurological, and QT interval prolongation adverse effects (164)(165)(166).\nAdditional considerations. As latergeneration fluoroquinolones have become generic, their cost has decreased greatly and their use has expanded to many different indications, so procurement and availability have not been problematic, but resistance is more common than among aminoglycosides. Some foods or beverages and antacids high in content of divalent or AMERICAN THORACIC SOCIETY DOCUMENTS trivalent cations can reduce fluoroquinolone absorption (16,(167)(168)(169). When feasible, taking fluoroquinolones on an empty stomach minimizes the potential of delays in or reduction of fluoroquinolone absorption. Moxifloxacin and to a lesser extent levofloxacin prolong the QT interval. Moxifloxacin may necessitate ECG monitoring, especially if patients have a baseline QTc . 500 milliseconds or take other QT-prolonging drugs.\nPharmacokinetic modeling studies for levofloxacin and moxifloxacin use in children are ongoing: recent data suggest that for children, a levofloxacin dose of at least 15 to 20 mg/kg daily (170,171), and a moxifloxacin dose of 10 to 15 mg/kg/d are effective (based on data showing too low exposure at 7.5-10 mg/kg) (172). Although a modeling paper suggests a dose of 25 mg/kg/d for infants to 3 months of age and 20 mg/kg/d for toddlers, safety at these doses has not been verified (173).\nConclusions. In our PS-matched IPDMA, patients treated with moxifloxacin and levofloxacin had better outcomes than patients not treated with any fluoroquinolones, or compared with patients treated with ofloxacin, after adjustment for numerous covariates that in themselves were strong determinants of outcome, such as clinical characteristics, extent of drug resistance, and number of other effective drugs in the treatment regimen. Moxifloxacin or levofloxacin should be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB. Our recommendation for the use of moxifloxacin or levofloxacin is strong despite very low certainty in the evidence, because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment that includes these latergeneration fluoroquinolones (compared with no fluoroquinolones) as having a particularly favorable balance of benefits over harms. NCT01918397) and dosing regimens, as preliminary work suggests these drugs may be more effective at higher doses (174). The activity, safety, and tolerability of using higher doses of fluoroquinolones against isolates with modestly elevated MICs should also be explored. Modest increases in toxicity can be minimized and managed by clinicians and may still be preferable to treating MDR-TB without quinolones. Higher doses may also limit acquired resistance (175,176).\nInjectables: Amikacin, Capreomycin, Kanamycin, and Streptomycin\nThe term \"injectable drugs\" in general encompasses four drugs: the aminoglycoside antibiotics streptomycin, amikacin, and kanamycin; and the cyclic polypeptide antibiotic capreomycin (155,162,177). Aminoglycosides are highly cationic and water soluble, but insoluble in organic solvents and hydrophobic environments, explaining much about their pharmacology, limited ability to cross lipid membranes, poor absorption from the gastrointestinal tract, and poor penetration into the CNS. Consequently, they are administered parenterally through slow intravenous infusion or through intramuscular injection (177). Streptomycin's core ring structure differs from all other aminoglycosides, explaining in part why cross-resistance between streptomycin and other aminoglycosides is uncommon (155,177). These drugs block protein synthesis at the ribosomal level by binding to a highly conserved nucleotide sequence in the prokaryotic 16S ribosomal subunit, the mRNA decoding region, where translation of mRNA codon to aminoacyltransfer RNA anticodon normally takes place (155,177). Aminoglycosides share three important characteristics: 1) concentration-dependent killing, 2) a postantibiotic effect, and 3) synergism with other antibacterial drugs (155). These drugs kill bacteria in proportion to drug concentration, so a single daily dose is more effective than divided doses or a continuous infusion. Moreover, antibacterial activity continues many hours after serum levels become undetectable, the so-called \"postantibiotic\" effect (155).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PS-matched IPDMA, treatment outcomes for 613 patients who did not receive an injectable drug were compared with 1,554 patients treated with streptomycin, 4,330 treated with kanamycin, 2,275 treated PICO Question 12-Fluoroquinolones: In patients with MDR-TB, are outcomes safely improved when regimens include fluoroquinolones compared with regimens that do not include fluoroquinolones? Recommendation 12: We recommend including moxifloxacin or levofloxacin in a regimen for treatment of patients with MDR-TB (strong recommendation, low certainty in the evidence). Our recommendation for the use of moxifloxacin or levofloxacin is strong despite very low certainty in the evidence because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment that includes these latergeneration fluoroquinolones (compared with no fluoroquinolones) as having a particularly favorable balance of benefits over harms.\nPICO Question 13-Injectables: In patients with MDR-TB, are outcomes safely improved when regimens include an injectable compared with regimens that do not include an injectable? Recommendation 13: We suggest including amikacin or streptomycin in a regimen for treatment of patients with MDR-TB when susceptibility to these drugs is confirmed (conditional recommendation, very low certainty in the evidence). Because of their toxicity, these drugs should be used when more effective or less toxic therapies cannot otherwise be assembled to achieve a total of five effective drugs. We suggest NOT including kanamycin or capreomycin (conditional recommendation, very low certainty in the evidence).\nwith amikacin, and 2,401 treated with capreomycin. Patients who received two or more injectable drugs (n = 875) were excluded, because the outcome could not be ascribed to one of the drugs (3). The noinjectable comparison group had notably fewer AFB smear-positive patients and patients with cavitary disease. On the other hand, patients in this group had more past treatment with second-line drugs; more resistance to quinolones, injectables, and XDR TB; and much more treatment with linezolid. In these respects, the capreomycin group was similar (more past treatment with second-line drugs, worse pretreatment drug resistance) to the other three drugs. Analysis was based on patients whose isolates were susceptible to the drug they received, with exceptions noted below.\n\n# Benefits. INJECTABLE DRUGS COMPARED\nWITH NO INJECTABLE DRUG. Compared with 613 patients treated without an injectable drug, 1,554 streptomycin-treated patients had increased treatment success (aOR, 1.5; 95% CI, 1.1-2.1). In the subgroup with quinolone resistance (17.8% of the total), streptomycin-treated patients had increased treatment success (aOR, 3.0; 95% CI, 1.3-6.6). Compared with 613 patients not treated with injectable drugs, 2,275 amikacin-treated patients had increased treatment success (aOR, 2.0; 95% CI, 1.5-2.6). In the subgroup with quinolone resistance, amikacin was also associated with increased treatment success (aOR, 3.0; 1.6-5.6). Among patients with XDR-TB, amikacin was associated with reduced deaths (aOR, 0.4; 95% CI, 0.2-0.8). In contrast, neither kanamycin nor capreomycin was associated with any benefit on treatment success or death versus no injectable drug at all. To the contrary, kanamycin treatment was associated with fewer treatment successes (aOR, 0.5; 95% CI, 0.4-0.6). Capreomycin was associated with an increased risk of death (aOR, 1.4; 95% CI, 1.1-1.7). In XDR-TB, capreomycin was associated with increased deaths (aOR, 3.4; 95% CI, 2.7-4.3) when compared with regimens with no injectable drug.\nIn a pediatric IPDMA, the use of second-line injectable agents (amikacin, kanamycin, capreomycin) in children with confirmed MDR-TB was associated with more treatment success compared with those not receiving second-line injectable agents (aOR, 2.94; 95% CI, 1.05-8.28; P = 0.041) (113). However, a high proportion of children with less-severe disease who received no second-line injectable agents still did well; therefore, children may be able to be spared from injectables and the associated toxicities if newer, more-effective drugs can be included in an all-oral regimen (113).\n\n# INJECTABLE DRUGS COMPARED AGAINST\nEACH OTHER. Compared with streptomycintreated patients, patients treated with amikacin had increased treatment successes (aOR, 1.7; 95% CI, 1.3-2.2) but with no significant impact on death (aOR, 1.0; 95% CI, 0.8-1.2). Kanamycin and capreomycin were both significantly inferior to streptomycin in every respect. Amikacin was superior to kanamycin and capreomycin in every respect, with higher treatment success rates, lower death rates, or both. In the quinolone-resistant subgroup, on the other hand, use of amikacin did not have a significant effect on treatment success (aOR, 1.7; 95% CI, 0.9-3.4) or death (aOR, 1.2; 95% CI, 0.7-2.0) compared with use of streptomycin.\nHarms. All aminoglycosides and capreomycin share important toxicities, especially nephrotoxicity, ototoxicity, and electrolyte disturbances, as well as other less common toxicities (155,162,177). The ototoxicity can be vestibular, resulting in loss of balance, or cochlear, resulting in hearing loss. Because these drugs date back to the early years of antibiotic discovery and development, there is vast published experience with their toxicities. In the treatment of MDR-TB, the risk of toxicity is substantial, because the duration of treatment is many months. Ototoxicity may be severe and irreversible but with close monitoring can be minimized or prevented. Nephrotoxicity is often reversible when identified early and addressed appropriately; however, ototoxicity can progress even after the drug is stopped. Monitoring (measuring drug levels; monthly high-quality audiometry, electrolytes, and serum creatinine) and skilled management can prevent or mitigate these effects and are part of standard practice for MDR-TB experts. Risk of hearing loss increases with increasing duration of treatment. For aminoglycosides in general, the estimated frequency of nephrotoxicity is 5% to 15% and of ototoxicity 2% to 14%, including 2% to 10% cochlear and 3% to 14% vestibular (155). In a survey of clinical trials performed between 1975 and 1982 and totaling z10,000 patients, the incidence of amikacin nephrotoxicity was 8.7% (178). Cumulative dose and duration predicted toxicity; older age, dehydration/hypovolemia/hypotension, prior aminoglycoside treatment, coexisting hepatic or renal disease, and concomitant medications were important as well (155). Significant hearing impairment exceeds 50% in some reported series, renal dysfunction approaches 50%, and vestibular dysfunction as high as 20% has been reported (155,162,177). At the other extreme, series have been published with no significant or permanent toxicity, including with longer-term use (155,162,177). Direct comparisons of drug toxicity for the four drugs used in TB are scarce. Experience suggests streptomycin may be more ototoxic, but that may be a consequence of far longer and wider use of streptomycin. Observational studies suggest amikacin may be more ototoxic than the other drugs (179)(180)(181).\nIn children, ototoxicity (hearing loss) has been documented in up to 24% of cases in a retrospective study, which also brings serious implications for development of normal speech (182). Pain of intramuscular injections can be safely reduced by adding lidocaine to amikacin injections without interference of pharmacokinetics (183). Dose range of amikacin should be 15 to 20 mg/kg as single daily dose.\nAdditional considerations. When injectables are used, serum creatinine, electrolyte measurements, clinical assessment for vertigo and tinnitus, highquality audiometry (including hearing frequency of 6,000-8,000 Hz, as highfrequency hearing loss is seen initially), and clinical examinations should be conducted at least monthly, or more frequently if adverse effects occur. Limited data suggest there may be a genetic predisposition for hearing loss associated with specific mitochondrial gene mutations (184). Although routine genetic testing is not currently suggested, the provider should be aware of these genetic mutations and the risks of ototoxicity (185,186). Because bactericidal activity is concentration dependent, high peak levels and single daily dosing are preferred to divided doses. Because of the postantibiotic effect, toxicity can be minimized by allowing trough levels between doses to remain below detectable levels for many hours. Some experts take advantage of these AMERICAN THORACIC SOCIETY DOCUMENTS pharmacokinetic and pharmacodynamic properties with thrice-weekly dosing, especially after conversion of cultures to negative, decreasing healthcare system demands and the requirement for daily injections (16,177). Intramuscular injections are painful, and 6 months of injections can be traumatic, especially to younger patients. Patients' values may differ sharply from providers in this respect and should be considered when determining whether to use injectable agents.\nConclusions. In our PS-matched IPDMA, the use of amikacin and streptomycin when the patient's isolate was susceptible to these drugs was associated with an increase in treatment success when compared with the control group not receiving these injectables. However, because of their toxicity and modest efficacy compared with other drugs, which also are less toxic, these drugs should be reserved for when more-effective or lesstoxic therapies cannot be assembled to achieve a total of five effective drugs. In our analyses, amikacin and streptomycin had similar aORs for treatment success in a minority of patients with fluoroquinolone resistance. Kanamycin and capreomycin were ineffective. We recommend against using kanamycin or capreomycin. As is the case for adults, the use of amikacin and streptomycin for children should also be reserved to when more-effective or less-toxic therapies cannot be assembled to achieve a total of five effective drugs.\nResearch needs. N-acetylcysteine, a thiol-containing antioxidant, may limit the severity and irreversibility of aminoglycoside-induced ototoxicity (187,188), warranting additional research into this and other otoprotective measures that may improve the balance of benefits and harms for using these injectable agents.\n\n# Linezolid\nLinezolid is an oxazolidinone antibiotic that inhibits bacterial protein synthesis by preventing the fusion of 30S and 50S ribosomal subunits (189). It also binds to human mitochondria and inhibits protein synthesis, which is the mechanism of toxicity in clinical use (190,191). Linezolid was initially used off-label in the absence of consistent scientific evidence as part of the regimen for difficult-to-treat cases of MDR-and XDR-TB (192). The first large retrospective observational study suggested linezolid was effective, but with frequent and often severe adverse events (192). The same study suggested, for the first time, that reducing the daily dose from 1,200 mg to 600 mg per day might be associated with fewer adverse events and improved tolerability. Several systematic reviews, IPDMAs, and one controlled clinical trial have been published on linezolid for treatment of MDR-TB (87,(193)(194)(195)(196). The clinical trial confirmed previous observational findings and, in particular, the effectiveness of linezolid and its potential toxicity (195). A meta-analysis with 121 cases of patients with MDR-TB from 11 countries, treated with linezolid, confirmed linezolid effectiveness (culture conversion, 93.5%; treatment success, 81.8%) and that the 600mg daily dose was safer than the 1,200-mg dose (46.7% adverse events vs. 74.5%, respectively) without lowering its effectiveness (196). The clinical trial confirmed the efficacy, safety, and tolerability of linezolid in patients with XDR-TB (194). There are insufficient data regarding the effectiveness of initiating treatment with doses ,600 mg daily to recommend lower doses. Recently, the importance of therapeutic drug monitoring to reduce adverse events potentially due to linezolid has been emphasized (197,198).\nSummary of the evidence. Linezolid was used in regimens for MDR-and XDR-TB across 38 studies (3). The initial dose of linezolid was 1,200 mg/d for 91 patients in five studies, 600 mg/d for 784 patients in 28 studies, and 300 mg/d for 99 patients in five studies (3). Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B.\nBenefits. In our PS-matched IPDMA, patients who received linezolid-containing regimens were more likely to achieve treatment success (aOR, 3.4; 95% CI, 2.6-4.5) and to have a lower rate of death (aOR, 0.3; 95% CI, 0.2-0.3) than those who did not receive linezolid. The effect on treatment success was more pronounced when studies from only high-income countries were included (aOR, 3.9; 95% CI, 2.6-5.8). The greatest impact was found in patients with XDR-TB, where the aOR for successful treatment versus failure or relapse was 6.3 (95% CI, 3.9-10.1) and the aOR for death was 0.1 (95% CI, 0.1-0.2). When PS-matched pairs analyses were performed comparing the effects of bedaquiline and linezolid with those of no bedaquiline or linezolid, the combination of bedaquiline and linezolid was associated with an aOR of 2.7 (95% CI, 1.5-4.9) for success versus failure/relapse, and of 0.3 (95% CI, 0.2-0.4) for death versus success/failure/relapse. The efficacy of linezolid in children with TB has been shown in two studies of children ,18 years of age, albeit with few patients (199,200).\nHarms. Adverse effects associated with linezolid in patients with TB include neurotoxicity (i.e., peripheral neuropathy and optic neuritis), myelosuppression, hyperlactatemia, and diarrhea, all of which are presumably secondary to the inhibition of mitochondrial protein synthesis (190,201). A published systematic review of 12 studies conducted in 11 countries globally reported an adverse event rate of 58.9% (hematological, neurological, and gastrointestinal), predominantly noted in individuals treated with a dosages .600 mg/d (196). Hematological toxicity can occur quickly after starting treatment and can involve any cell line. Neurotoxicity, including optic neuritis and peripheral neuropathy, occur later, usually after 12 to 20 weeks of treatment. Toxicity has been associated with trough levels of .2.0 PICO Question 14-Linezolid: In patients with MDR-TB, are outcomes safely improved when regimens include linezolid compared with regimens that do not include linezolid?\nRecommendation 14: We suggest including linezolid in a regimen for the treatment of patients with MDR-TB (conditional recommendation, very low certainty in the evidence). This is a conditional recommendation despite linezolid-containing regimens showing large reduction in mortality and improved treatment success, similar to bedaquiline and later-generation fluoroquinolones, because linezolid had more adverse effects and the balance of benefits and harms was less favorable compared with those drugs. (202)(203)(204). Adverse effects, especially myelosuppression, are also noted to be common at the currently recommended dose of 10 mg/kg twice daily in children ,10 years of age.\nAdditional considerations. Although use of linezolid for the FDA-approved 28 days or less for non-TB indications is associated with an acceptable adverse effect profile (205), the data on the longer-term use necessary for MDR-TB are limited (3,195,200). Strict clinical monitoring for potential toxicity (in particular peripheral neuropathy, optic neuritis, anemia, and leukopenia) is necessary because of the risk of adverse events associated with the longterm use of linezolid (16). If optic neuritis occurs, many patients may be rechallenged successfully with linezolid once vision normalizes. Assessment for visual toxicity must continue after restarting linezolid. Some patients are able to be rechallenged with the full dose; others are able to avoid recurrent visual toxicity with a reduced dose of linezolid at 300 mg daily (195). Linezolid should generally not be administered to patients taking serotonergic agents, such as monoamine oxidase inhibitors, because of the potential for serious CNS reactions, such as serotonin syndrome. Because monoamine oxidase type A deaminates serotonin, and selective serotonin reuptake inhibitors potentiate the action of serotonin by inhibiting its neuronal reuptake, administration of linezolid concurrently with a selective serotonin reuptake inhibitor can lead to serious reactions, such as serotonin syndrome or neuroleptic malignant syndrome-like reactions (16). One randomized clinical trial demonstrated that lowering the dose from 600 mg/d to 300 mg/d after culture conversion reduced toxicity (195). For children, one modeling study reported that linezolid dose of 15 mg/kg in full-term neonates and infants aged 90%, with ,10% achieving linezolid area under the concentration-versus-time curve (AUC) of 0 to 24 associated with toxicity (173). On the basis of modeling of pharmacokinetic data from 48 children, WHO and Sentinel Project recommend pediatric doses of linezolid as 15 mg/kg once daily for children ,15 kg and 10 to 12 mg/kg once daily for those weighing .15 kg (7,17). It is common practice for patients on linezolid to be prescribed vitamin B6 (16).\nConclusions. In our PS-matched IPDMA, patients who received linezolidcontaining regimens were more likely to achieve treatment success and to have a lower rate of death than those who did not receive linezolid. We suggest including linezolid in a regimen for the treatment of patients with MDR-TB. This is a conditional recommendation despite linezolid-containing regimens showing large reduction in mortality and improved treatment success, similar to bedaquiline and later-generation fluoroquinolones, because linezolid had more adverse effects and the balance of benefits and harms was less favorable compared with those drugs.\nResearch needs. Clinical trials of combinations of new chemical entities plus linezolid, including when administered at different doses and durations to optimize its therapeutic effect while minimizing toxicity are underway (Nix-TB, ClinicalTrials.gov Identifier: NCT02333799; ZeNix , NCT03086486). Further linezolid pharmacokinetic and safety data are needed to find optimal dosing in adults and children.\n\n# Macrolides: Azithromycin and Clarithromycin\nThe macrolides azithromycin and clarithromycin have unclear efficacy and role in the treatment of MDR-TB (23). Macrolides are commonly used to treat upper and lower respiratory tract infections and have an essential role in the treatment of nontuberculous mycobacteria (206). They are believed to have immunomodulatory and antiinflammatory effects. M. tuberculosis has intrinsic, inducible resistance to clarithromycin (207,208), and in vivo murine TB models confirm the lack of activity of macrolides (209). Clarithromycin may increase linezolid serum exposure when used in combination (210), prompting some consideration of potential synergy between macrolides and other MDR-TB drugs (211). WHO does not recommend use of macrolides to treat MDR-TB (23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PSmatched IPDMA, patients who received macrolides (n = 1,067) were more likely to have been treated with second-line drugs and to have resistance to fluoroquinolones or any PICO Question 15-Macrolides: In patients with MDR-TB, are outcomes safely improved when regimens include macrolides compared with regimens that do not include macrolides? Recommendation 15: We recommend NOT including the macrolides azithromycin and clarithromycin in a treatment regimen for patients with MDR-TB (strong recommendation, very low certainty in the evidence). Our recommendation against the use of the macrolides azithromycin and clarithromycin in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug class as having a notably unfavorable balance of benefits to potential harms.\nPICO Question 16-p-Aminosalicylic Acid: In patients with MDR-TB, are outcomes safely improved when regimens include p-aminosalicylic acid compared with regimens that do not include p-aminosalicylic acid? Recommendation 16: We suggest NOT including p-aminosalicylic acid in a treatment regimen for patients with MDR-TB (conditional recommendation, very low certainty in the evidence). When the individualized treatment regimen for patients with MDR-TB contains newer-generation, more-effective drugs, the addition of p-aminosalicylic acid does not appear to provide a benefit.\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS\nsecond-line injectable (3). Patients who received macrolides were more likely to receive later-generation fluoroquinolones, capreomycin, and linezolid. In adjusted analyses, patients who received macrolides were less likely to achieve treatment success (aOR, 0.6; 95% CI, 0.5-0.8) and had a higher rate of death (aOR, 1.6, 95% CI, 1.2-2.0) than patients who did not receive macrolides.\nBenefits. The available evidence does not support the use of macrolides in the treatment of MDR-TB.\nHarms. In our PS-matched IPDMA, patients who received macrolides were less likely to achieve treatment success (aOR, 0.6; 95% CI, 0.5-0.8) and had a higher rate of death (aOR, 1.6; 95% CI, 1.2-2.0) than patients who did not receive macrolides.\nConclusions. Macrolides, specifically azithromycin or clarithromycin, should not be included in a regimen for the treatment of patients with MDR-TB. Our recommendation against the use of the macrolides azithromycin and clarithromycin in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug class as having a notably unfavorable balance of benefits to potential harms.\nResearch needs. Further research may be warranted on newer-generation macrolides and to elucidate if there is potential synergy of macrolides with linezolid or other second-line agents.\n\n# p-Aminosalicylic Acid\nOne of the first agents found to be effective against TB (212), p-aminosalicylic acid has been widely used clinically, although its precise mode of action remains uncertain (213). With the discovery of other more potent drugs, including rifampin, p-aminosalicylic acid, initially used combined with streptomycin, was no longer considered in first-line regimens. It is now used as part of a treatment regimen for MDR-and XDR-TB, although the benefits of p-aminosalicylic acid are not clear and toxicity limits its use. Current guidance recommends that p-aminosalicylic acid be used to compose a regimen when five effective drugs cannot otherwise be assembled (16,23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PS-matched IPDMA, p-aminosalicylic acid was not associated with any benefit on treatment success (aOR, 0.8; 95% CI, 0.7-1.0) and was associated with increased death (aOR, 1.2; 95% CI, 1.1-1.4) (3). The potential to cause adverse events (12.2% in a previous meta-analysis) has also limited the tolerability of p-aminosalicylic acid (23).\nBenefits. No association with any benefit on treatment success was identified for p-aminosalicylic acid in our PS-matched IPDMA. In an IPDMA of children with MDR-TB, there was no benefit identified for the inclusion of p-aminosalicylic acid in regimens (aOR, 0.75; 95% CI, 0.25-1.96; P = 0.483) (113).\nHarms. Gastrointestinal distress is common with p-aminosalicylic acid but reported to occur less with the PASER formulation than with older preparations (16). Rare hepatotoxicity and thrombocytopenia have been reported, as has reversible hypothyroidism, particularly when used concomitantly with ethionamide (120). In the setting of hypothyroidism, some experts provide thyroid replacement therapy rather than discontinuing p-aminosalicylic acid. Clinical experience has shown paminosalicylic acid to be better tolerated regarding gastrointestinal disturbance in children than in adults, although hypothyroidism also remains common in children.\nAdditional considerations. Indirect comparison suggests that ethionamide may be better than p-aminosalicylic acid if a fifth drug is needed to construct a regimen with at least five effective drugs. Old studies have shown p-aminosalicylic acid to be a good companion drug to protect other drugs from developing resistance and also have shown efficacy in combination with first-line drugs (214,215). It has recently been suggested by pediatric DR-TB experts that in children p-aminosalicylic acid may replace an injectable agent in the absence of better drugs (83). When p-aminosalicylic acid is used, experts recommend monitoring thyroid-stimulating hormone, electrolytes, blood counts, and liver function tests.\nConclusions. When the individualized treatment regimen for patients with MDR-TB contains newer-generation, more-effective drugs, the addition of p-aminosalicylic acid does not appear to provide benefit.\nResearch needs. Given the limited armament of TB drugs available for treating MDR-TB, some experts have advocated for the evaluation of doseoptimized p-aminosalicylic acid to improve efficacy while minimizing toxicity (216). Research on whether p-aminosalicylic acid, among other agents, may offer protection against the acquisition of resistance to other drugs in the regimen would also be valuable.\n\n# Pyrazinamide\nPyrazinamide, a nicotinamide analog, is a prodrug that is converted in vivo into pyrazinoic acid, which interferes with mycobacterial fatty acid synthase. Pyrazinamide has demonstrated effectiveness against M. tuberculosis; it is included in standard regimens for treatment of drug-susceptible TB and also used in regimens for MDR-TB (11,16,23). However, recent population-based studies conducted as part of multicountry surveillance activities have shown that pyrazinamide resistance is highly associated with rifampin resistance (217,218). This finding, in conjunction with evidence that pyrazinamide efficacy is reduced in the setting of pncA gene mutations (219)(220)(221)(222), underscores the importance of documenting drug susceptibility to pyrazinamide by WGS, molecular tests, or traditional DST, if the drug is to be included as part of a regimen for MDR-TB.\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS\nPyrazinamide has been demonstrated to have substantial sterilizing activity as part of combination regimens and has allowed for treatment shortening in drugsusceptible TB (223,224). Higher doses have been shown to be more effective in animal models and phase 2A studies, but doses of 40 to 70 mg/kg were found to be too toxic to be pursued further in human studies (224). Summary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA compared outcomes in 1,986 individuals with isolates susceptible to pyrazinamide who received the drug with 307 individuals with isolates susceptible to pyrazinamide who did not receive the drug (3). However, the groups were not balanced with regard to other effective drugs; in particular, the patients not receiving pyrazinamide were more likely to receive linezolid and a latergeneration fluoroquinolone. Thus, the ability to detect an effect of pyrazinamide might have been partially obscured. In a previous IPDMA, before linezolid and bedaquiline were more commonly used, administration of pyrazinamide among patients with susceptible isolates was associated with an aOR of 1.9 (95% CI, 1.3-2.9) for cure/complete versus failure/relapse and an aOR of 1.6 (95% CI, 1.3-2.1) for cure/complete versus failure/relapse/death, compared with patients receiving pyrazinamide whose isolates were resistant in vitro (6).\nBenefits. In our PS-matched IPDMA, treatment success was significantly less likely with regimens containing pyrazinamide (aOR, 0.7; 95% CI, 0.5-0.9), but death was also significantly less frequent (aOR, 0.7; 95% CI, 0.6-0.8). This paradox may be due to confounding in our PS-matched IPDMA, as patients who did not receive pyrazinamide were substantially more likely to receive linezolid. Moreover, our PS-matched IPDMA did not assess the potential ability of pyrazinamide to Levofloxacin doses of up to 1,250 mg have been used safely when needed to achieve therapeutic concentrations. A recent population pharmacokinetic study in South African children found that higher levofloxacin doses from 18 mg/kg/d for younger children, up to 40 mg/kg/d for older children, may be required to achieve adult-equivalent exposures (170). ‡ Higher moxifloxacin doses have been used safely when the isolate is resistant to ofloxacin and the minimum inhibitory concentration for levofloxacin or moxifloxacin suggests higher doses may overcome resistance. Higher doses also are used in cases of malabsorption.\nx Cycloserine doses can be divided if needed (typically twice daily). Doses .750 mg are difficult for many patients to tolerate. jj Cycloserine dose may be lowered if serum concentrations exceed 35 mg/ml, even if patient is not experiencing toxicity, to prevent central nervous system toxicity. ¶ Modified from adult intermittent dose of 25 mg/kg, and accounting for larger total body water content and faster clearance of injectable drugs in most children. Dosing can be guided by serum concentrations. Ethionamide can be given at bedtime or with a meal to reduce nausea. Experienced clinicians suggest starting with 250 mg once daily and gradually increasing the dose over 1 week. Serum concentrations may be useful in determining the appropriate dose. Few patients tolerate 500 mg twice daily. † † Studies are ongoing evaluating meropenem at higher doses (ClinicalTrials.gov identifiers: NCT03174184 and NCT02349841). ‡ ‡ Some experts prescribe p-aminosalicylic acid at 6 g, and up to12 g, administered once daily (16,216).\nxx For children, some experts prescribe p-aminosalicylic acid at 200 mg/kg administered once daily (216). jjjj Isoniazid is tested at two concentrations. Some experts use these results (or resistance conferred through mutations in inhA) to select a higher dose when it tests resistant at the lower concentration and susceptible at the higher concentration. The higher dose may achieve in vivo concentrations sufficiently high to overcome low-level resistance (16,216).\nAMERICAN THORACIC SOCIETY DOCUMENTS e120 contribute to treatment shortening, as has been achieved in drug-susceptible TB. Because pyrazinamide is associated with increased success only when used to treat patients whose isolates are susceptible to the drug (144), whenever feasible, the decision to include pyrazinamide in a regimen should be based on pyrazinamide susceptibility results.\nIn an IPDMA of children with MDR-TB, the addition of pyrazinamide to a regimen showed no benefit in the treatment of confirmed MDR-TB cases (aOR, 1.63; 95% CI, 0.41-6.56; P = 0.484) (113). Pyrazinamide resistance was, however, not tested and improved selection of cases on the basis of resistance might change this outcome.\nHarms. Pyrazinamide has been used extensively in the treatment of TB, and toxicities are well documented (225). The most common is gastrointestinal upset or intolerance. In a recent review of the tolerability of TB drugs, pyrazinamide was associated with serious adverse events in 56 of 2,023 (2.8%) patients (226). This is consistent with previous reports of pyrazinamide toxicity (11,225,227). Hepatic enzyme elevations are common with pyrazinamide, and significant hepatotoxicity, although less common, can occur. Modest elevated serum uric acid levels are also expected, although the clinical significance of this is unclear. Nongouty polyarthralgias and hypersensitivity reactions can occur. Flares of clinical gout can also occur, especially in those with a history of prior gouty arthritis.\nAdditional considerations. All patients receiving pyrazinamide as part of an MDR-TB treatment regimen should be monitored carefully for signs or symptoms of hepatotoxicity and have their pyrazinamide dose held or decreased if such toxicity is detected. Isolated increases in uric acid without symptoms of gout are common and are not an indication to discontinue the drug. Recent population-based studies have found that pyrazinamide resistance is common in the setting of MDR with some regional variability, suggesting that pyrazinamide susceptibility should be confirmed or suspected if the drug is included in the regimen (217,228,229). Although there are known challenges related to accurately determining phenotypic DST for pyrazinamide, recent highly predictive DNA sequencing techniques show significant promise for newer genomic approaches (230).\nWhen included in the regimen, most experts use doses of 25 to 40 mg/kg/d orally. The recommended dose of pyrazinamide in children is 30 to 40 mg/kg daily.\nConclusions. We suggest including pyrazinamide in a regimen for the treatment of patients with MDR-TB, when the M. tuberculosis isolate has not been found resistant to pyrazinamide.\nResearch needs. Pyrazinamide is being evaluated as part of novel treatment regimens for both DS and MDR-TB in multiple clinical trials (56). Development of a reliable, simple molecular test for pyrazinamide susceptibility is a critically important research need. Dose optimization studies for pyrazinamide are warranted, as higher doses may be more efficacious but also may be more toxic.\n\n# Building a Treatment Regimen for MDR-TB\nThe guideline committee proposes a clinical strategy tool for building a treatment regimen for MDR-TB (Table 10). The clinical strategy tool incorporates the evidence-based review of the individual drugs, with consideration of the balance of benefits and harms for each drug, the experience of MDR-TB experts on the committee, as well as perspectives of patients. This clinical strategy tool encourages the building of all oral regimens with five effective drugs (to which the isolate is susceptible or has low likelihood of resistance) for the treatment of MDR-TB. In our PS-matched IPDMA, significant favorable synergies were identified with improved treatment success and reduced mortality when bedaquiline was used in combination with linezolid or clofazimine. As noted, amikacin and streptomycin show modest effectiveness when the patient's isolate is susceptible to these drugs; however, because of their significant toxicities, aminoglycosides should be reserved for when a more-effective or lesstoxic regimen cannot otherwise be assembled. The final choice of drugs and drug classes is contingent on many factors, including patient preferences, harms and benefits associated with agents, the capacity to appropriately monitor for significant adverse effects, consideration of drug-drug interactions, comorbidities, and drug availability. Final regimen development, therefore, is individualized and may differ substantially from the approach described in Table 10. Doses of the drugs for treating adults and children with MDR-TB are provided in Table 9, modified and updated from the 2016 ATS/CDC/IDSA Treatment of Drug-Susceptible TB Practice Guidelines (11).\n\n# Role of Therapeutic Drug Monitoring in Treatment of MDR-TB\nSpecific pharmacokinetic (PK)/ pharmacodynamic (PD) targets, especially the AUC divided by the MIC over 24 hours (AUC 0-24 /MIC), are being recognized as playing an important role in determining efficacy (231). This has been demonstrated most clearly in hollow fiber systems in vitro that isolate the activity of the drug against the organism (232,233). Further evidence has been provided by animal models (mouse, rabbit, nonhuman primates) and through human clinical trials (234)(235)(236)(237). Drug levels are usually chosen to be four to five times greater than the MIC. Because of the complexities of clinical disease, it is more challenging to isolate the PK/PD contribution of individual drugs, but studies have nonetheless been informative on the relationships between efficacy and drug exposure (238)(239)(240). In human TB, a combination of drugs is used, and each patient has his or her unique duration of disease, host genetics, and particular strain of M. tuberculosis. The general term for these PK/PD data is \"exposure-response\" data (i.e., for a given amount of drug exposure, how much response can you expect?). Much of the published data focus on the first-line TB drugs, with some emerging data becoming available for second-line drugs (241)(242)(243).\nIn clinical practice, the actual MIC for each drug often is not available. Epidemiological cut-off values or \"critical concentrations\" that separate wild-type from more resistant isolates can be used for selecting what drugs to include in a regimen (244). These in vitro cut-offs are based on patterns of susceptibility compared with achievable concentrations within humans. An organism is not just \"susceptible\" as an inherent property; it is susceptible to inhibition or killing by specific, tested concentrations of the AMERICAN THORACIC SOCIETY DOCUMENTS drugs. Individual MIC values might be preferred; however, in practice, there are technical and financial barriers to such individualized data. Following standardized dosing, clinical experience over the past 3 decades clearly shows that some patients have low drug concentrations, leading to clinical failures (11,231,241,242,244).\nMany MDR-TB experts use therapeutic drug monitoring (TDM) to identify patients with problems with drug absorption, thereby informing dose adjustments.\nIndividuals who have poor response to TB treatment despite adherence may benefit from TDM (11). Patients with TB with gastrointestinal problems that increase risk of malabsorption, concurrent HIV infection, impaired renal clearance, or diabetes should be prioritized for TDM (11). Furthermore, some experts use TDM for all patients being treated for MDR or XDR-TB early in treatment, rather than waiting for a poor response. TDM should be used and interpreted in consultation with an expert in MDR-TB.\nTDM also provides patient-specific information that may help limit toxicity due to certain drugs, including the injectable drugs cycloserine and linezolid (245)(246)(247). In particular, linezolid toxicity is associated with elevated trough values (202)(203)(204). \"Target\" ranges for the injectable drugs and cycloserine have been proposed, and research continues on refining these. Fluoroquinolones display concentrationdependent efficacy, and higher doses of moxifloxacin and levofloxacin are being studied (174,248). Currently, Table 10. Clinical Strategy to Build an Individualized Treatment Regimen for MDR-TB d Build a regimen using five or more drugs to which the isolate is susceptible (or has low likelihood of resistance), preferably with drugs that have not been used to treat the patient previously. d Choice of drugs is contingent on capacity to appropriately monitor for significant adverse effects, patient comorbidities, and preferences/values (choices therefore subject to program and patient safety limitations). d In children with TB disease who are contacts of infectious MDR-TB source cases, the source case's isolate DST result should be used if an isolate is not obtained from the child. d TB expert medical consultation is recommended (ungraded good practice statement).\nStep 1: Choose one later-generation fluoroquinolone Levofloxacin Moxifloxacin\nStep 2: Choose both of these prioritized drugs Bedaquiline Linezolid\nStep 3: Choose both of these prioritized drugs Clofazimine Cycloserine/terizidone\nStep 4: If a regimen cannot be assembled with five effective oral drugs, and the isolate is susceptible, use one of these injectable agents- Amikacin Streptomycin\nStep 5: If needed or if oral agents preferred over injectable agents in Step 4, use the following drugs † Delamanid ‡ Pyrazinamide Ethambutol\nStep 6: If limited options and cannot assemble a regimen of five effective drugs, consider use of the following drugs Ethionamide or prothionamide x Imipenem-cilastatin/clavulanate or meropenem/clavulanate jj p-Aminosalicylic acid ¶ High-dose isoniazid\nThe following drugs are no longer recommended for inclusion in MDR-TB regimens:\nCapreomycin and kanamycin Amoxicillin/clavulanate (when used without a carbapenem) Azithromycin and clarithromycin Definition of abbreviations: DST = drug susceptibility testing; INH = isoniazid; IPDMA = individual patient data meta-analyses; MDR = multidrug-resistant; PS = propensity score; TB = tuberculosis. *Amikacin and streptomycin should be used only when the patient's isolate is susceptible to these drugs. Because of their toxicity, these drugs should be reserved for when more-effective or less-toxic therapies cannot be assembled to achieve a total of five effective drugs. † Patient preferences in terms of the harms and benefits associated with injectables (the use of which is no longer obligatory), the capacity to appropriately monitor for significant adverse effects, consideration of drug-drug interactions, and patient comorbidities should be considered in selecting Step 5 agents over injectables. Ethambutol and pyrazinamide had mixed/marginal performance on outcomes assessed in our PS-matched IPDMA; however, some experts may prefer these drugs over injectable agents to build a regimen of at least five effective oral drugs. Use pyrazinamide and ethambutol only when the isolate is documented as susceptible. ‡ Data on dosing and safety of delamanid are available in children >3 years of age.\nx Mutations in the inhA region of the Mycobacterium tuberculosis genome can confer resistance to ethionamide/prothionamide as well as to INH. In this situation, ethionamide/prothionamide may not be a good choice unless the isolate is shown to be susceptible with in vitro testing. jj Divided daily intravenous dosing limits feasibility. Optimal duration of use not defined. ¶ Fair/poor tolerability and low performance. Adverse effects reported to be less common in children. Data not reviewed in our PS-matched IPDMA, but high-dose isoniazid can be considered despite low-level isoniazid resistance but not with high-level INH resistance.\nAMERICAN THORACIC SOCIETY DOCUMENTS e122 avoiding low serum concentrations seems advisable.\nA common clinical practice is to collect samples at 2 and 6 hours after drug administration to measure concentrations that may distinguish normal drug absorption (a 2-h value within the normal range) from delayed absorption (a 6-h value greater than the 2-h value, approaching the normal range) and malabsorption (both values are below the normal range). This approach also works for injectable drugs. Furthermore, trough values for linezolid can be helpful (11,231,241,242,244). Although it is clearly possible to cure patients without TDM and even in the setting of lower serum drug concentrations, the available data suggest that the probability of cure decreases with decreasing drug concentrations (231)(232)(233)(234)(235)(236)(237)(238)(239)(240)(241). Given the incomplete information currently available, many expert clinicians use in vitro susceptibility data and TDM as available tools for optimizing the treatment of patients with MDR-and XDR-TB. For all patients, but in particular those receiving outpatient treatment, TDM should be coordinated and conducted using patientcentered approaches.\nShorter-Course, Standardized, 9-to 12-Month Regimen for MDR-TB A randomized, phase 3, noninferiority trial, STREAM Stage 1 (ClinicalTrials.gov identifier: NCT02409290) was recently conducted to assess a shorter-course regimen composed of existing drugs for MDR-TB (8). This regimen had achieved success rates of 83% (95% CI, 71.0-90.3%) in cohort studies (249,250). The shortercourse regimen is standardized and composed of kanamycin, moxifloxacin (in place of gatifloxacin, which was the fluoroquinolone originally used in the \"Bangladesh\" regimen), prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol for an initial period (4-6 mo) and moxifloxacin, clofazimine, pyrazinamide, and ethambutol for the continuation phase (5 mo) (23). The total duration of therapy is between 9 and 11 months, compared with an individualized regimen of 18 to 24 months of therapy. The medication costs of the shorter regimen are believed to be less than that of conventional regimens, currently undergoing a formal economic evaluation as part of the STREAM trials (251).\n\n# Summary of the Evidence\nIn the STREAM Stage 1 clinical trial, of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population (8). Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group-a difference, with adjustment for HIV status, of 1.0 percentage point (95% CI, 27.5 to 9.5). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PS-matched IPDMA of 12,030 patients (n = 50 studies), 169 (n = 33 studies) were eligible for analysis of death and 1,369 (n = 33 studies) were eligible for analysis of treatment success (249) once the criteria used for the shorter-course regimen were applied (249). There were data from 532 individuals (n = 3 studies) on the shorter regimen available for analysis of death and 498 (n = 3 studies) for analysis of treatment success. After using PS matching to adjust for age, sex, HIV, smear status, past TB treatment with first-line drugs, and number of effective drugs, there were no statistically significant associations for the shorter regimen with treatment success (aOR, 0.5; 95% CI, 0.02-13), or deaths (aOR, 1.7; 95% CI, 0.6-4.6), compared with individualized regimens.\n\n# Benefits\nThe shorter regimen allows for a significantly shorter duration of therapy compared with the individualized regimen and consequently less pill burden, medication cost, and associated provider administration costs. The burden on patients of lost productivity or lost wages and out-of-pocket costs is considerably less with a shorter regimen. From preliminary results of the STREAM Stage 1 trial, there was a documented reduction in costs to patients due to less time away from work, fewer clinic visits, and less spending on supplementary food (252).\n\n# Harms\nIn the STREAM Stage 1 clinical trial, an adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group (8). Prolongation of either the QT interval or the QTc to 500 milliseconds occurred in 11.0% of participants in the short-regimen group, compared with 6.4% in the long-regimen group (P = 0.14). Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. Among the participants who had HIV coinfection at baseline, 18 of 103 (17.5%) in the short-regimen group died, compared with 4 of 50 (8.0%) in the PICO Question 18-Shorter-course, standardized regimen: In patients with MDR-TB, does treatment with a standardized MDR-TB regimen for <12 months lead to better outcomes than treatment with an MDR-TB regimen for 18-24 months? Recommendation 18: The shorter-course regimen is standardized with the use of kanamycin (which the committee recommends against using) and includes drugs for which there is documented or high likelihood of resistance (e.g., isoniazid, ethionamide, pyrazinamide). Although the STREAM Stage 1 randomized trial found the shorter-course regimen to be noninferior to longer injectable-containing regimens with respect to the primary efficacy outcome (8), the guideline committee cannot make a recommendation either for or against this standardized shorter-course regimen, compared with longer individualized all-oral regimens that can be composed in accordance with the recommendations in this practice guideline. We make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is documented or highly likely.\nAMERICAN THORACIC SOCIETY DOCUMENTS long-regimen group (HR in a post hoc analysis, 2.23; 95% CI, 0.76-6.60) (8). Similarly, in a recently published IPDMA, a greater proportion of individuals who received the shorter regimen had less treatment success and more death (249). In the IPDMA, other adverse effects were also statistically insignificant with the shorter regimen, including deafness and ototoxicity (relative risk, 1.5; 95% CI, 0.6-4.0), liver injury (relative risk, 2.2; 95% CI, 0.5-10.3), hepatitis (relative risk, 2.5; 95% CI, 0.3-21.2), and renal impairment (relative risk, 4.5; 95% CI, 0.6-35.2). One of the most concerning adverse effects of the shorter regimen is hearing loss, with 7.1% reported in the African study and between 0% and 23% in the meta-analysis (249,250). The STREAM Stage 1 trial found that ear and labyrinth disorders occurred in 7.4% participants on the shorter regimen, compared with 5.7% with the longer regimen, which was not statistically significant (8); the frequency may have been lower than in cohort studies because hearing loss was not monitored by audiometry in STREAM Stage 1.\n\n# Additional Considerations\nWhen applying the eligibility criteria from WHO for using the shorter-course, standardized regimen to the population included in our PS-matched IPDMA (7,253), .15% of individuals would have been eligible for the standardized, shorter regimen. In Europe, patient eligibility for the shorter-course regimen has ranged from 7.9% (48 of 612 new cases) in a study performed at TB reference centers (254) to 16.9% in a surveillance-based study performed by the European Centre for Disease Prevention and Control (ECDC) (93,107,255). In the United States, .15% of patients with MDR-TB would be eligible for the shorter-course MDR-TB regimen (256). Data from California showed either 14.6% or 20.5% eligibility, based on whether high-dose isoniazid or ethionamide would be determined effective on the basis of genetic katG or inhA mutations, respectively (257). The availability of molecular and growth-based DST is key to determining the potential eligibility of shorter-course regimen use. The combined use of both modalities can better inform drug resistance and potential treatment regimens. High-dose isoniazid is likely to be active against organisms with low-level isoniazid resistance, commonly associated with a mutation in the inhA gene that also confers resistance to ethionamide (257). Ethionamide is more likely to be active against M. tuberculosis organisms with high-level resistance to isoniazid, associated with a mutation in katG and which are less commonly resistant to ethionamide (257). Global data have shown that katG is present in 64.3% of the cases tested and inhA in 19.2%, with some regional differences (258). The shorter regimen includes both ethionamide and high-dose isoniazid and therefore is likely to be effective against both of these common MDR-TB resistance patterns (257,259). There is uncertainty regarding the diagnostic accuracy and reproducibility of ethambutol and pyrazinamide growthbased DST assays (260). For ethambutol, the ECDC has reported that the growth-based DST when performed on Mycobacteria Growth Indicator Tube (MGIT) is reliable (107), whereas Model Performance Evaluation Program data have identified variability in detecting ethambutol resistance, with the majority of laboratories having disagreement on one to several strains with ethambutol resistance (261). Alternatively, molecular testing for pncA mutations as a method for determining pyrazinamide resistance may be more reliable, because on average 85% of TB strains resistant to pyrazinamide will have such a mutation (217,221,222). In limited-resourced settings, testing all the drugs composing the shorter-course regimen may not be possible (106,108). In contrast, in Europe, DST for ethambutol (93,107) and pyrazinamide ( 106) is well studied, but katG and inhA genetic mutations are not. In the United States, growth-based DST data are available for ethambutol, pyrazinamide, high-and lowlevel isoniazid, and ethionamide, and molecular testing is available through some state public health laboratories and through the CDC's MDDR service (257). Therefore, considering patients with either katG or inhA (but not both) mutations to be eligible for the shorter regimen might be rational. Last, the rate of cross-resistance between ofloxacin and moxifloxacin is likely not complete. Data from the ECDC showed that 81% of M. tuberculosis isolates that were resistant to ofloxacin were also resistant to moxifloxacin. However, other settings (e.g., Bangladesh and Pakistan) have shown cross-resistance as low as 7% (107).\n\n# Conclusions\nThe shorter-course regimen was judged by the guidelines committee to have minimal desirable effects (on treatment success, mortality, and culture conversions) and small to moderate undesirable effects (adverse events, limited applicability, and the use of kanamycin as part of the standardized regimen), and includes drugs for which there is documented or high likelihood of resistance (e.g., isoniazid, ethionamide, and pyrazinamide). Although the WHO's STREAM Stage 1 randomized trial found the shorter-course regimen to be noninferior to a long regimen with respect to the primary efficacy outcome (8), the guideline committee cannot make a recommendation either for or against this standardized shorter-course regimen compared PICO Question 19-Surgery for MDR-TB: Should elective lung resection surgery (i.e., lobectomy or pneumonectomy) be used as an adjunctive therapeutic option in combination with antimicrobial therapy, versus medical therapy alone, for adults with MDR-TB? Recommendation 19a: We suggest elective partial lung resection (e.g., lobectomy or wedge resection), rather than medical therapy alone, for adults with MDR-TB receiving antimicrobial-based therapy (conditional recommendation, very low certainty in the evidence). The writing committee believes this option would be beneficial for patients for whom clinical judgement, supported by bacteriological and radiographic data, suggests a strong risk of treatment failure or relapse with medical therapy alone.\nRecommendation 19b: We suggest medical therapy alone, rather than including elective total lung resection (pneumonectomy), for adults with MDR-TB receiving antimicrobial therapy (conditional recommendation, very low certainty in the evidence).\nwith longer individualized regimens. We instead make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is confirmed or deemed to be highly likely. If this shorter-course regimen is used, we recommend obtaining DST for all medications in the regimen, with the exception of clofazimine, for which reliable testing is not available, and recommend careful side effect monitoring, including high-quality audiometry, monthly microbiologic monitoring, and close case management, especially in persons with HIV.\n\n# Research Needs\nWe make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is confirmed or deemed to be highly likely. Further research is needed on medications such as linezolid, bedaquiline, and other medications currently in clinical trials as substitutions in the regimen if patients experience adverse effects or resistance develops to any of the medications in the regimen (262). Research on modified shorter-course regimens for pediatric patients and in individuals living with HIV is also needed. Until more data regarding the use and outcomes of the shorter-course regimens in patients with HIV are available, this treatment approach should preferentially be considered only within a research study. Current trials are underway to help answer some these questions (262).\n\n# Role of Surgery in MDR-TB\nSurgery was one of the first therapeutic approaches for treating TB. It was replaced by chemotherapy between 1960 and 1975. However, several scientific societies and national and international organizations suggest consideration of surgery as an adjunctive therapy for MDR-TB. This is based on the results of observational retrospective studies. Selected indications are highlighted, including failure of drug therapy, relapse, localized (e.g., an isolated cavity) or extensive pulmonary TB, and clinical complications (e.g., hemoptysis or empyema) (23,(263)(264)(265)(266)(267)(268)(269)(270).\n\n# Summary of the Evidence\nSystematic reviews and meta-analyses have been performed on the role of surgery in patients with MDR-and XDR-TB (263,271,272). The main limitation of systematic reviews of surgery in MDR and XDR-TB that summarize results of observational studies combining study-level data is the tremendous variability in patient characteristics, background chemotherapy regimens, and types of surgical procedures (263,271,272). An IPDMA of surgery in MDR-TB was designed to address those shortcomings (271). Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B.\nThe IPDMA identified 67 cohort studies, of which 45 could not be used because either individual patient data were not available or the surgical status of patients was not known. Twenty-six studies comprising 6,431 patients with MDR-TB were included (271). We used data from this IPDMA to generate the evidence profiles. Despite the analytic advantages of an IPDMA, which allows for adjustment on baseline imbalance in many prognostic factors, there was a substantial residual risk of bias in the results. There is no information about the impact of surgery on adverse effects or quality of life.\n\n# Benefits\nPatients with partial lung resection had a higher probability of treatment success, as opposed to treatment failure, relapse, or death (aOR, 3.0; 95% CI, 1.5-5.9). However, the estimate is very uncertain because of the limitations of individual studies and lack of precision in results.\n\n# Harms\nIn the published IPDMA, a substantially higher proportion of patients who had a pneumonectomy died (8.5%) compared with those who had a partial resection (2.2%), but the authors could not establish whether patients died as a result of surgical complications or of their TB (271). The estimates of the effects of pneumonectomy on risk of death (aOR, 1.8; 95% CI, 0.6-5.1) and treatment success (aOR, 0.8; 95% CI, 0.1-6.0) were not statistically significant. As for partial lung resection, both estimates are very uncertain. Treatment success in patients with XDR-TB was noted to be lower when patients underwent surgery compared with patients who did not (aOR, PICO Question 20-Treatment of isoniazid-resistant TB: PICO Question 20a: Should patients with isoniazid-resistant TB be treated with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 months compared with rifampin, ethambutol, and pyrazinamide (without a fluoroquinolone) for 6 months? PICO Question 20b: Should patients with isoniazid-resistant TB be treated with a regimen composed of fluoroquinolone, rifampin, and ethambutol for 6 months and pyrazinamide for the first 2 months compared with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 months? Recommendation 20a: We suggest adding a later-generation fluoroquinolone to a 6-month regimen of daily rifampin, ethambutol, and pyrazinamide for patients with isoniazid-resistant TB (conditional recommendation, very low certainty in the evidence).\n\n# Recommendation 20b:\nIn patients with isoniazid-resistant TB treated with a daily regimen of a later-generation fluoroquinolone, rifampin, ethambutol, and pyrazinamide, we suggest that the duration of pyrazinamide can be shortened to 2 months in selected situations (i.e., noncavitary and lower-burden disease or toxicity from pyrazinamide) (conditional recommendation, very low certainty in the evidence).\nAMERICAN THORACIC SOCIETY DOCUMENTS 0.4; 95% CI, 0.2-0.9), an effect that was heterogeneous across studies and may also be confounded by factors that predisposed to poor outcomes in these patients (271). Alternatively, patients who were healthy enough to withstand surgery may have intrinsically lower mortality, so it is difficult to predict the direction of potential bias.\n\n# Additional Considerations\nIn the MDR-TB treatment guidelines updated in 2016, WHO recommended elective partial surgery as an intervention complementary to chemotherapy in specifically selected individuals (23). The committee acknowledged there is significant uncertainty, with a paucity of publications and data regarding patient preferences, acceptability by surgical personnel, cost, and feasibility of performing elective surgery as an intervention for MDR-TB.\n\n# Conclusions\nOn the basis of the limited evidence that is available, there appears to be a net benefit from an elective partial lung resection (e.g., lobectomy or wedge resection) when offered together with a recommended MDR-TB regimen, compared with medical therapy alone. Committee members believed that this therapeutic option would probably be more beneficial when clinical judgement, supported by bacteriological and radiographic data, suggests a strong risk of relapse or treatment failure with medical regimen alone. We found no currently available evidence that pneumonectomy would be beneficial for patients with MDR TB receiving a background drug regimen.\n\n# Research Needs\nRigorously designed and conducted studies, ideally well-done randomized trials that measure and report benefits but also adverse effects and quality of life, are needed to clarify the role of surgery in the management of patients with MDR-TB. The following specific issues need to be addressed: the optimal timing for surgery, the optimal drug regimens and their duration before and after surgery, the role of surgery in special populations and patients with comorbid conditions (e.g., those living with HIV), the optimal surgical approaches, the optimal infection control measures to be implemented perioperatively, and the role of pulmonary rehabilitation (263,267,270,273).\n\n# Treatment of Isoniazid-Resistant TB\nIsoniazid is an important first-line agent for the treatment of TB, possessing potent early bactericidal activity against M. tuberculosis. However, monoresistance to isoniazid is frequent worldwide, with an estimated prevalence of 8% (range, 5-11%) of TB cases (12). A recent systematic review and metaanalysis compared the treatment outcomes of isoniazid-resistant TB to outcomes of drugsusceptible TB and found that treatment of isoniazid-resistant TB with first-line drugs resulted in suboptimal outcomes, with higher treatment failure (11% vs. 1%) and relapse (10% vs. 5%) (274). In addition, the study found that standardized empirical treatment of new isoniazid-resistant TB cases may be contributing to higher rates of acquired drug resistance (8% vs. 0.3%). Prior ATS, CDC, and IDSA guidelines recommended treatment with a standard four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) for 6 months, with discontinuation of isoniazid after the results of DST are known and if isoniazid resistance was found (275).\n\n# Summary of the Evidence\nProcedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. An IPDMA of 33 datasets with 6,424 patients, of whom 3,923 patients in 23 studies received regimens related to isoniazid-resistant TB, was used as the evidence (276). Regimens of interest for our analyses (all with or without isoniazid) were 1) rifampin, ethambutol, and pyrazinamide; and 2) rifampin, ethambutol, and pyrazinamide, plus a fluoroquinolone. For these analyses, isoniazid-resistant TB was defined based on phenotypic resistance to isoniazid and susceptibility to rifampicin, with or without additional resistance to pyrazinamide, ethambutol, or streptomycin. Critical concentrations of 0.1 mg/ml or 0.2 mg/ml were used in 21 out of 23 centers for the definition of resistance to isoniazid (276). For PICO Question 20a, we found few studies that used regimens of 6 months of rifampin, ethambutol, and pyrazinamide, plus a fluoroquinolone, but several that used regimens of 8 to 9 months of this regimen; hence, we combined 6 with .6 months for this PICO. For the comparator of rifampin, ethambutol, pyrazinamide with or without isoniazid, we similarly combined regimens of 6 and .6 months' duration regimens, after comparison between these durations showed outcomes were not significantly different. For PICO Question 20b, few patients received regimens that had a fluoroquinolone, rifampin, ethambutol, and a shorter duration of pyrazinamide. A total of 118 patients received 1 to 3 months of pyrazinamide in conjunction with 6 and .6 months' durations of rifampin, ethambutol, and fluoroquinolone-containing regimen and were available for analyses.\n\n# Benefits\nCompared with 6 months of daily rifampin, ethambutol, and pyrazinamide (with or without isoniazid), adding a fluoroquinolone to this regimen was associated with significantly greater treatment success (aOR, 2.8; 95% CI, 1.1-7.3) but with no significant effect on mortality (aOR, 0.7; 95% CI, 0.4-1.1) or acquired rifampicin resistance (aOR, 0.1; 95% CI, 0.0-1.2). When evaluating the impact of shortening the duration of pyrazinamide (ranging from 1-3 mo) in a regimen that contains a fluoroquinolone, the treatment success was very high, with 117 of 118 patients achieving treatment success. On the other hand, comparisons of shorter pyrazinamide regimens to regimens including both a fluoroquinolone and pyrazinamide for >6 months did not show significantly different results (aOR, 5.2; 95% CI, 0.6-46.7). Similar results were obtained when the comparisons were restricted to patients receiving latergeneration fluoroquinolones, namely moxifloxacin, levofloxacin, and gatifloxacin (data not shown).\n\n# Harms\nThe outcome of adverse events from TB drugs was intended to be assessed in the IPDMA but could not be analyzed because these outcomes were either not reported or reported with very different definitions. The adverse events associated with TB drugs, especially pyrazinamide, are well established (227,277).\n\n# Additional Considerations\nWe note that the estimates of effect were imprecise from the IPDMA because of the small number of patients who received the AMERICAN THORACIC SOCIETY DOCUMENTS e126 regimens of interest. Given that pyrazinamide is the most toxic of the present first-line drugs, a key potential advantage of adding a fluoroquinolone would be to shorten the duration of pyrazinamide to the initial 2 months of treatment. Although the IPDMA only had 118 patients receiving fluoroquinolone-containing regimens with shorter durations of pyrazinamide, it is noted that treatment success was very high in this group (117 of 118). On the basis of the efficacy signals seen and the known toxicities of prolonged pyrazinamide, the committee viewed the balance of benefits and harms to favor shortening the duration of x Increases in serum creatinine via decrease in renal tubular creatinine excretion are commonly seen with cobicistat and dolutegravir usage. This is not a toxicity. jj Indirect hyperbilirubinemia is expected with atazanavir and indinavir. This is not a toxicity.\n\n# AMERICAN THORACIC SOCIETY DOCUMENTS\npyrazinamide when a later-generation fluoroquinolone is included in the regimen in patients in whom there is toxicity anticipated or experienced because of pyrazinamide or when the patient has noncavitary, lower burden of disease. Finally, plasma peak concentration and exposure to moxifloxacin have been shown to decrease by approximately 30% when coadministered with rifampin (278,279). The impact of these decreased exposures on outcomes has not been established. However, some experts opt to use levofloxacin when combined with rifampin.\n\n# Conclusions\nWe conclude that in patients with isoniazidresistant TB, the addition of a later-generation fluoroquinolone to 6 months of daily rifampin, ethambutol, and pyrazinamide improves treatment success rates. In patients in whom toxicity from pyrazinamide is anticipated or experienced, or in patients with active TB with lower burden of disease (i.e., noncavitary), the committee viewed the balance of benefits and harms to favor shortening the duration of pyrazinamide when a later-generation fluoroquinolone is included in the regimen, acknowledging that the certainty in the evidence is very low and more research is needed.\n\n# Research Needs\nAll but 2 of the 23 studies included in the IPDMA were observational. Moreover, the analyzed population included only 37 children, 119 patients with diabetes, and 249 patients with HIV infection. Given the burden of isoniazid-resistant TB worldwide, clinical trials that include these special populations and evaluate new regimens, including the evaluation of the efficacy, safety, and tolerability of shorter versus longer durations of pyrazinamide, are urgently needed.\n\n# Treatment of MDR-TB in Special Situations\n\n# HIV Infection\nAmong patients with HIV and TB, rifampin resistance has been identified more often compared with those without HIV (280,281).\nPatients with MDR-TB and HIV have up to a fourfold higher risk of mortality compared with patients with MDR-TB without HIV (282). Low CD4 cell counts (e.g., <50 cells/ml) in patients with HIV and MDR-TB further correlate with higher mortality (283,284). Numerous practice guidelines recommend HIV testing of people with suspected or confirmed TB (11,20,34,285), regardless of drug resistance. Because of their high risk for mortality early in the course of TB disease, people with HIV in whom TB is suspected are recommended to receive rapid testing for TB using nucleic acid amplification tests coupled with molecular diagnostic DST for rifampin (with or without isoniazid) (13,20). For patients with HIV receiving therapy for drug-susceptible TB, studies found significantly lower mortality among patients receiving concurrent antiretroviral therapy (ART) compared with those not receiving ART (286)(287)(288). U.S. practice guidelines recommend starting ART within 2 weeks of initiating treatment for drug-susceptible non-CNS TB for patients with CD4 cell counts ,50 cells/ml and by 8 to 12 weeks for patients with higher CD4 cell counts (11,289). Although the optimal timing for starting ART to reduce patient mortality has not yet been adequately determined for patients with MDR-TB, lower mortality rates have been shown in multiple studies among patients with MDR-TB receiving concurrent ART compared with those not receiving ART (283,(290)(291)(292)(293)(294)(295)(296)(297), especially among patients with TB with CD4 counts ,50 cells/ml (283,292). The decreased mortality seen in patients treated for MDR-TB who concurrently receive ART, especially among those with CD4 cell counts ,50 cells/ml, supports a similar ART management approach as recommended for drugsusceptible TB.\nMDR-TB of the CNS in patients with HIV presents additional challenges. TB meningitis with isoniazid-resistant TB, RR-TB, or MDR-TB can be associated with higher mortality compared with drugsusceptible disease (298)(299)(300). Starting ART early in patients with TB is associated with a higher incidence of immune reconstitution inflammatory syndrome (286,288,301), and this can be even more problematic in CNS disease. A recent study in Vietnam of patients with advanced AIDS found a higher incidence of potentially lifethreatening (grade 4) adverse events among patients with TB meningitis starting ART early compared with those delaying ART until after 2 months of standardized firstline TB treatment and did not show a survival benefit of starting ART early (302). It has been recommended to delay starting ART by 8 weeks in patients with CNS TB and HIV (11); however, there is a paucity of data in patients with MDR-TB of the CNS. The optimal approach for initiation of ART in patients with this medical condition remains uncertain, and close clinical monitoring is warranted.\nDrug interactions between antiretroviral and anti-TB agents are common in the management of patients with HIV and TB, particularly with rifamycins. Because the rifamycins (with the possible exception of rifabutin) are not used for treatment of MDR-TB, interactions of other TB medication classes with ART should be considered. Bedaquiline and/or delamanid might be considered for use in patients with HIV. Although efavirenz can produce a decrease in serum bedaquiline concentrations and this combination is avoided, other ART drugs, including the protease inhibitors and cobicistat, can result in increased serum bedaquiline levels. The current WHO recommendations for the use of delamanid apply to patients living with HIV (7). Drug-drug interaction studies in healthy volunteers of delamanid with tenofovir, efavirenz, and lopinavir/ritonavir show that no dose adjustments were needed (303). Nonetheless, when delamanid is included in the regimen for MDR-TB in HIVinfected patients, the design of their PICO Question 21-Treatment of Contacts Exposed to MDR-TB: Should contacts exposed to an infectious patient with MDR-TB be offered LTBI treatment versus followed with observation alone? Recommendation 21: For contacts with presumed MDR LTBI due to exposure to an infectious patient with MDR-TB, we suggest offering treatment for LTBI (conditional recommendation, very low certainty in the evidence). We suggest 6 to 12 months of treatment with a later-generation fluoroquinolone alone or with a second drug, on the basis of drug susceptibility of the source-case M. tuberculosis isolate. On the basis of evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug.\nOn the basis of recent modeling studies, it is estimated that there are about 1 million incident cases of TB in children annually and 230,000 deaths caused by the disease (306,307). About 35,000 cases of MDR-and XDR-TB occur in children annually (308,309). Our PS-matched IPDMA did not include sufficient numbers of children to allow the formulations of GRADE-based recommendations. Nonetheless, on the basis of a recent IPDMA of 975 children with MDR-TB from 18 countries, recent pharmacokinetic studies in children, and several observational studies showing good outcomes, the recommendations noted on choice of drugs, composition of regimens, and durations of treatment for adults can also be applied to children with MDR-TB (113,119,124,161,165,170,200,310).\nThere are some special considerations for formulating effective regimens for children of various ages and adolescents. The bacterial burden in young children with TB is much smaller than that in most adults with TB. As a result, most drug resistance in children was present when the organism was inhaled (primary resistance), and further development of resistance while on therapy (secondary resistance) is much less common in children. However, the paucibacillary nature of childhood TB also makes microbiologic confirmation much more difficult. The only way to determine drug susceptibility in cases that meet clinical definitions of TB disease (i.e., microbiologic confirmation is not available) is by linking the child to a specific source case for whom the drug susceptibilities of the organism are known. Linking the child and a specific case is more feasible in lowburden settings to which these guidelines apply but can be difficult in high-burden settings when there may be more than one possible source case. Also, standard definitions of relapse and treatment failure for pediatric TB trials are inconsistent because the low burden of organisms in children makes microbiologic confirmation of these outcomes difficult.\nThere are several technical factors that can affect the outcome of treatment for MDR-and XDR-TB in children. The two age extremes of childhood have been somewhat neglected in studies of MDR-and XDR-TB. Little is known about the pharmacokinetics, safety, and tolerability of the drugs used to treat drug-resistant TB in neonates, infants, and toddlers (115). Children, especially those ,2 years of age, are more prone to developing disseminated TB, including meningitis. Drugs that penetrate well into the CSF, such as linezolid, might have an advantage over drugs that appear to have less penetration, such as ethambutol and bedaquiline. Adolescents can develop TB similar to that found either in adults or in young children. However, adolescent patients often have been excluded from TB treatment trials. Most of the oral drugs used to treat MDRand XDR-TB are not licensed for children. Although the Global Drug Facility has pediatric dispersible tablets available ( available.asp), these formulations are not registered with FDA or the European Medicines Agency, which has limited commercial availability of child-friendly dosage forms. As a result, for younger children, the medication often has to be crushed or put into suspension or capsules once opened, and the pharmacokinetics and pharmacodynamics of these various preparations are unknown. HIV-infected children may be exposed to lower concentrations of certain orally administered drugs than HIV-uninfected children given the same bodyweight dose. Unfortunately, the pharmacokinetics in HIV-infected children of drugs used to treat MDR-and XDR-TB are largely unstudied. Children generally have a more difficult time tolerating injectable medications because of pain and the fact that many children with TB are malnourished and have diminished muscle mass. With the recent development of new oral drugs, it is hoped that injectable drugs can be avoided in children whenever possible. Fortunately, children generally tolerate the oral TB drugs better than adults, with fewer serious adverse events resulting in fewer breaks in therapy. Also, most children with TB have not developed the common chronic diseases of adulthood and will not suffer complications of them during treatment. However, drug adverse effects can be difficult to assess in children and likely are underreported. In general, the same schedules used to monitor adverse events and laboratory abnormalities in adult patients treated for MDR-or XDR-TB also should be used for children.\n\n# Outcomes of MDR-TB treatment in children.\nA recently published systematic review (33 studies) and IPDMA (28 of the studies) described treatment outcomes for 975 children with MDR-TB using random effects multivariate logistical regression adjusted for age, sex, HIV infection, malnutrition, severe extrapulmonary disease, and severe pulmonary disease on chest radiograph (113). Overall, 78% had a successful treatment outcome, including 75% of the microbiologically confirmed cases. However, treatment was successful in only 56% of HIV-infected children who did not also receive ART during TB treatment compared with an 82% success rate in those also treated with ART. In children with confirmed MDR-TB, the use of injectable agents and high-dose isoniazid was associated with treatment success. Unfortunately, limitations of this study included that the vast majority of patients AMERICAN THORACIC SOCIETY DOCUMENTS came from one site (Cape Town, South Africa), difficulty in estimating the treatment effects of individual drugs within multidrug regimens, the availability of only observational cohort studies, and that treatment decisions were based on the clinician's perception of illness, with resulting potential for bias.\nConclusions. Excellent treatment outcomes have been demonstrated in both trials and extensive clinical experience for children with MDR-and XDR-TB using individualized treatment regimens with the currently available drugs. Microbiologic cure and probable cure rates in children can reach 80% to 90% with early recognition of drug resistance and adequate treatment (311). The greatest difficulties have been recognizing that the child has MDR-TB and the ability of the child to tolerate injectable drugs; fortunately, with expanded knowledge of and experience with the newer oral drugs, such as bedaquiline and delamanid, pediatricians with expertise in MDR-TB believe that the majority of children with MDR-TB likely can be cured with an all-oral drug regimen.\n\n# Pregnant Women\nUntreated MDR-TB during pregnancy can be associated with adverse maternal and fetal outcomes. Crucial gaps exist in the literature on treatment of MDR-TB in pregnant women, including the effectiveness, safety, and tolerability of available treatment regimens, as well as timing and duration of second-line drugs. In support of these guidelines, we conducted a systematic literature review with a focus on pregnant women with MDR-TB and included all original research reporting MDR-TB treatment outcomes during pregnancy, including case reports and case series, in all languages. We excluded animal studies, review articles, letters to the editor, and articles without documentation of MDR-TB treatment during pregnancy. Fulltext review and data extraction were conducted by three reviewers. Our initial search yielded 280 publications, of which 16 met inclusion criteria for full-text review (312)(313)(314)(315)(316)(317)(318)(319)(320)(321)(322)(323)(324)(325)(326)(327); however, 3 publications were eventually excluded because of lack of data on medications or outcomes (315,325,327). The remaining 13 articles were observational case reviews without any comparison groups. Treatment regimens reported were individualized according to drug susceptibility and tolerability of drugs.\nSummary of the evidence. Of the 65 pregnant women for whom MDR-TB treatment outcome data were available, 49% (n = 32) were cured and 20% (n = 13) completed treatment for a treatment success proportion of 69%. Fourteen percent (n = 9) of the women died. Treatment failure was reported in 9% (n = 6), and 3% (n = 2) were lost to followup. Across these studies, four women were still receiving treatment at the time of publication. Fetal outcomes included 78.5% (n = 51) healthy births, with eight children being born premature or having low birth weight. Medical abortions were obtained by 12% of the patients (n = 8), and 3% (n = 2) underwent spontaneous abortions. Stillbirth was reported for one child (1.5%), 3% (n = 2) of children were born with HIV, and 1.5% (n = 1) had TB/HIV coinfection.\nConclusions. On the basis of the limited data available, we conclude that there is evidence to support treatment of MDR-TB during pregnancy, including the prescription of second-line drugs. Most of the second-line drugs are pregnancy category C per the U.S. Food and Drug Administration, with the exception of bedaquiline and meropenem, which are classified as category B (according to the previous FDA letter-based classification system, currently undergoing revision ), and aminoglycosides, which are category D (71,320,329). Despite low cure rates reported in the literature, we believe that the benefits of treatment to mother, child, and the community outweigh the harms. There is no evidence to support one particular regimen; however, most MDR-TB experts avoid aminoglycosides and ethionamide in pregnant women if alternative agents can be used for an effective treatment regimen.\nResearch needs. Global registries aimed at collecting data on the efficacy, safety, and tolerability, and maternal and fetal outcomes associated with MDR-TB regimens in pregnant women are urgently needed. Furthermore, given the significant morbidity and mortality associated with MDR-TB, a reconsideration of the current approach of assumed exclusion of pregnant women from MDR-TB clinical trials is warranted. A recent consensus statement from an international expert panel advocated for allowing pregnant and lactating women to remain eligible for phase III MDR-TB trials, unless there is a compelling reason for exclusion (330).\n\n# Treatment of Contacts Exposed to MDR-TB\nIn 1992 and 2000, ATS and CDC advised: 1) no treatment for MDR LTBI for persons not at high risk for progression to TB disease, but provision of clinical follow-up for TB disease signs and symptoms; 2) 6 to 12 months of treatment with two or more medications to which the isolate of the source case is susceptible (331,332).\n\n# Summary of the Evidence\nProcedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. A systematic review of 21 published observational studies that examined outcomes of TB incidence, treatment completion, adverse effects, and cost effectiveness was used as the evidence (333). Six articles compared TB incidence among contacts receiving MDR LTBI treatment versus untreated contacts: 10 presented TB incidence only for contacts who received MDR LTBI treatment, and 5 presented TB incidence only for untreated contacts.\n\n# Benefits\nUsing data from five non-registry-matched comparison studies included in the systematic review of 21 published observational studies, MDR-TB incidence occurred in 2 of 190 (1.1%) patients treated for MDR LTBI, compared with 18 of 126 (14.3%) in those who received no MDR LTBI treatment (290). The estimated MDR-TB incidence reduction was 90% (9-99%), using a negative binomial model controlling for person time and overdispersion (333).\n\n# Harms\nFrom 11 studies having data by regimen on treatment discontinuation due to adverse effects, there was high (51%) treatment discontinuation among patients taking pyrazinamide-containing regimens (333). About one-third of patients taking fluoroquinolone-containing regimens, without pyrazinamide, had adverse effects, but only 2% discontinued treatment. For children <15 years of age regardless of regimen, treatment discontinuation due to adverse effects was substantially less (5% vs. 33%) (333).\n\n# Additional Considerations\nModeled cost-effectiveness studies have shown greatest benefit using a fluoroquinolone-based MDR LTBI treatment. In one study, the most costeffective regimen was fluoroquinolone/ethambutol, followed by fluoroquinolone alone, then by pyrazinamide/ethambutol (333). A pyrazinamide/fluoroquinolone regimen was particularly toxic, as measured by treatment discontinuation, and prevented about half as many TB cases as the most cost-effective option (333). An expert panel generated a policy brief on this topic recently, acknowledged that further evidence is urgently needed, but still endorsed the immediate implementation of postexposure management of household contacts of MDR-TB, endorsing the approach as being effective, feasible, and cost efficient (334). The Curry International TB Center Drug Resistant TB: Clinician's Survival Guide suggests an LTBI regimen of levofloxacin or moxifloxacin alone or combined with a second medication to which the isolate of the infectious source patient is susceptible (16).\nAmong those with presumed MDR LTBI, there is probable effectiveness of preventing TB through MDR LTBI treatment. From systematic reviews of studies reporting incidence for both treated and untreated contacts, TB incidence was significantly lower with MDR LTBI treatment (333,(335)(336)(337)(338)(339). In studies that published outcomes by regimen, there were high treatment discontinuation rates due to adverse effects and toxicity in persons taking pyrazinamide-containing MDR-LTBI regimens (336,337,(339)(340)(341)(342). There were low treatment discontinuation rates due to adverse effects and toxicity in persons taking fluoroquinolone-containing MDR-LTBI regimens. Finally, children are at high risk for developing MDR-TB if infected with MDR LTBI and generally experience fewer adverse effects than adults. Given the uncertainties above, many TB experts and programs provide extended post-treatment completion follow-up for patients treated for presumed MDR LTBI.\n\n# Conclusions\nFor contacts with presumed MDR LTBI due to exposure to an infectious patient with MDR-TB, we suggest offering treatment for LTBI versus following with observation alone. For treatment of MDR LTBI, we suggest 6 to 12 months' treatment with a fluoroquinolone alone or with a second drug, on the basis of source-case isolate DST. On the basis of evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug. In lieu of fluoroquinolone-based treatment, there are few data for the use of other secondline medications and, because of toxicity, they are not recommended by experts. For contacts to fluoroquinolone-resistant, pre-XDR-TB, pyrazinamide/ethambutol may be an effective option, if source-case isolate DST shows susceptibility to these drugs. In children, TB drugs are generally better tolerated, and levofloxacin is preferred because of the availability of an oral suspension formulation. ): 6 months of daily delamanid versus 6 months of isoniazid. In addition, more information is needed on the cost effectiveness of treating contacts with presumed DR-TB infection using these newer MDR LTBI regimens.\n\n# Summary of Key Differences between ATS/CDC/ERS/IDSA and WHO 2019 Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment\nThe 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment guidelines were based on a modified set of data that expanded on the initial individual patient dataset used for these ATS/CDC/ERS/IDSA guidelines (3). For the 2019 WHO update, data from 625 patients were included by WHO from eight other datasets received in 2018 (Australia, Belarus, Brazil, France, Latvia, Republic of Korea, Russian Federation, and the EndTB project), as well as a sample of 3,626 patients receiving treatment in South Africa, including 1,210 cases started on bedaquiline in 2015. With these newer data added, the WHO individual patient dataset removed 3,367 records because of incomplete DST documentation (7). Despite the changes in the datasets described, WHO and ATS/CDC/ERS/IDSA recommendations are largely concordant, as they were derived concurrently, using a similar approach (GRADE methodology and a multidisciplinary Guideline Development Group), and were informed by an individual patient data meta-analysis that overlapped substantially. The main differences are highlighted below. This official clinical practice guideline was prepared by an ad hoc subcommittee of the ATS, CDC, ERS, and IDSA.\nMembers of the subcommittee are as follows:\nART regimens should be developed in consultation with HIV and ART experts. A thorough review of all patients' medications should be performed, in consultation with MDR-TB experts, to select individualized regimens with less potential for overlapping ART/TB drug toxicities (Table 11). Useful webpages regarding drug interactions (TB/HIV and other) are available from AIDSinfo (), CDC (/ guidelines/TB_HIV_Drugs/default.htm), University of California San Francisco (http:// hivinsite.ucsf.edu/insite?page=ar-00-02), University of Liverpool (/), and Indiana University (/ clinpharm/ddis/).\nThe management of MDR-TB is more complex among patients with HIV infection. The higher pill burden of combined ART with expanded TB drug therapy, potential drug-drug interactions, the management of immune reconstitution inflammatory syndrome, and other concurrent HIV-associated opportunistic diseases all pose unique challenges in the care of these patients. The management of patients with HIV and MDR-TB can best be performed by a multidisciplinary care team composed of health providers experienced in MDR-TB, HIV, and public health case management (304,305"},"raw_text":{"kind":"string","value":"jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampinresistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided. Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.# Overview\nTreatment of tuberculosis (TB), regardless of the results of drug susceptibility testing (DST), is focused on both curing the individual patient and minimizing the transmission of Mycobacterium tuberculosis to other persons. Thus, effective treatment of TB has benefits for both the individual patient and the community in which the patient resides. However, notable complexities need to be addressed to successfully treat disease resulting from drug-resistant M. tuberculosis isolates compared with treatment of drugsusceptible TB disease, including additional molecular and phenotypic diagnostic tests to determine drug susceptibility; the use of second-line drugs, which have toxicities that increase harms that must be balanced with their benefits; and prolonged treatment durations. The new recommendations provided in this guideline are for the treatment of drug-resistant TB (DR-TB), including multidrug-resistant TB (MDR-TB) and isoniazid-resistant TB, and are intended to help providers identify the therapeutic options associated with improved outcomes (i.e., greater treatment success, fewer adverse events, and fewer deaths) and in the context of individual patient values and preferences. Worthy of emphasis, the committee recommends that only drugs to which the patient's M. tuberculosis isolate has documented, or high likelihood of, susceptibility be included in an effective treatment regimen, noted as an ungraded good practice statement, and consistent with ongoing stewardship efforts for the optimal use of antibiotics (1). Drugs known to be ineffective on the basis of in vitro growth-based or molecular DST should not be used. The following alphabetically listed drugs and drug classes were considered for inclusion in treatment regimens: amoxicillin/clavulanate, bedaquiline, carbapenem with clavulanic acid, clofazimine, cycloserine, delamanid, ethambutol, ethionamide, fluoroquinolones, injectable agents, linezolid, macrolides, p-aminosalicylic acid, and pyrazinamide. Of note, pretomanid in combination with bedaquiline and linezolid was recently approved by U.S. Food and Drug Administration (FDA) for the treatment of a specific limited population of adults with pulmonary extensively drugresistant (XDR-TB) or treatment-intolerant or nonresponsive MDR-TB; however, the preparation and completion of these guidelines predated this approval (2). For each drug or drug class, the following Population, Intervention, Comparator, and Outcomes (PICO) question was addressed: In patients with MDR-TB, are outcomes safely improved when regimens include the following individual drugs or drug classes compared with regimens that do not include them?\nThe recommendations in this practice guideline were supported by scientific evidence, including results of a propensity score (PS)-matched individual patient data meta-analyses (IPDMA) conducted using a database of more than 12,000 patient records from 25 countries in support of these guidelines (see APPENDIX A: METHODOLOGY in the online supplement) (3). We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to appraise the quality of evidence and to formulate, write, and grade most recommendations (4,5).\nAlthough published data on costs are noted in these guidelines, the committee did not conduct formal cost-effectiveness analyses of the treatments reviewed to determine a recommendation. The treatment of DR-TB can be complicated and thus is necessarily preceded and accompanied by important components of care relating to the access to TB experts, microbiological and molecular diagnosis, education, monitoring and followup, and global patient-centered strategies. The writing committee considered that these topics are crucial but do not require formal and extensive evidence appraisal in the context of the present guidelines. Following GRADE guidance, it was thus decided that these practices would be addressed in good practice statements. Below, six ungraded good practice statements as well as 25 GRADE-based recommendations addressing 21 PICO questions (Table 1) are listed. Questions were selected according to their importance to clinical practice, as determined by the guideline panel, expert advisors, and patient advocates. The implications of the strength of recommendation, conditional or strong, for patients, clinicians, and policy makers are described in APPENDIX A and shown in Table 2. Detailed and referenced information on treatment of MDR-TB is available below, including a summary of the evidence, and the benefits, harms, and additional considerations of each practice or recommendation.\n# Summary of Good Practices\nFor patients being evaluated and treated for any form of drug-resistant TB, the following six ungraded good practice statements are emphasized, as the writing committee had high confidence in their net benefit:\n1. Consultation should be requested with a TB expert when there is suspicion of or confirmation of DR-TB. In the United States, TB experts can be found through CDC-supported TB Centers of Excellence for Training, Education, and Medical Consultation (http://www. cdc.gov/tb/education/rtmc/default.htm), through local health department TB control programs (https://www.cdc. gov/tb/links/tboffices.htm), and through international MDR-TB expert groups such as the Global TB Network (6). 2. Molecular DSTs should be obtained for rapid detection of mutations associated with resistance. When rifampin resistance is detected, additional DST should be performed immediately for first-line drugs, fluoroquinolones, and aminoglycosides. Resistance to fluoroquinolones should be excluded whenever isoniazid resistance is found. 3. Regimens should include only drugs to which the patient's M. tuberculosis isolate has documented or high Table 1. Questions Regarding the Treatment of Drug-Resistant Tuberculosis Selected by the Guideline Writing Committee Number of effective drugs in a regimen for MDR-TB 1. Should patients with MDR-TB be prescribed five effective drugs vs. more or fewer agents during the intensive and continuation phases of treatment? Duration of intensive and continuation phases of treatment for MDR-TB 2. Should patients with MDR-TB undergoing intensive-phase treatment be treated for >6 mo after culture conversion or ,6 mo after culture conversion? 3. Should patients with MDR-TB undergoing continuation-phase treatment be treated for >18 mo after culture conversion or ,18 mo after culture conversion? Drug and drug classes for the treatment of MDR-TB 4. In patients with MDR-TB, are outcomes safely improved when regimens include amoxicillin/clavulanate compared with regimens that do not include amoxicillin/clavulanate? 5. In patients with MDR-TB, are outcomes safely improved when regimens include bedaquiline compared with regimens that do not include bedaquiline? 6. In patients with MDR-TB, are outcomes safely improved when regimens include carbapenems with clavulanic acid compared with regimens that do not include them? 7. In patients with MDR-TB, are outcomes safely improved when regimens include clofazimine compared with regimens that do not include clofazimine? 8. In patients with MDR-TB, are outcomes safely improved when regimens include cycloserine compared with regimens that do not include cycloserine? 9. In patients with MDR-TB, are outcomes safely improved when regimens include delamanid compared with regimens that do not include delamanid? 10. In patients with MDR-TB, are outcomes safely improved when regimens include ethambutol compared with regimens that do not include ethambutol? 11. In patients with MDR-TB, are outcomes safely improved when regimens include ethionamide/prothionamide compared with regimens that do not include ethionamide/prothionamide? 12. In patients with MDR-TB, are outcomes safely improved when regimens include fluoroquinolones compared with regimens that do not include fluoroquinolones? 13. In patients with MDR-TB, are outcomes safely improved when regimens include an injectable compared with regimens that do not include an injectable? 14. In patients with MDR-TB, are outcomes safely improved when regimens include linezolid compared with regimens that do not include linezolid? 15. In patients with MDR-TB, are outcomes safely improved when regimens include macrolides compared with regimens that do not include macrolides? 16. In patients with MDR-TB, are outcomes safely improved when regimens include p-aminosalicylic acid compared with regimens that do not include p-aminosalicylic acid? 17. In patients with MDR-TB, are outcomes safely improved when regimens include pyrazinamide compared with regimens that do not include pyrazinamide? Use of a standardized, shorter-course regimen of <12 mo for the treatment of MDR-TB 18. In patients with MDR-TB, does treatment with a standardized MDR-TB regimen for <12 mo lead to better outcomes than treatment with an MDR-TB regimen for 18-24 mo? Treatment of isoniazid-resistant, rifampin-susceptible TB:\n19a. Should patients with isoniazid-resistant TB be treated with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 mo compared with rifampin, ethambutol, and pyrazinamide (without a fluoroquinolone) for 6 mo? 19b. Should patients with isoniazid-resistant TB be treated with a regimen composed of fluoroquinolone, rifampin, and ethambutol for 6 mo and pyrazinamide for the first 2 mo compared with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 mo? Surgery as adjunctive therapy for MDR-TB:\n20. Among patients with MDR/XDR TB receiving antimicrobial therapy, does lung resection surgery (i.e., lobectomy or pneumonectomy) lead to better outcomes than no surgery? Management of contacts exposed to an infectious patient with MDR-TB:\n21. Should contacts exposed to an infectious patient with MDR-TB be offered LTBI treatment vs. followed with observation alone?\nlikelihood of susceptibility (hereafter defined as effective). Drugs known to be ineffective based on in vitro growthbased or molecular resistance should NOT be used. This recommendation applies to all drugs and treatment regimens discussed in this practice guideline, unless reliable methods of testing susceptibility for a drug have yet to be developed. 4. Treatment response should be monitored clinically, radiographically, and bacteriologically, with cultures obtained at least monthly for pulmonary TB. When cultures remain positive after 3 months of treatment, susceptibility tests for drugs should be repeated.\nWeight and other measures of clinical response should be recorded monthly. 5. Patients should be educated and asked about adverse effects at each visit. Adverse effects should be investigated and ameliorated. 6. Patient-centered case management helps patients understand their diagnoses, understand and participate in their treatment, and discuss potential barriers to treatment. Patient-centered strategies and interventions should be used to minimize barriers to treatment.\n# Summary of Recommendations\nFor the selection of an effective MDR-TB treatment regimen and duration of MDR-TB treatment:\n1. We suggest using at least five drugs in the intensive phase of treatment and four drugs in the continuation phase of treatment (conditional recommendation, very low certainty in the evidence). 2. We suggest an intensive-phase duration of treatment of between 5 and 7 months after culture conversion (conditional recommendation, very low certainty in the evidence). 3. We suggest a total treatment duration of between 15 and 21 months after culture conversion (conditional recommendations, very low certainty in the evidence). 4. In patients with pre-XDR-TB and XDR-TB, which are both subsets of MDR-TB, we suggest a total treatment duration of between 15 and 24 months after culture conversion (conditional recommendations, very low certainty in the evidence).\nFor the selection of oral drugs for MDR-TB treatment (in order of strength of recommendation):\n5. We recommend including a latergeneration fluoroquinolone (levofloxacin or moxifloxacin) (strong recommendation, low certainty of evidence). 6. We recommend including bedaquiline (strong recommendation, very low certainty in the evidence). 7. We suggest including linezolid (conditional recommendation, very low certainty in the evidence).\n8. We suggest including clofazimine (conditional recommendation, very low certainty of evidence). 9. We suggest including cycloserine (conditional recommendation, very low certainty in the evidence). 10. We suggest including ethambutol only when other more effective drugs cannot be assembled to achieve a total of five drugs in the regimen (conditional recommendation, very low certainty in the evidence). 11. We suggest including pyrazinamide in a regimen for treatment of patients with MDR-TB or with isoniazidresistant TB, when the M. tuberculosis isolate has not been found resistant to pyrazinamide (conditional recommendation, very low certainty in the evidence). 12. The guideline panel was unable to make a clinical recommendation for or against delamanid because of the absence of data in the PS-matched IPDMA conducted for this practice guideline. We make a research recommendation for the conduct of randomized clinical trials and cohort studies evaluating the efficacy, safety, and tolerability of delamanid in combination with other oral agents. Until additional data are available, the guideline panel concurs with the conditional recommendation of the 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis \n# For patients\nThe overwhelming majority of individuals in this situation would want the recommended course of action, and only a small minority would not.\nThe majority of individuals in this situation would want the suggested course of action, but a sizeable minority would not.\n# For clinicians\nThe overwhelming majority of individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.\nDifferent choices will be appropriate for different patients, and you must help each patient arrive at a management decision consistent with her or his values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences.\nClinicians should expect to spend more time with patients when working toward a decision.\nFor policy makers The recommendation can be adapted as policy in most situations, including for the use as performance indicators.\nTreatment that delamanid may be included in the treatment of patients with MDR/rifampin-resistant (RR)-TB aged >3 years on longer regimens (7).\nFor selected oral drugs previously included in regimens for the treatment of MDR-TB: 13. We recommend NOT including amoxicillin-clavulanate, with the exception of when the patient is receiving a carbapenem wherein the inclusion of clavulanate is necessary (strong recommendation, very low certainty in the evidence). 14. We recommend NOT including the macrolides azithromycin and clarithromycin (strong recommendation, very low certainty in the evidence). 15. We suggest NOT including ethionamide/prothionamide if more effective drugs are available to construct a regimen with at least five effective drugs (conditional recommendation, very low certainty in the evidence). 16. We suggest NOT including p-aminosalicylic acid in a regimen if more effective drugs are available to construct a regimen with at least five effective drugs (conditional recommendation, very low certainty in the evidence).\nFor the selection of drugs administered through injection when needed to compose an effective treatment regimen for MDR-TB: 17. We suggest including amikacin or streptomycin when susceptibility to these drugs is confirmed (conditional recommendation, very low certainty of evidence). 18. We suggest including a carbapenem (always to be used with amoxicillinclavulanic acid) (conditional recommendation, very low certainty of evidence). 19. We suggest NOT including kanamycin or capreomycin (conditional recommendation, very low certainty in the evidence).\nA summary of the recommendations on drugs, the certainty in the evidence, and the relative risks of success and death is provided in Figure 1. Additional details and other outcomes of interest are provided in the section on Drugs and Drug Classes and For the use of the WHO-recommended standardized shorter-course 9-to 12-month regimen for MDR-TB: 20. The shorter-course regimen is standardized with the use of kanamycin (which the committee recommends against using) and includes drugs for which there is documented or high likelihood of resistance (e.g., isoniazid, ethionamide, pyrazinamide). Although the STREAM (Standard Treatment Regimen of Anti-Tuberculosis Drugs for Patients with MDR-TB) Stage 1 randomized trial found the shorter-course regimen to be noninferior to longer injectablecontaining regimens with respect to the primary efficacy outcome (8), the guideline committee cannot make a recommendation either for or against this standardized shorter-course regimen, compared with longer individualized all-oral regimens that can be composed in accordance with the recommendations in this practice guideline. We make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is documented or highly likely.\nFor the role of surgery in the treatment of MDR-TB: 21. We suggest elective partial lung resection (e.g., lobectomy or wedge resection), rather than medical therapy alone, for adults with MDR-TB receiving antimicrobial-based therapy (conditional recommendation, very low certainty in the evidence). The writing committee believes this option would be beneficial for patients for whom clinical judgement, supported by bacteriological and radiographic data, suggest a strong risk of treatment failure or relapse with medical therapy alone. 22. We suggest medical therapy alone, rather than including elective total lung resection (pneumonectomy), for adults with MDR-TB receiving antimicrobial therapy (conditional recommendation, very low certainty in the evidence).\nFor the treatment of isoniazid-resistant TB: 23. We suggest adding a later-generation fluoroquinolone to a 6-month regimen of daily rifampin, ethambutol, and pyrazinamide for patients with isoniazid-resistant TB (conditional recommendation, very low certainty in the evidence). 24. In patients with isoniazid-resistant TB treated with a daily regimen of a latergeneration fluoroquinolone, rifampin, ethambutol, and pyrazinamide, we suggest that the duration of pyrazinamide can be shortened to 2 months in selected situations (i.e., noncavitary and lower burden disease or toxicity from pyrazinamide) (conditional recommendation, very low certainty in the evidence).\nFor the management of contacts to patients with MDR-TB: 25. We suggest offering treatment for latent TB infection (LTBI) for contacts to patients with MDR-TB versus following with observation alone (conditional recommendation, very low certainty in the evidence). We suggest 6 to 12 months of treatment with a later-generation fluoroquinolone alone or with a second drug, on the basis of drug susceptibility of the source-case M. tuberculosis isolate. On the basis of evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug.\nIn this guideline, we provide new recommendations for treatment of MDR-TB and for treatment of isoniazid-resistant TB. On the basis of the evidence review conducted for this guideline, a clinical strategy tool for building a treatment regimen for MDR-TB is provided.\n# Introduction\nThe American Thoracic Society (ATS), U.S. Centers for Disease Control and Prevention, European Respiratory Society (ERS), and Infectious Diseases Society of America (IDSA) have jointly developed these Drug-Resistant Tuberculosis guidelines. These new recommendations are based on the certainty in the evidence (also known as the quality of evidence) and developed based on the evidence that was appraised using GRADE methodology, which incorporates patient values and costs as well as judgments about trade-offs between benefits and harms (4,5). A carefully selected panel of experts, screened for conflicts of interest, including specialists in pulmonary medicine, infectious diseases, pediatrics, primary care, public health, epidemiology, economics, pharmacokinetics, microbiology, systematic review methodology, and patient advocacy, was assembled to assess the evidence supporting each recommendation. In contrast to prior analytic approaches, wherein systematic reviews of aggregate data were used for decision-making, a new PS-matched meta-analysis of IPDMA from 12,030 patients, in 50 studies, from 25 countries with confirmed pulmonary RR-TB was conducted for this guideline (3). Given the paucity of high-quality randomized controlled trials conducted in DR-TB, individual data from observational studies represent the next best level of evidence for analyses. Nonetheless, the writing committee noted that observational data are prone to bias and confounding. The 21 PICO questions and associated recommendations are summarized below, all appraised using GRADE methodology (see APPENDIX B). Questions were selected according to their importance to clinical practice, as determined by the guideline panel, expert advisors, and patient advocates. The implications of the strength of recommendation, conditional or strong, for patients, clinicians, and policy makers are described in APPENDIX A. On the basis of the GRADE methodology framework, all recommendations in these guidelines are based on very low certainty in the evidence. The writing committee selected death, treatment success, and serious adverse effects as the endpoints of critical importance on which to generate recommendations. Our meta-analytic approaches included PS matching to AMERICAN THORACIC SOCIETY DOCUMENTS e98 reduce confounding (on the basis of individual-level covariates of age, sex, HIV coinfection, acid-fast bacilli [AFB] smear results, cavitation on chest radiographs, history of TB treatment with first-line or second-line TB drugs, and number of possibly effective drugs in the regimen, among other variables), described in detail in the publication of the PS-matched IPDMA publication and in APPENDIX A (3). However, the risk of bias remained serious, because the average loss to follow-up across included studies was 10% to 20%. In addition, despite the efforts, there was a large residual imbalance in background regimens used in experimental and control groups.\nThese guidelines are intended for settings in which treatment is individualized and where mycobacterial cultures, molecular (genotypic) and culture-based (phenotypic) DSTs, and radiographic facilities are available (9,10). Of note, published data on costs are referenced in these guidelines, but the committee did not conduct formal costeffectiveness analyses of the treatments and interventions reviewed in relation to determining a recommendation.\nIn these guidelines, MDR-TB is defined specifically as resistance to at least isoniazid and rifampin, the two most important first-line drugs. XDR-TB is a subset of MDR-TB with additional resistance to a fluoroquinolone and a second-line injectable agent. Because XDR-TB evolves from MDR-TB in two steps, the term \"pre-XDR-TB\" was introduced to identify MDR-TB with additional resistance to either one but not both of these classes of drugs. In these guidelines, we also provide recommendations for the treatment of isoniazid-resistant TB.\n# Good Practices for Treating DR-TB\nThe fundamentals of TB care, regardless of the treatment selected, rest on ensuring timely diagnosis and initiation of appropriate therapy, with ongoing support and management to achieve successful treatment completion and cure. The responsibility for successful treatment of TB is placed primarily on the provider or program initiating therapy rather than on the patient (11). Nevertheless, a patientcentered approach, described more fully in the section on case management below, requires the involvement of the patient in decision-making. We recommend seeking consultation with an expert in TB when there is suspicion for or confirmation of DR-TB (ungraded good practice statement). In the United States, DR-TB experts can be found through CDCsupported TB Centers of Excellence for Training, Education, and Medical Consultation (http://www.cdc.gov/ tb/education/rtmc/default.htm), through local health department TB Control Programs (https://www.cdc.gov/tb/ links/tboffices.htm), and through international MDR-TB expert groups such as the British Thoracic Society MDR-TB Clinical Advisory Service (http://mdrtb. brit-thoracic.org.uk/) and the Global TB Network (6). Additional good practices in the treatment of patients in need of evaluation for DR-TB include the following:\n# Diagnosing TB and Identification of Drug Resistance\nThe potential for drug resistance is considered in every patient. An aggressive effort is made to collect biological specimens for detection of M. tuberculosis and for drug resistance. A rapid test for a least rifampin resistance should ideally be done for every patient, but especially for those at risk of drug resistance. The concern for possible resistance is heightened for patients from areas of the world with at least a moderate incidence of TB in general (>20/100,000) and a high primary MDR-TB prevalence (>2%) (12). Individuals who have or recently had close contact with a patient with infectious DR-TB, especially when the contact is a young child or has HIV infection, are at risk of developing DR-TB. Molecular methods, and more recently whole-genome sequencing (WGS), are increasingly available and can provide information on resistance to all first-line and many second-line drugs. Many public health laboratories provide molecular tests, and WGS is available in selected laboratories. These tests can be used to guide initial therapeutic decisions and contribute to population-level control of DR-TB. Providers should be familiar with phenotypic and genotypic laboratory services available in their locale. In the United States, CDC's Division of Tuberculosis Elimination Laboratory Branch provides testing services for both clinical specimens and isolates of M. tuberculosis (https://www.cdc. gov/tb/topic/laboratory/default.htm). CDC's Molecular Detection of Drug Resistance (MDDR) service serves to rapidly identify DR-TB. This service uses DNA sequencing for detection of mutations most frequently associated with resistance to both first-line (e.g., rifampin, isoniazid, ethambutol, and pyrazinamide) as well as second-line drugs (MDDR Service Request Form is available here: https:// www.cdc.gov/tb/topic/laboratory/ MDDRsubmissionform.pdf). Recently published ATS/CDC/IDSA Official Practice Guidelines for the diagnosis of TB provide additional details on the optimal use of diagnostic tools and algorithms (13).\n# Treatment and Monitoring of DR-TB\nRegimens should only include drugs to which the patient's isolate has documented or high likelihood of susceptibility. Drugs known to be ineffective, on the basis of in vitro resistance or clinical and epidemiological information (i.e., resistance in the index case or high population prevalence of resistance), should not be used, even when resistance is present in only a small percentage of the mycobacteria in the population. If at least 1% of organisms in a solid media culture exhibit resistance to a drug (the current standard laboratory definition of drug resistance) (14), using that drug in a regimen will increase the risk for poor treatment outcomes, and the isolate will eventually exhibit 100% resistance to the drug. Drugs should be selected based on their efficacy and the likelihood that patients will be able to tolerate them without significant toxicity. Treatment response is monitored clinically (decrease in cough and systemic symptoms and increase in weight), radiographically, and bacteriologically (15)(16)(17)(18). If sputum cultures remain positive after 3 months of treatment, or if there is bacteriological reversion from negative to positive at any time, DST should be repeated (11). Patients should be asked about the clinical response at each visit and weight recorded monthly. Monthly cultures help to identify early evidence of failure (19). Most persons have difficulty taking one or more of the drugs used to treat MDR-TB. Patients should be educated about adverse effects, and all adverse effects should be investigated and ameliorated. Some adverse effects are difficult to tolerate but do not put patients at risk for serious short-or long-term damage to organ systems and can be managed with symptom-specific ancillary medication and supportive care. Nausea\n# AMERICAN THORACIC SOCIETY DOCUMENTS\nwith vomiting is common and is not always an indication to discontinue therapy permanently. New-onset vomiting may indicate liver toxicity or, in children especially, increased intracranial pressure. If drug-induced liver toxicity (and increased intracranial pressure) is excluded, vomiting can be managed by changing dosing schedule, giving medications with a small snack (noting that this may affect plasma concentrations of the drug), or premedicating adult patients with an antiemetic (noting that some prolong the QT interval) before the dose. Patients may note fatigue or describe myalgia or arthralgia, but these symptoms are not typically treatment limiting. Although low-grade adverse effects can resolve gradually over time, recognizing the negative impact on patient's quality of life, all adverse effects must be addressed diligently. The Curry International TB Center's guides, Drug Resistant TB: Clinician's Survival Guide and the Nursing Guide for Managing Side Effects to Drug-Resistant TB Treatment, in addition to the World Health Organization (WHO) companion handbook, are good resources to assist in evaluation and management of patients (15,16,18).\n# Infection Control and DR-TB\nThree main strategies will reduce the transmission of DR-TB: rapid diagnosis, prompt appropriate treatment, and improved airborne infection control (11,13,20,21). Rapid molecular DST and conventional phenotypic culture-based DST are almost universally available in the United States, Europe, and low-incidence, high-resource countries (22). Targeted active case finding combined with rapid diagnostics leading to effective therapy is a strategy endorsed by WHO (13,23,24).\nTreatment delays have been associated with increased transmission. A systematic review and meta-analysis looking at patientrelated risk factors for transmission of M. tuberculosis found that treatment initiation delays of 28 to 30 days were significantly associated with increased transmission to contacts (25). Effective therapy renders patients with TB, even those with DR-TB, rapidly noninfectious (24,26). The rapid reduction in infectiousness even in the setting of MDR-TB makes outpatient therapy possible, but directly observed therapy (DOT) applied through patientcentered approaches plays an important role in this regard (11,23). Infection control measures such as administrative and environmental controls, and personal protective equipment, listed in order of priority, are important for preventing the transmission of M. tuberculosis regardless of drug susceptibility. Every healthcare facility should have these measures in place per CDC guidelines (27). Furthermore, patients should be educated about the importance of infection control measures, such as the value of good ventilation, open windows, and the risks of exposure for children ,5 years of age and immunocompromised individuals (21).\nCase Management for DR-TB Case management is a collaborative process that entails engaging with patients; comprehensively assessing, monitoring, and attending to patients' physical, psychological, social, material, and informational needs; care planning; medication management; facilitating access to services; and functioning as patient advocate/agent (28)(29)(30). Commonly, case management is used in community and public health settings to coordinate services for patients with chronic and complex health conditions and to attain good, quality, cost-effective outcomes. The practice of case management has long been considered an important component of care for patients with TB (20,31,32), and a patient-centered (or family-centered in case of children) approach is preferred (7,11,33). Patient-centered case management helps patients understand their diagnosis and treatment and participate in treatment selection and promotes communication about factors that matter to the patient (33)(34)(35). Importantly, a patient-centered approach includes discussions with the patient to identify potential barriers to care and the selection of strategies and interventions to address and minimize these barriers (7,11,33,(35)(36)(37).\nCase management tools for drugresistant TB include a drug-o-gram, which organizes clinical details in a format that aligns test results with treatment, as well as laboratory, bacteriology, and other toxicity monitoring flow sheets. This format is a visible representation of pertinent clinical parameters being tracked (16,38). A monitoring checklist or care plan can also help the case manager ensure timely drug toxicity monitoring and provision of examinations required to assess a patient's response to treatment. Case management interventions that have demonstrated favorable outcomes include the provision of patient education and counseling related to diagnosis, treatment, and adherence, as well as the use of treatment adherence interventions alongside suitable patientcentered administration options. For example, home or community-based DOT is shown to be preferred and associated with greater likelihood of treatment success compared with health facility-based DOT or self-administered therapy (11,39). Enhancing treatment completion through the use of patient-centered case management strategies, including DOT, also aims to reduce risk of acquisition of drug resistance, which aligns with international efforts in antibiotic stewardship (1). Recent WHO guidelines evaluated various adherence interventions and outcomes of TB treatment through a systematic review of clinical trials and observational studies, identifying data from 129 studies for quantitative analysis published through 2018 (39). Another meta-analysis of 22 randomized controlled trials of DOT and other interventions to improve adherence reported significant increases in cure with DOT (18%) and with patient education and counseling (16%). Compared with the complementary groups, loss to follow-up was 49% lower with DOT, 26% lower with financial incentives, and 13% lower with patient education and counseling. However, there was no significant reduction in mortality (40).\nThe use of video-enabled electronic devices to conduct DOT is expanding rapidly (41,42). Electronic methods for DOT have the potential to improve TB treatment outcomes and extend public health support to patients with TB when face-to-face DOT is not feasible. Pilot studies have reported that patients find electronic methods for DOT to be both acceptable and more convenient than traditional in-person DOT. These studies also reported good adherence, fewer unobserved doses, and high satisfaction among study participants (43)(44)(45)(46). Further evidence is needed to validate electronically observed therapy under more diverse conditions, with larger cross-sections of patient subgroups, including children, and to determine to what degree these methods impact treatment outcomes for patients with DR-TB (39,(47)(48)(49).\n# Treatment of MDR-TB, Number of Drugs, and Duration of Treatment Phases\n\n# Number of Drugs in the Regimen\nUp until the recent 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment (7), WHO has recommended at least five drugs in the intensive phase of treatment, defined by the use of a second-line injectable agent (23). The recent WHO change to recommending at least four effective drugs at initiation of treatment is graded as a conditional recommendation with very low certainty in the estimates of effect (7). Of note, both our guideline committee and the 2019 WHO guidelines promote the use of newer or repurposed oral agents with greater efficacy and deemphasize the use of injectable agents (7). Given these changes and that an injectable drug is no longer obligatory, the intensive phase can no longer be defined by the inclusion of injectables. In this guideline, we define the intensive phase to be the initiation phase of treatment with at least five effective drugs. These recommendations do not apply to the WHO-endorsed shorter-course 9-to 12-month (Bangladesh) regimen, which combines seven drugs for 4 months or until sputum smear conversion, whichever is the longer period, followed by four drugs in the continuation phase (23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. For the analysis of number of effective drugs, we counted drugs with published evidence from randomized trials of effectiveness (3). Hence, we counted ethambutol, pyrazinamide, all injectables and fluoroquinolones, ethionamide/prothionamide, cycloserine/terizidone, and p-aminosalicylic acid on the basis of DST showing susceptibility and counted clofazimine, linezolid, carbapenems, bedaquiline, and delamanid-if susceptible, or no DST for that drug. We did not count amoxicillin/clavulanate (in the absence of a carbapenem) and macrolides as effective drugs (see PICO Questions 4 and 15). The intensive phase was defined by the use of an injectable agent (other than imipenem-cilastatin or meropenem). Culture conversion was not an outcome measure. Instead, the analysis assessed the association of the number of possibly effective drugs included in the first 2 weeks of the intensive phase with the two final treatment outcomes: 1) \"treatment success,\" which includes both cure and treatment completed; and 2) mortality. For the intensive phase of treatment, final treatment outcomes were compared between those treated with five or more (n = 2,527) effective drugs and those treated with three or four effective drugs (n = 5,923).\nBenefits. In our PS-matched IPDMA, using zero to two effective drugs as the reference value, treatment success was most likely with regimens for MDR-TB containing five effective drugs in the intensive phase (Table 3). Mortality was also significantly reduced for those taking five or six effective drugs.\nThe number of drugs used in the continuation phase was also evaluated (Table 4). In the continuation phase, four Definition of abbreviations: aOR = adjusted odds ratio; CI = confidence interval. *World Health Organization definitions: fail = treatment terminated or need for permanent regimen change of at least two antituberculosis drugs because of: lack of conversion by the end of the intensive phase, bacteriological reversion in the continuation phase after conversion to negative, evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs or adverse drug reactions. † Relapse was defined as a positive bacteriological culture in the 12 months after treatment completion.\nPICO Question 1: Should patients with MDR-TB be prescribed five effective drugs versus more or fewer agents during the intensive and continuation phases of treatment?\nRecommendation 1a: We suggest using at least five drugs in the intensive phase of treatment of MDR-TB (conditional recommendation, very low certainty of evidence).\n# Recommendation 1b:\nWe suggest using at least four drugs in the continuation phase of treatment of MDR-TB (conditional recommendation, very low certainty of evidence).\n# AMERICAN THORACIC SOCIETY DOCUMENTS\ndrugs gave the greatest success (adjusted odds ratio [aOR], 2.3) and four or more drugs the greatest reduction in mortality. Few significant differences were found in patients with pre-XDR-TB or XDR-TB. Subgroup analyses in pre-XDR-TB and XDR-TB did not suggest that a different number of effective drugs for the intensive and continuation phases was required to achieve good outcomes.\nHarms. The recommendation places a higher value on reduced morbidity and greater treatment success than on the as yet unmeasured avoidance of the summative or synergistic toxicity across drugs in the treatment regimen.\nAdditional considerations. Each drug was counted as equivalent in effectiveness, representing the average effectiveness of the most widely used MDR-TB drugs, for the purpose of adjusting for the number of other effective drugs in the regimen. A regimen composition approach with suggested ranking of drugs is provided in the section BUILDING A TREATMENT REGIMEN FOR MDR-TB. The smallest number of drugs to achieve sputum conversion and ensure a cure without relapse minimizes problems with drug-drug interactions, reduces adverse effects, and is cost effective. Injectable drugs are problematic in terms of route of administration, patient preference, significant adverse effects such as hearing loss or vertigo, and costs of administration and monitoring blood levels. On the basis of these limitations, combined with evidence of low efficacy for injectable agents, the use of injectables in defining the intensive phase of treatment is no longer appropriate. WHO has recategorized injectables to a lower grouping and recommended that the injectables only be used when oral medicines from higher categories cannot be used (7). The South African National Department of Health also has endorsed replacing the injectable agents in the shorter-course MDR-TB treatment regimen in adults and children .12 years of age with bedaquiline, on the basis of a retrospective observational study of improved mortality with adding bedaquiline (50). In conjunction, experts from the Sentinel Project on Pediatric Drug-Resistant Tuberculosis (http://sentinel-project.org) have also called for replacing the injectable drug in children ,12 years of age with an alternative effective drug (51).\nConclusions. At least five drugs should be used in the intensive phase of treatment and four drugs in the continuation phase of treatment of MDR-TB (conditional recommendation, very low certainty of evidence). Drugs of poor or doubtful efficacy should not be added to a regimen purely to ensure that the recommended number of drugs is obtained.\nResearch needs. Randomized controlled trials with fewer but more effective and safer drugs should be undertaken (e.g., TB-PRACTECAL, [Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen] ClinicalTrials.gov identifier NCT02589782). Randomized trials comparing regimens with and without injectable agents are underway (e.g., STREAM-stage 2, NCT02409290; Evaluating Newly Approved Drugs for Multidrug-resistant TB: endTB, NCT02754765). The effect of duration of individual drugs in the intensive phase on culture conversion as well as treatment cure without relapse should be explored (52).\n# Duration of Intensive and Continuation Phases in Treating MDR-TB\nTreatment of both drug-susceptible and MDR-TB has typically been divided across PICO Question 2: Should patients with MDR-TB undergoing intensive-phase treatment be treated for >6 months after culture conversion or ,6 months after culture conversion? Recommendation 2: In patients with MDR-TB, we suggest an intensivephase duration of treatment of between 5 and 7 months after culture conversion (conditional recommendation, very low certainty of evidence). two phases, with an initial \"intensive\" phase that contains more drugs than the subsequent \"continuation\" phase. For MDR-TB, this intensive phase has historically been characterized by the use of an aminoglycoside (amikacin or kanamycin) or a polypeptide (capreomycin) delivered parenterally (53). This approach has been intended to provide greater bactericidal activity during the time when the bacillary burden is highest and reducing the number of drugs in the continuation phase to reduce risk of toxicity and intolerability caused by the multidrug regimen at a phase when the microbial burden has diminished. The 6-month duration of bedaquiline treatment, in part, was developed by analogy, and clinical trials are underway to determine whether this drug may replace aminoglycosides in terms of an initial intensive phase of treatment. The duration of the intensive phase has never been examined through a randomized, controlled clinical trial. Rather, it has been defined by a combination of practicality, the clinical experiences of MDR-TB experts, and, most recently, an IPDMA that resulted in the WHO practice guideline recommendations of 2011 that an intensive phase of at least 8 months' duration be used (54). This represented a departure from the prior recommendations in 2008 that the injectable agent should be continued for at least 6 months and at least 4 months after the patient first becomes and remains smear or culture negative (55). This is similar to current expert guidance provided by the Curry International TB Center Drug Resistant TB: Clinician's Survival Guide, namely \"Intensive phase: recommend at least 6 months beyond culture conversion for the use of injectable agent\" (16). The PS-matched IPDMA completed as part of the present guideline development process includes cohorts that were treated according to this range of durations of the intensive phase and represents the available evidence base for our recommendation. Our analyses and recommendations for the duration of intensive and continuation phases of therapy are anchored to the timing of culture conversion, as this approach factors in that treatment response may vary by patient, resistance patterns, and regimen composition and potency, among other factors. Summary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. The association between treatment duration of the intensive phase (defined by the use of an injectable agent) after culture conversion and outcomes (success, failure, relapse) was examined among 4,122 (49.3%) subjects from 29 studies who had sufficient information to be included in this analysis (3). This total reflected exclusion of studies without a reported intensive-phase duration (n = 942 [11.3%] patients) or time to culture conversion (n = 1,880 [22.5%] patients), as well as 955 (11.4%) patients in the included studies but for whom intensive-phase duration or time to conversion was not known. Patients taking the 9-to 12-month standardized shorter-course regimen were excluded (see PICO Question 18). An additional 464 (5.0%) patients were excluded for conversion after the end of the intensive phase or after 14.3 months, or for an intensive phase exceeding 24.3 months. Among the 4,122 patients included, 3,303 (80.1%) had MDR-TB without resistance to fluoroquinolone or second-line injectable. The remainder had pre-or XDR-TB. To reflect meaningful variations in the duration of the intensive regimen after conversion, stratified analyses were conducted: strata were 0 to 1.0 months, 1.01 to 3.0 months, 3.01 to 5.0 months, 5.01 to 7.0 months, and 7.1 to 15.0 months (see Table 5). The largest proportion (28.6% [1,179]) received treatment for 5.01 to 7 (mean, 5.9) months after conversion. Time to conversion was roughly inversely proportional to duration of intensive phase, suggesting that the tendency in the included studies was to treat for a total intensive-phase duration of 5 to 8 months.\nBenefits. The patients who received treatment for 5.01 to 7 months after conversion experienced a 3.3-fold increase in adjusted odds of treatment success (95% confidence interval [CI], 2.1-5.2) compared with the reference group (0-1.0 months of intensive phase after conversion). Some variability was observed in distribution of intensive-phase duration after culture conversion by baseline characteristics: ,10.0% of patients who received longer durations of intensive phase were HIVcoinfected, compared with .15% in the 0.0 to 3.0 month interval groups. Number of (effective) drugs was greater in longer durations than in shorter.\nPatients with MDR-TB who received 5.01 to 7.0 months of intensive-phase treatment after conversion had the highest odds of success in adjusted PS-matched analysis; although other, shorter intervals showed improvement over the reference, <1.0 month of postconversion treatment, the benefits of 5 to 7 months of treatment after conversion were more pronounced (Table 6). The effect estimates were also better for subgroups of MDR only (aOR, 2.0; 95% CI, 1.1-3.4) and pre-XDR (aOR, 1.5; 95% CI, 0.6-3.7) subgroups.\n# Harms\nDetailed data on duration-related toxicities were not available through our PS-matched IPDMA. On the basis of the clinical observations and experiences of the MDR-TB experts on the guideline committee, the intensive phase should not be prolonged beyond that considered necessary to optimize treatment outcomes.\nAdditional considerations. No information is available in the datasets on AMERICAN THORACIC SOCIETY DOCUMENTS how duration was selected. Duration selected may reflect interim response to treatment or may reflect a planned duration that is not conditioned on treatment response; the latter is suggested by the observation that duration was inversely related to time to conversion except in the 7.01-to 15-month interval. Analyses were adjusted for possible baseline confounders, relying on PS matching, to reduce the bias introduced. However, the possibility of unmeasured confounding by indication, in particular by time-varying characteristics (such as toxicity, microbiological, radiographic, or clinical results), cannot be ruled out. Such confounding by indication would likely result in an underestimate of the benefit of a longer intensive phase after conversion: patients in the 7.01-to 15-month interval had slower conversion and more poor outcomes than those in the 5.01-to 7.0month interval. Last, the optimal total duration of treatment for MDR-TB using injectable-free, all-oral regimens cannot be determined from these datasets, but clinical trials evaluating newer drugs and all-oral regimens for MDR-TB are underway (56).\nConclusions. We suggest an intensivephase treatment of between 5 and 7 months after culture conversion in patients with MDR-TB (conditional recommendation, very low certainty in the evidence). The clinical context, extent of disease, and response to treatment, among other factors, will play a role in choosing a final duration from within the recommended range. There were limited data in pre-XDR-TB and XDR-TB. Subgroup analyses in pre-XDR and XDR-TB did not suggest that a different duration for the intensive phase would be required to achieve good outcomes. This intensive-phase duration recommendation does not apply to the 9-to 12-month shortercourse regimen addressed in PICO 18.\nResearch needs. Further research is urgently needed to define the optimal durations of treatment using newer drugs and all-oral regimens. Research in defining optimal duration that prevents death or loss to follow-up is also needed. In the short term, further research on datasets that include longitudinal observations that can inform choice of regimen duration would be important to reducing the uncertainty around the present recommendations. In the long term, randomized controlled trials evaluating various intensive phases and durations are needed. Research on stratified medicine approaches that use measures of burden of disease and consider subgroups in the selection of the optimal duration may allow for greater precision and better inform decision-making around the balance of benefits and harms of durations for individual patients (57).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. The association between total duration of treatment after culture conversion and outcomes (success, failure, relapse) was performed on 4,691 observations from 32 studies (3). We excluded 18 studies (n = 2,615) that did not report time to culture conversion and 798 patients from included studies because endpoints were missing. Last, 259 patients were excluded for outlier values in total duration or culture conversion; patients whose outcome was loss to follow-up or death were excluded. Among the 4,691 included, 3,034 had MDR-TB. The remainder had pre-XDR or XDR-TB. To reflect meaningful variations in the duration of treatment after conversion, stratified analyses were conducted: Time to conversion was inversely related to duration of treatment after conversion (Table 7).\nBenefits. Among all resistance groups, durations of 15.01 to 21 months after conversion outperformed the reference (12.01-15 mo); intervals of 15.01 to 18 (aOR, 2.1; 95% CI, 1.4-3.1), 18.01 to 21 (aOR, 1.6; 95% CI, 1.1-2.3), and 21.01 to 24 (aOR, 1.2; 95% CI, 0.9-1.8) months were indistinguishable from each other (Table 8). In the MDR-only subgroup, the duration of 15.01 to 18.0 months was associated with similar to slightly improved outcomes compared with reference (aOR, 1.8; 95% CI, 1.0-3.0) (data not shown). Results for the pre-XDR-TB subgroup supported the notion that longer intervals were associated with success; effects were statistically significant, with confidence intervals that were wide and overlapping across durations of 15.01 to 24 months (data not shown). PICO Question 3: Should patients with MDR-TB undergoing continuation-phase treatment be treated for >18 months after culture conversion or ,18 months after culture conversion?\nRecommendation 3a: In patients with MDR-TB, we suggest a total treatment duration of between 15 and 21 months after culture conversion (conditional recommendations, very low certainty in the evidence).\n# Recommendation 3b:\nIn patients with pre-XDR-TB and XDR-TB, we suggest a total treatment duration of between 15 and 24 months after culture conversion (conditional recommendations, very low certainty in the evidence).\n# AMERICAN THORACIC SOCIETY DOCUMENTS e104\nHarms. Extending treatment longer than necessary can engender additional toxicity and costs to patients and health systems. For this reason, recommendations are for the minimum duration found to have a significant treatment advantage, and different recommendations are made for the MDR only and XDR/pre-XDR subgroups.\nAdditional considerations. No information on how duration was selected is available from the data. Duration selection may reflect interim response to treatment or may reflect a planned duration that is not conditioned on treatment response; the latter is suggested by the observation that duration was inversely related to time to conversion except in the longest interval. Analyses were adjusted for all possible baseline confounders, relying on PS matching, to minimize the bias introduced. Nevertheless, the possibility of unmeasured confounding by indication, in particular by time-varying characteristics, cannot be ruled out. Such confounding by indication would likely result in an underestimate of the benefit of a longer treatment duration after conversion. No significant difference in outcomes was observed across durations for the XDR-TB subgroup, likely because of small numbers and the aforementioned potential bias.\nConclusions. We suggest a total treatment duration of at least 15 and up to 21 months after culture conversion for patients with MDR-TB only. In patients with pre-XDR-TB and XDR-TB, we suggest a total treatment duration of between 15 and 24 months after culture conversion (conditional recommendations, very low certainty in the evidence). The clinical context and extent of disease will be relevant for choosing a final duration from within the recommended range.\nResearch needs. The optimal total duration of regimens composed of only oral drugs urgently needs further research. Defining optimal total durations that prevent death or loss to follow-up also needs study. In the short term, further research on datasets that include longitudinal observations that can inform choice of regimen duration would be very important to reducing the uncertainty around the present recommendation. In the long term, randomized controlled trials comparing different intensive phases and durations are needed. As with the duration of the intensive phase, research is needed in stratified medicine approaches that consider measures of burden of disease, and subgroups in the selection of the optimal total duration will allow for greater precision in selecting and individualizing regimen duration (57).\n# Drugs and Drug Classes\nThese guidelines are intended for settings in which treatment is individualized based on DST results and clinical and epidemiological factors. Individualized treatment regimens should only include drugs to which the patient's isolate has documented or high likelihood of susceptibility. Treatment regimens should favor medications that are associated with improved outcomes, as identified in our PS-matched IPDMA, that limit toxicity and that incorporate patient preferences. The following alphabetically listed drugs and drug classes were considered for inclusion in treatment regimens: amoxicillin/clavulanate, bedaquiline, carbapenem with clavulanic acid, clofazimine, cycloserine, delamanid, ethambutol, ethionamide, fluoroquinolones, injectable agents, linezolid, macrolides, p-aminosalicylic acid, and pyrazinamide. For each drug or drug class, the following PICO was addressed: In patients with MDR-TB, are outcomes safely improved when regimens include the following individual drugs or drug classes compared with regimens that do not include them? Amoxicillin/Clavulanate Amoxicillin-clavulanate, consisting of the b-lactam antibiotic amoxicillin and the b-lactamase inhibitor potassium clavulanate, is considered safe and effective for numerous bacterial infections. Although M. tuberculosis has an impenetrable cell wall and produces a b-lactamase inhibitor (58), amoxicillin-clavulanate has been used to treat TB. It is viewed as a \"salvage\" agent when few other PICO Question 4-Amoxicillin/Clavulanate: In patients with MDR-TB, are outcomes safely improved when regimens include amoxicillin/clavulanate compared with regimens that do not include amoxicillin/clavulanate? Recommendation 4: We recommend NOT including amoxicillin-clavulanate in a treatment regimen for patients with MDR-TB, with the exception of when the patient is receiving a carbapenem, wherein the inclusion of clavulanate is necessary (strong recommendation, very low certainty in the evidence). Our recommendation against the use of amoxicillin-clavulanate (except to provide clavulanate when using a carbapenem) in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug as having a notably unfavorable balance of benefits to potential harms. (63,64), and the combination has been reported to be efficacious, safe, and tolerable when added to linezolid and other drugs (65)(66)(67)(68)(69). See PICO Question 6 for the evaluation of carbapenems with amoxicillin-clavulanate.\nSummary of the evidence. Procedures and methodology to assemble and the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA showed that patients who received amoxicillinclavulanate were more likely to have been treated with second-line drugs and to be resistant to fluoroquinolones or any second-line injectable (3). They were more likely to have received a later-generation fluoroquinolone (72%), capreomycin (58%), linezolid (25%), and bedaquiline (8%). In adjusted analyses, patients who received amoxicillin-clavulanate were less likely to have treatment success (aOR, 0.6; 95% CI, 0.5-0.8) and more likely to die (aOR, 1.7; 95% CI, 1.3-2.1) compared with patients who did not receive amoxicillin-clavulanate.\nBenefits. The addition of amoxicillinclavulanate (without coadministration with carbapenems) to a regimen for MDR-TB does not appear to provide benefit.\nHarms. Patients who received amoxicillin-clavulanate were less likely to have treatment success and more likely to die than patients who did not receive amoxicillin-clavulanate. Data on adverse effects were not collected systematically across studies in our PS-matched IPDMA or in most trials. A published systematic review identified diarrhea and candidiasis as key adverse effects associated with amoxicillin-clavulanic acid use (70).\nAdditional considerations. Clavulanic acid is only available as a coformulation with amoxicillin. Therefore, amoxicillin-clavulanate must be given whenever carbapenems are included in an MDR-TB regimen (see PICO Question 6 on carbapenems with clavulanate).\nConclusions. Patients who received amoxicillin-clavulanate were less likely to achieve treatment success and more likely to die than patients who did not receive amoxicillin-clavulanate. These data suggest amoxicillin-clavulanate should not be used in MDR-TB treatment, except to provide clavulanate when using a carbapenem (see PICO Question 6 on carbapenems with clavulanate). Our recommendation against the use of amoxicillin-clavulanate (except to provide clavulanate when using a carbapenem) in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug as having a notably unfavorable balance of benefits to potential harms.\nResearch needs. The development of a clavulanic acid formulation without amoxicillin, for use in combination with carbapenems, would be helpful and would avoid unnecessary toxicities from amoxicillin as well as adhere to international efforts in promoting antimicrobial stewardship (1).\n# Bedaquiline\nBedaquiline, a diarylquinoline, approved by FDA in 2013, is the first drug with a novel mechanism of action against M. tuberculosis to have been approved by FDA in .40 years (71,72). Bedaquiline is bactericidal to nonreplicating and actively replicating mycobacteria, through ATP synthase inhibition, and has bactericidal and sterilizing activity in the murine model of TB infection (73). No cross-resistance has been found between bedaquiline and the following: isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin, amikacin, or moxifloxacin. There have been a few reports of cross-resistance with clofazimine PICO Question 5-Bedaquiline: In patients with MDR-TB, are outcomes safely improved when regimens include bedaquiline compared with regimens that do not include bedaquiline? Recommendation 5: We recommend including bedaquiline in a regimen for the treatment of patients with MDR-TB (strong recommendation, very low certainty in the evidence). Our recommendation for the use of bedaquiline is strong despite very low certainty in the evidence because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment including bedaquiline (compared with no bedaquiline) as having a particularly favorable balance of benefits over harms. AMERICAN THORACIC SOCIETY DOCUMENTS e106 (74,75). Bedaquiline is customarily used as part of combination therapy (minimum four-drug therapy) for adults aged >18 years with a diagnosis of pulmonary MDR-TB when an effective treatment regimen cannot otherwise be provided (e.g., mycobacterial isolates show a complicated drug resistance pattern, drug intolerance, or drug-drug interactions) (76). The recommended dose of bedaquiline for the treatment of pulmonary MDR-TB in adults is 400 mg administered orally once daily for 2 weeks, followed by 200 mg administered orally three times weekly, for an entire treatment duration of 24 weeks (72,(76)(77)(78).\nBedaquiline has recently has been identified as the key drug in assembling an all-oral, injectable-free drug regimen in South Africa (79).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PSmatched IPDMA included 411 patients who received bedaquiline-containing regimens, for whom it was assumed that there was no bedaquiline resistance, and 10,932 patients who did not receive bedaquiline (3). Patients who received bedaquiline-containing regimens were more likely to have cavitary disease (82% vs. 62%), to have been treated with second-line drugs (34% vs. 14%), to be infected with an organism resistant to fluoroquinolones (57% vs. 21%) or to any second-line injectable (58% vs. 23%), and to have XDR-TB (29% vs. 13%). They were also more likely to have received a latergeneration fluoroquinolone (69% vs. 54%), linezolid (64% vs. 4%), or clofazimine (48% vs. 4%). Treatment success (cure and completion) was slightly greater (70% vs. 60%; P = 0.001) with bedaquiline, whereas failure/relapse (6% vs. 9%), death (10% vs. 15%), and loss to follow-up (14% vs. 16%) were less frequent in PS-adjusted analyses.\nBenefits. Our PS-matched IPDMA showed that patients treated with bedaquiline-containing regimens were more likely to have treatment success (aOR, 2.0; 95% CI, 1.4-2.9), less likely to experience failure/relapse, and less likely to die (aOR, 0.4; 95% CI, 0.3-0.5; absolute risk reduction, 7.2%). Results were similar when only patients from high-income countries treated with bedaquiline-containing regimens were included and when comparing only patients with XDR-TB who were and were not treated with bedaquiline.\nA recent large program-based observational multinational study confirmed a high treatment success rate (76.9%) with bedaquiline-containing regimens, with a low proportion (5.8%) of interruptions owing to adverse events (80). In our IPDMA, using PS-matched pairs comparing the effects of bedaquiline to those of clofazimine, statistically significant differences for success versus failure/relapse favoring bedaquiline use were observed (aOR, 2.1; 95% CI, 1.1-4.1) (using .170 PS-matched pairs), but statistically significant findings were not observed in mortality or when restricting analyses to high-income countries. PS-matched pairs analyses comparing the effects of various combinations of drugs used with bedaquiline all noted improved outcomes. When comparisons of effects of bedaquiline and linezolid with those of no bedaquiline or linezolid were performed, combination of bedaquiline and linezolid was associated with an aOR of 2.7 (95% CI, 1.5-4.9) for success versus failure/relapse and with an aOR of 0.3 (95% CI, 0.2-0.4) for death versus success/failure/relapse. Similarly, when PS-matched pair analyses comparing the effects of bedaquiline and clofazimine to those of no bedaquiline or clofazimine were performed, combination of bedaquiline and clofazimine was associated with an aOR of 5.0 (95% CI, 2.4-10.6) for success versus failure/relapse, and with an aOR of 0.3 (95% CI, 0.2-0.5) for death versus success/failure/relapse. Of note, patients to whom bedaquiline was administered tended to have more cavitary disease or to have pre-XDR or XDR-TB. Prescription of bedaquiline was associated with greater success and less death than clofazimine, but the greatest success and least mortality was found when bedaquiline was administered together with linezolid or clofazimine.\nFinally, a recent retrospective routinecare observational study in South Africa showed that a bedaquiline-containing regimen was associated with significantly lower mortality (128 [12.6%] deaths among 1,016 patients receiving bedaquiline compared with 4,612 deaths [24.8%] among 18,601 patients on the standard regimens). Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with MDR-or RR-TB (hazard ratio [HR], 0.35; 95% CI, 0.28-0.46) and XDR-TB (HR, 0.26; 95% CI, 0.18-0.38) compared with standard regimens (50).\nHarms. In a review of cases treated with bedaquiline, only 44 of 1,266 (3.5%) cases with information available discontinued bedaquiline because of adverse events. Only 8 of 875 (0.9%) discontinued bedaquiline because of QT interval prolongation (two restarted the drug after resolution of the acute episode without further problems) (81).\nAdditional considerations. When bedaquiline is included in the regimen, most experts obtain ECGs after the initial 2 weeks of therapy and then at monthly intervals to monitor for QT interval prolongation. Serum electrolytes, including calcium, magnesium, and potassium, are also monitored.\nThe 2013 CDC guidelines on the use of bedaquiline note that there is insufficient evidence to provide guidance on the use of bedaquiline in children but that its use can be considered on a case-by-case basis given the high mortality and limited treatment options for MDR-TB (71). More recently, adolescents .10 years old and weight .34 kg have been safely treated off-label with the recommended adult dose of bedaquiline (82). The Sentinel Project on Pediatric Drug-Resistant Tuberculosis has recommended that children >12 years of age and >31 kg body weight receive bedaquiline at the same dose as adults, and children >6 years with 16 to 30 kg body weight could receive half the adult bedaquiline dose for the same indications (7,17,83).\nConclusions. In our PS-matched IPDMA, bedaquiline-containing regimens were more likely to achieve treatment success and to have a lower rate of death than those that did not include bedaquiline. Bedaquiline should be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB. Our recommendation for the use of bedaquiline is strong despite very low certainty in the evidence because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment including bedaquiline (compared with no bedaquiline) as having a particularly favorable balance of benefits over harms.\nResearch needs. Further research is needed to elucidate the potential synergy of bedaquiline with other agents. Studies underway are evaluating the use of bedaquiline together with linezolid, clofazimine, or nitroimidazoles AMERICAN THORACIC SOCIETY DOCUMENTS (i.e., pretomanid and delamanid). Research is also needed on the safety, tolerability, and efficacy of bedaquiline-based shorter-course regimens as well as on the use of bedaquiline for durations .24 weeks, an approach currently considered when effective treatment cannot otherwise be provided (71,84). Finally, research is urgently needed on the risk factors and any interventions (e.g., the selection of companion drugs) that influence acquisition of bedaquiline resistance.\n# Carbapenems with Clavulanic Acid\nThe combination of carbapenems and clavulanate, a b-lactamase inhibitor, has been shown to have in vitro bactericidal activity (65,85,86). As clavulanate is not available by itself, the combination drug amoxicillin-clavulanate must be given with the carbapenems. Carbapenems have been used primarily for MDR and XDR TB, and a recent systematic review found that carbapenems are safe and likely to be effective (65). Carbapenem drugs have been recently included in WHO guidelines for the treatment of DR-TB (23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA compared death, treatment success, and culture conversion among 169 individuals who received carbapenems to 9,535 individuals from centers that did not use any of the drugs previously classified by WHO as \"Group 5\" drugs (3). In addition, we considered adverse events reported in a recent review (65), IPDMA, and systematic review that summarize the available evidence on carbapenems from five primary studies (all observational studies) (23,(65)(66)(67)(87)(88)(89)(90)(91)(92). The reviewed evidence showed that there was concomitant use of linezolid and bedaquiline in large proportions of the patient population receiving carbapenems, suggestive of confounding, which was considered in the review of the efficacy results.\nBenefits. In our PS-matched IPDMA, inclusion of carbapenems in the treatment regimen had no effect on the risk of death (aOR, 1.0; 95% CI, 0.5-1.7) or culture conversion (aOR, 2.3; 95% CI, 0.8-6.9). However, treatment success was more likely among patients treated with regimens including a carbapenem compared with those treated with regimens not including a carbapenem (aOR, 4.0; 95% CI, 1.7-9.1).\nHarms. In our meta-analysis, the rate of treatment discontinuation due to an adverse event was lower among patients treated with regimens including a carbapenem than those treated with regimens not including a carbapenem, although this difference was not statistically significant (relative risk, 0.82; 95% CI, 0.23-2.94). In the published literature, treatment discontinuation due to adverse events has been reported in 0 to 3% of patients, with minor adverse events occurring in 5% to 6% of patients (65).\nAdditional considerations. Of note, clavulanic acid is only available as a coformulation with amoxicillin. Therefore, amoxicillin-clavulanate must be given to achieve a dose of 125 mg of the clavulanate with each dose of carbapenem daily, whenever carbapenems are included in an MDR-TB regimen. DST is currently not available for carbapenems. When used, imipenem-cilastatin/clavulanate or meropenem/clavulanate have been administered intravenously in a hospital setting, with multiple injections required daily (67). There is no clear evidence of whether imipenem-cilastatin or meropenem is more efficacious (66). Ertapenem belongs to the same family (65,93); because of its longer half-life and the possibility to administer it once a day intramuscularly or intravenously, ertapenem may be useful when a patient treated with meropenem or imipenem-cilastatin intravenously during hospitalization is discharged and needs to continue carbapenem-based treatment outpatient (92). Long-term intravenous administration requires long-term venous access through an indwelling catheter, which carries risks of infection, thrombosis, and thromboembolism. Data on the use of a carbapenem combined with amoxicillin-clavulanate in children are lacking-only two adolescents are included in one review (65). However, efficacy has been shown in adults, and both carbapenems and amoxicillinclavulanate have been used safely in children for other purposes (although there are no long-term treatment safety data in young children); therefore, this combination could be used in children with MDR-TB where there is no other option to build an effective regimen.\nConclusions. In our PS-matched IPDMA, inclusion of carbapenems with clavulanic acid was associated with an increase in treatment success when compared with the control group not receiving carbapenems with clavulanic acid. Carbapenems with clavulanic acid can be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB.\nResearch needs. Randomized, controlled clinical trials that confirm the role of carbapenems used for different durations of time within different regimens are needed. A comparative evaluation of the safety, tolerability, and efficacy of the different agents is also necessary. Because of the high cost of these drugs, economic analyses will also be useful (65). The development of oral formulations of carbapenems is underway, which, if proven safe and effective, would enhance feasibility of using these agents significantly. Additional advances in rapid DST for carbapenems would enhance potential scale-up of use for this class of drugs. \n# AMERICAN THORACIC SOCIETY DOCUMENTS e108\nClofazimine Clofazimine, a fat-soluble riminophenazine dye, has shown in vitro and in vivo activity as a sterilizing drug to treat MDR-TB (94)(95)(96).\nClofazimine has been used as a leprosy drug and was first developed in the 1950s because of in vitro and in vivo activity against M. tuberculosis (94, 95, 97). Although the exact mechanism of action is not known, it is a prodrug that appears to have both antimycobacterial and antiinflammatory properties (98). The published clinical evidence on the safety and efficacy of clofazimine for treatment of TB is modest (99). However, interest in the drug has increased since WHO endorsed the new shorter-course regimen (23, 100), which includes clofazimine (101)(102)(103)(104)(105)(106)(107)(108).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PSmatched IPDMA compared death, treatment success, and culture conversion among 639 individuals who received clofazimine to 7,398 individuals from centers that did not use any of the drugs previously classified by WHO as \"Group 5\" drugs (3). In addition, we considered adverse events reported in a published systematic review of nine observational studies (six MDR-TB and three XDR-TB) including 599 patients treated with clofazimine (427 from a single cohort study from Bangladesh) (95) and two studies published after the systematic review. They include a trial at six specialty hospitals in China that randomized 105 patients to 21 months of treatment with an optimized background regimen with or without clofazimine (100 mg/d) ( 94) and a retrospective cohort study from Brazil that compared outcomes in patients with MDR-TB treated with clofazimine (100 mg/d)-containing regimens versus pyrazinamide-containing regimens (109).\nBenefits. Our PS-matched IPDMA showed that treatment success was more likely with regimens containing clofazimine compared with regimens that did not (aOR, 1.5; 95% CI, 1.1-2.1). Addition of clofazimine was associated with an aOR of 0.8 (95% CI, 0.6-1.0) for the outcome of death and with an aOR of 1.1 (95% CI, 0.6-1.8) for culture conversion within 6 months. As noted in PICO Question 5 on bedaquiline, when PSmatched pair analyses were performed comparing the effects of bedaquiline and clofazimine to those of no bedaquiline or clofazimine, the combination of bedaquiline and clofazimine was associated with an aOR of 5.0 (95% CI, 2.4-10.6) for success versus failure/relapse and with an aOR of 0.3 (95% CI, 0.2-0.5) for death versus success/failure/relapse.\nHarms. In our PS-matched IPDMA, 2 of 81 (2.5%) patients treated with regimens including clofazimine had treatment discontinued because of adverse events. Brownish skin pigmentation has been observed in 75% to 100%, ichthyosis in 8% to 20%, gastrointestinal intolerance in 40% to 50%, and neurological disturbances in up to 13% of patients (94,95,109). Clofazimine was judged to have small to moderate desirable effects (on treatment success, mortality, and culture conversions) and small undesirable effects (low risk of serious adverse events requiring treatment discontinuation). However, there is important uncertainty about how patients value skin discoloration. Some patients perceive skin discoloration as significant, which may become a key factor in the acceptability of this drug in some settings. Recent publications have noted the potential QT interval-prolonging effects of clofazimine when used in combination with bedaquiline and delamanid (110)(111)(112).\nAdditional considerations. Access is a limitation to expanded use of clofazimine for treatment of MDR-TB, especially in the United States and Europe, where clofazimine lacks a TB indication. In the United States, clofazimine is currently only available under an investigational new drug protocol administered by FDA, which can be a burdensome procedure. Significant improvements in the mechanisms for accessing clofazimine are necessary for more expanded use of this drug. Quality-assured clofazimine is available through the Global Drug Facility, although currently in limited quantities. Although our PS-matched IPDMA had limited pediatric data, the efficacy in children is believed by experts to be the same as in adults. A recent IPDMA in children with MDR-TB did not show a benefit using clofazimine, which might be related to selection of cases and very small numbers (23 of 641) receiving clofazimine (113). Moreover, children are included in the WHO shortercourse regimen for MDR-TB treatment, which includes clofazimine, albeit on the basis of limited data. Dosing clofazimine in children is challenging because of the lack of childfriendly formulations and lack of pharmacokinetic data. The currently recommended dose for clofazimine in children varies from 2 to 5 mg/kg daily. Skin discoloration is common; some improve during treatment and others resolve rapidly after discontinuation of treatment. Ichthyosis is less common and improves with intensive efforts at applying lubricants during treatment. As noted, QT interval prolongation may occur and is especially important to monitor by ECG if given together with other QT interval-prolonging medication (68, 83, 110-112, 114, 115). Clofazimine may have cross-resistance with bedaquiline, which may need to be considered when building a regimen for MDR-TB (75).\nConclusions. In our PS-matched IPDMA, inclusion of clofazimine was associated with increase in treatment success when compared with the control group not receiving clofazimine. Clofazimine can be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB.\nResearch needs. The value of using loading doses and the optimal dosing for clofazimine requires additional research. Pharmacokinetic data in adults and children are needed.\n# Cycloserine\nCycloserine is an oral bacteriostatic drug that has been part of the backbone regimen for MDR-TB treatment in the past. Cycloserine is a broad-spectrum antibiotic that inhibits cell wall synthesis (116,117). Terizidone is a structural analog that is a combination of two cycloserine molecules; it appears to be used interchangeably by experts, although it is currently not available in the United States (118). Although some advantages of cycloserine include the absence of crossresistance to other drugs and reasonable gastrointestinal tolerability, a significant drawback relates to psychological side effects, which occasionally necessitate discontinuation of the drug (16).\nSummary of the evidence. Previous studies showed an increase of the likelihood of treatment success when cycloserine was included in the MDR-TB regimen (marginally statistically significant) (96). Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B.\nBenefits. Our PS-matched IPDMA showed that inclusion of cycloserine was associated with an increase in treatment success (aOR, 1.5; 95% CI, 1.4-1.7) and a decrease in AMERICAN THORACIC SOCIETY DOCUMENTS mortality (aOR, 0.6; 95% CI, 0.5-0.6) when compared with the control group. A published IPDMA of children with successful treatment of MDR-TB showed that cycloserine as a single drug had an aOR of 1.7 (95% CI, 0.9-3.0; 641 children with MDR-TB, of whom 356 [56%] received cycloserine/terizidone) (113). Limited pharmacokinetic data are available on cycloserine (or terizidone) in children, but a recent study of 25 children (only 5 to ,12 yr of age) receiving a median of 14.3 mg/kg (range, 10.0-18.0 mg/kg) showed that the maximum concentration of the drug achieved in the plasma after dose administration was similar to the adult target maximum concentration of 20 to 35 mg/L (119). The recommended dose for children of 10 to 20 mg/kg/d seems adequate. An advantage of cycloserine in children, as in adults, with miliary and/or central nervous system (CNS) TB is that it penetrates the CNS well. Cycloserine may interfere with the pharmacokinetics and absorption of isoniazid and ethionamide/prothionamide; therefore, it may be advisable to give it separately from these drugs if used together in the same regimen (117).\nHarms. Cycloserine has CNS adverse effects, which are reported to occur in about 20% to 30% of adults (120). A meta-analysis of published articles identified adverse events in 201 of 2,164 patients across all studies (118). An average weighted proportion of patients receiving cycloserine who discontinued treatment owing to adverse effect pooled across the studies was 9.1% (95% CI, 6.4-11.7%). An average weighted proportion of patients with psychiatric adverse effects was 5.7% (95% CI, 3.7-7.6%) (118). Limited data exist on cycloserine adverse effects in children. In older pediatric studies, no adverse effects were reported with the use of cycloserine (121)(122)(123). In a systematic review of outcomes of MDR-TB in children, 6 of 182 (3.3%) children had adverse effects attributed to cycloserine, which included depression, anxiety, hallucinations, transitory psychosis, and blurred vision (124).\nAdditional considerations. Lowerthan-recommended serum cycloserine concentrations and delayed absorption have been reported (125). Some experts obtain peak concentrations within the first 1 to 2 weeks of therapy and continue to monitor serially. Because of specific technical challenges related to cycloserine DST, poor accuracy of testing in liquid media, and poor intrinsic reproducibility of results, few laboratories perform DST for cycloserine (16).\nConclusions. In our PS-matched IPDMA, inclusion of cycloserine was associated with a decrease in mortality and increase in treatment success when compared with the control group not receiving cycloserine. Cycloserine can be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB.\nResearch needs. Studies are needed to determine the effect of cycloserine on the absorption of isoniazid and ethionamide.\n# Delamanid\nDelamanid is a nitro-dihydro-imidazooxazole derivative, which was approved for the treatment of MDR-TB by the European Medicines Agency in 2013 but has not yet received FDA approval. In 2014, WHO issued interim policy guidance on the use of delamanid for the treatment of MDR-TB on the basis of phase 2b clinical trial data. The interim policy guidance stated that \"delamanid may be added to an MDR-TB regimen in adult patients with pulmonary TB conditional upon: i) careful selection of patients likely to benefit; ii) patient informed consent; iii) adherence to WHO recommendations in designing a longer MDR-TB regimen; iv) close monitoring of clinical treatment response; and v) active TB drug-safety monitoring and management (aDSM)\" (126). WHO issued an updated position statement on the use of delamanid for MDR-TB in 2018 on the basis of final results from the phase 3 randomized controlled trial, Trial 213 (127).\nSummary of the evidence. Delamanid data were not available as part of the PS-matched IPDMA completed for this guideline development process; however, the 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment, wherein individual-level data on delamanid were attained for analyses, provides practice guidance on the use of delamanid for treatment of MDR-TB (7,128). Several recent reports, clinical trials, and cohort studies report on delamanid-containing regimens achieving success rates of 77% to 84%, in absence of major adverse events (128)(129)(130)(131). In the United States, through a compassionate use program, delamanid has recently been successfully accessed and used in the care of patients with MDR-TB (132). Regarding use of delamanid in children, only a small number of children (.6 yr of age) have had documented access to the drug, also by compassionate use (133,134). On the basis of review of the data available in the IPDMA conducted by WHO, delamanid has been included in \"Group C\" in their guidelines, corresponding to drugs that can be added \"to complete the regimen and when medicines from Groups A and B cannot be used.\" WHO has recommended that \"delamanid may be included in the treatment of MDR/RR-TB patients aged 3 years or more on longer regimens\" (7,135). The guideline writing committee concurs with the updated 2019 WHO guidance (7). As noted for other drugs discussed in this practice guideline, QT interval PICO Question 9-Delamanid: In patients with MDR-TB, are outcomes safely improved when regimens include delamanid compared with regimens that do not include delamanid?\nRecommendation 9: The guideline panel was unable to make a clinical recommendation for or against delamanid because of the absence of data in the PSmatched IPDMA conducted for this practice guideline. We make a research recommendation for the conduct of randomized clinical trials and cohort studies evaluating the efficacy, safety, and tolerability of delamanid in combination with other oral agents. Until additional data are available, the guideline panel concurs with the conditional recommendation of the 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment that delamanid may be included in the treatment of patients with MDR/RR-TB aged >3 years on longer regimens (7).\nPICO Question 8-Cycloserine: In patients with MDR-TB, are outcomes safely improved when regimens include cycloserine compared with regimens that do not include cycloserine?\nRecommendation 8: We suggest including cycloserine in a regimen for treatment of patients with MDR-TB (conditional recommendation, very low certainty in the evidence).\nprolongation may occur with delamanid use, and routine ECG monitoring is recommended. A recent evaluation of the cardiac safety of delamanid and bedaquiline given together as part of multidrug therapy for MDR-TB concluded that the combined effect on the corrected QT interval (QTc) using the Fridericia formula (QTcF) is clinically modest and no more than additive (ClinicalTrials.gov Identifier: NCT02583048), with mean change in QTcF from baseline at 11.9 milliseconds (95.1% CI, 7.4-16.5 ms) in the bedaquiline arm, 8.6 milliseconds (95.1% CI, 4.0-13.2 ms) in the delamanid arm, and 20.7 milliseconds (95.1% CI, 16.1-25.4 ms) in the combined bedaquiline and delamanid arm (136).\nConclusions. The guideline panel was unable to make a recommendation for or against delamanid because of the absence of data in the IPDMA conducted for this practice guideline. In 2018, WHO updated the IPDMA with additional data and recommended delamanid be included in the third tier of drugs, Group C, and for the drug to be used in the treatment of patients with MDR/RR-TB aged >3 years on longer regimens. The guideline writing committee agrees with the updated 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment that delamanid may be included in the treatment of patients with MDR/RR-TB aged >3 years on longer regimens (7). We make a research recommendation for the conduct of randomized clinical trials and cohort studies evaluating the efficacy, safety, and tolerability of all-oral, shortened regimens inclusive of delamanid in combination with other oral agents.\nResearch needs. The companion drugs with which to combine delamanid for optimal efficacy, safety, and tolerability remain uncertain. The conduct of randomized clinical trials and cohort studies evaluating all-oral, shortened regimens, inclusive of delamanid and in combination with other oral agents are urgently needed. The endTB trial is a phase 3 multicountry randomized clinical trial evaluating the efficacy and safety of five new, all-oral, shortened regimens including combinations of bedaquiline and delamanid (ClinicalTrials.gov Identifier: NCT02754765). Recent cohort data are also emerging on the use of delamanid and bedaquiline in combination, which to date has been generally reserved for severe cases with extensive resistance and when other options are not feasible (137)(138)(139)(140). The Nix-TB (A Phase 3 Study Assessing the Safety and Efficacy of Bedaquiline Plus PA-824 Plus Linezolid in Subjects with Drug-Resistant Pulmonary Tuberculosis) trial (ClinicalTrials.gov Identifier: NCT02333799) evaluated an all-oral 6-month regimen comprising bedaquiline, pretomanid (member of the nitroimidazooxazines class of compounds), and linezolid for the treatment of either XDR-TB or treatment-intolerant or nonresponsive MDR-TB. FDA granted priority review of the new drug application for pretomanid in March 2019, the Antimicrobial Drugs Advisory Committee discussed pretomanid in June 2019, and in August 2019 FDA approved pretomanid in combination with bedaquiline and linezolid for the treatment of a specific limited population of adults with pulmonary XDR-TB or treatment-intolerant or nonresponsive MDR-TB (2,141). Given FDA approval, additional trials that include diverse patient populations will be essential to understand optimal use of the regimen, in addition to head-to-head comparisons of pretomanid with delamanid to determine if these drugs can be used interchangeably.\n# Ethambutol\nEthambutol is an ethylenediamine that inhibits arabinosyl transferases, which contribute to M. tuberculosis cell wall synthesis (142). The drug is included in standard regimens for treatment of drugsusceptible TB and commonly used in regimens for MDR-TB (11,16,23). The published evidence available on its safety and efficacy is modest, and its use as part of the first-line drug-susceptible TB regimen rests largely on its ability to prevent the emergence of resistance to the other drugs in the regimen rather than on its own sterilizing activity (143). Ethambutol has been demonstrated to have modest sterilizing activity as part of combination regimens when used against ethambutolsusceptible isolates for treatment of drugsusceptible TB. The drug is not effective when used for ethambutol-resistant isolates, and such use is not recommended (54,96).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA compared outcomes among 3,002 individuals with isolates susceptible to ethambutol who received the drug to 667 individuals with isolates susceptible to ethambutol who did not receive the drug (3). Receipt of ethambutol was associated with an aOR of 0.9 (95% CI, 0.7-1.1) for the outcome of treatment success; receipt of ethambutol was associated with an aOR of 1.0 (95% CI, 0.9-1.2) for the outcome of death. However, the groups were not balanced with regard to other effective drugs; in particular, the patients not receiving ethambutol were more likely to receive linezolid. Thus, the ability to detect an effect of ethambutol might have been obscured. In a previous IPDMA, before linezolid and bedaquiline use were common, administration of ethambutol among patients with susceptible isolates was associated with an aOR of 1.7 (95% CI, 1.2-2.4) for cure/complete versus failure/relapse and an aOR of 1.6 (95% CI, 1.1-2.4) for cure/complete versus failure/relapse/death, compared with patients receiving ethambutol whose isolates were resistant in vitro (144).\nBenefits. Our PS-matched IPDMA showed that treatment success was not significantly more likely with regimens containing ethambutol. However, a number of earlier studies indicate that ethambutol is associated with increased success when used to treat patients whose isolates are susceptible to the drug (143). Moreover, these earlier studies determined that the effectiveness of ethambutol is directly related to dose, and that a dose of 25 mg/kg was more effective than a dose of 15 mg/kg (143). Dosages were not available for analysis in our PS-matched IPDMA. Finally, our PS-matched IPDMA did not address a key attribute of ethambutol, the prevention of the emergence of resistance, which is a substantial concern among patients with MDR-TB (145).\nPICO Question 10-Ethambutol: In patients with MDR-TB, are outcomes safely improved when regimens include ethambutol compared with regimens that do not include ethambutol?\nRecommendation 10: We suggest including ethambutol in a regimen for treatment of patients with MDR-TB only when more effective drugs cannot be assembled to achieve a total of five effective drugs in the regimen (conditional recommendation, very low certainty in the evidence).\n# AMERICAN THORACIC SOCIETY DOCUMENTS\nHarms. In a recent review of the tolerability of TB drugs, ethambutol was associated with serious adverse events in 6 of 1,325 (0.5%) patients (23). This is consistent with previous reports of ethambutol toxicity, in which optic neuropathy (including optic neuritis and retrobulbar neuritis) was attributed to ethambutol, manifesting as symptoms of decreased visual acuity, scotomata, color blindness, or visual defects. These toxic effects are dose dependent and, although serious, are generally reversible if recognized promptly and the drug is discontinued or the dose reduced.\nAdditional considerations. When ethambutol is used, some experts recommend using the higher dose of 25 mg/kg, which is associated with increased efficacy but also slightly greater ocular toxicity. Other experts recommend using 15 to 20 mg/kg, counting the drug predominantly as providing protection against the acquisition of additional resistance. All patients receiving ethambutol as part of an MDR-TB treatment regimen should be monitored monthly for signs of ocular toxicity, particularly visual impairment, and if this is detected, ethambutol should be discontinued. If optic neuritis occurs in patients taking both ethambutol and linezolid, both drugs must be stopped. Many patients may be rechallenged successfully with linezolid once vision normalizes, but rechallenge with ethambutol is not recommended. The efficacy of ethambutol is not expected to be different in children compared with adults. A dose of 25 mg/kg is recommended by experts for children with MDR-TB. Two reviews on safety of ethambutol relating to vision have shown low risk of ocular toxicity (143,146). However, other drugs, such as linezolid, may also cause optic neuritis, and this should be taken into consideration when treating MDR-TB in children, especially as screening for visual loss is difficult in young children.\nConclusions. We suggest including ethambutol in a regimen for treatment of patients with MDR-TB only when more effective drugs cannot be used to achieve a total of five effective drugs in the regimen (conditional recommendation, very low certainty in the evidence). The committee was divided on the value of recommending ethambutol, given the drug was not associated with any benefit in terms of treatment success or mortality. Concerns about the comparability of IPDMA patient groups treated with and without ethambutol were noted. Unlike ethionamide/prothionamide, where there are substantial undesirable effects, ethambutol had small undesirable effects (low risk of serious adverse events requiring treatment discontinuation). Finally, our PS-matched IPDMA did not address the prevention of emergence of resistance-a recognized attribute of ethambutol in the treatment of drug-susceptible TB-although the applicability of this attribute to MDR-TB regimens is unknown. Overall, the committee suggested that ethambutol can be used only when more effective drugs cannot be assembled to achieve the necessary five effective drugs in the regimen.\nResearch needs. More evidence is needed on the beneficial role that ethambutol may play in preventing emergence of drug resistance in MDR-TB, including to newer oral drugs. More research is also needed to improve on the reliability of DST for ethambutol in different settings.\n# Ethionamide and Prothionamide\nEthionamide and prothionamide are derivatives of isonicotinic acid, somewhat similar in structure to isoniazid. Ethionamide is a prodrug and requires activation, after which it inhibits mycobacterial fatty acid synthesis that is necessary for cell wall synthesis and repair. Clinical studies indicate efficacy of these drugs, and they have been included in regimens for treatment of MDR-TB and for treatment of TB meningitis in adults and children (16,23,147,148).\nSummary of evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA showed that ethionamide/prothionamide were not associated with any benefit, even if susceptible by phenotypic DST (3). Previous studies have shown, however, an increase in the likelihood of treatment success if ethionamide was included in the MDR-TB regimen (23,149). These different results can be explained by the inclusion of newer and more effective drugs, improving outcomes in the comparator groups, potentially biasing the observed effect against ethionamide; fewer patients in the ethionamide/prothionamide group, compared with control subjects, received newer-generation fluoroquinolone (51% vs. 76%), amikacin (17% vs. 35%), and linezolid (5% vs. 18%), and more patient in the ethionamide/prothionamide groups received kanamycin (51% vs. 12%) and capreomycin (27% vs. 16%).\nBenefits. No benefits were identified for inclusion of ethionamide/prothionamide in regimens, even if susceptible by phenotypic DST. A pediatric IPDMA of MDR-TB cases also did not show benefit using ethionamide/ prothionamide; however, the majority of children (590 of 641) in this study did receive ethionamide or prothionamide, potentially limiting the ability to discern a benefit (113).\nHarms. The potential of ethionamide to cause adverse events can also limit its tolerability (120). A review of studies comparing a regimen containing ethionamide or prothionamide (all studies before 1970) showed that adverse effects leading to discontinuation of treatment were equally frequent with ethionamide (11.3%; range 6-42%) and prothionamide (11.9%; range 6-40%). Adverse effects, when reported, included abnormal liver function tests, gastrointestinal intolerance, endocrine dysfunction, and hypothyroidism, the latter occasionally requiring treatment with thyroxine (147). Hypothyroidism is a common adverse effect of ethionamide (experienced by approximately 20%) (150,151) and is particularly noted if used with p-aminosalicylic acid and in HIV-infected children (152). Gastrointestinal disturbance is common but usually resolve within the first 2 weeks of treatment in children.\nAdditional considerations. When ethionamide/prothionamide is included in a regimen for which five other effective drugs cannot be assembled, experts recommend dose escalation (drug ramping) at time of treatment initiation, as well as monitoring of thyroid-stimulating hormone for evidence of hypothyroidism requiring replacement (16). Of note, in the presence of inhA mutation, many isolates will show PICO Question 11-Ethionamide/ prothionamide: In patients with MDR-TB, are outcomes safely improved when regimens include ethionamide/ prothionamide compared with regimens that do not include ethionamide/prothionamide? Recommendation 11: We suggest NOT including ethionamide/ prothionamide in a treatment regimen for patients with MDR-TB if newer and more effective drugs are available to construct a regimen with at least five effective drugs (conditional recommendation, very low certainty in the evidence). cross-resistance between isoniazid and ethionamide/prothionamide (153).\nConclusions. When the individualized treatment regimen for patients with MDR-TB contains newer-generation, moreeffective drugs, the addition of ethionamide/prothionamide does not appear to provide benefit.\nResearch needs. Research efforts are underway to identify potential boosters of potency for ethionamide, which, if successful when coadministered, may result in improved therapeutic index and overall better risk-benefit ratio for use (154).\n# Fluoroquinolones: Levofloxacin, Moxifloxacin, Ciprofloxacin, and Ofloxacin\nThe fluoroquinolones are a family of chemically related drugs characterized by a common core dual-ring structure (155). Ofloxacin, then levofloxacin, then moxifloxacin sequentially improved on earlier generation's spectrum of activity, including mycobacteria, and their antimycobacterial action increased as evidenced by lower minimum inhibitory concentrations (MICs) and increasing success in clinical use (156,157). Physicians began using these drugs to treat MDR-TB on the basis of in vitro data, with subsequent case series and observational studies showing efficacy (158), although none of the fluoroquinolones are currently indicated by regulatory authorities for the treatment of TB. In general, these drugs are well absorbed orally, have favorable pharmacological profiles for once-daily dosing, are generally well tolerated, and now are available in generic formulations (155).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PSmatched IPDMA, ofloxacin was used most commonly (n = 4,020), followed by levofloxacin (n = 3,872), moxifloxacin (n = 2,132), and ciprofloxacin (n = 431); 734 patients did not receive a fluoroquinolone, the comparison group for subsequent analyses, and 828 patients received two or more quinolones and were excluded (3). The groups were similar in age, sex, proportion AFB smear positive, proportion with cavitary disease on chest radiograph, and prior treatment with first-line drugs. However, the no-quinolone group had substantially more HIV coinfection (44% vs. 13-28%; proportion with HIV coinfection across different quinolones), more past treatment with secondline drugs (52% vs. 8-25%), more quinolone resistance (86% vs. 6-33%), more second line injectables resistance (74% vs.12-34%), and more XDR TB (73% vs. 4-19%). In terms of treatment, the no-fluoroquinolone group received less amikacin (7% vs. 18-43%) and kanamycin (13% vs, 26-65%) and more capreomycin (66% vs. 6-34%). Therefore, the median number of effective drugs (intensive phase) was lower in the no-fluoroquinolone group (2.1) than in the other groups (3.3-4.0). Thus, treatment success was lower in the nofluoroquinolone group (35% vs. 55-68%) and failure/relapse was higher than but not greatly different from the others (13% vs. 2-10%); mortality, however, was much higher (40% vs. 11-15%).\nBenefits. In our PS-matched IPDMA, among patients with susceptible isolates, levofloxacin-containing regimens compared with no quinolone were associated with significantly more treatment successes (aOR, 4.2; 95% CI, 3.3-5.4) and significantly fewer deaths (aOR, 0.6; 95% CI, 0.5-0.7). Moxifloxacin, compared with no quinolone, was also associated with significantly more treatment successes (aOR, 3.8; 95% CI, 2.8-5.2) and significantly fewer deaths (aOR, 0.5; 95% CI, 0.4-0.6). In the subgroup with resistance to an injectable drug(s), levofloxacin or moxifloxacin were associated with a significant improvement in treatment success (aOR, 1.8; 95% CI, 1.2-2.8) and reduction in death (aOR, 0.6; 95% CI, 0.4-0.8), although the corresponding adjusted risk differences were not statistically significant. In pairwise comparisons, both levofloxacin and moxifloxacin were associated with significantly better treatment outcomes than ofloxacin. The aORs of death were lower for the two later-generation quinolones when compared with ofloxacin (levofloxacin: aOR, 0.8; 95% CI, 0.6-0.9; moxifloxacin: aOR, 0.8; 95% CI, 0.6-1.0) (data not shown). Ofloxacin and ciprofloxacin are considered inferior quinolones against M. tuberculosis (144,149,159,160). Levofloxacin and moxifloxacin did not differ significantly from each other.\nIn a recent IPDMA describing treatment outcomes in children treated for MDR-TB (113), new and repurposed TB drugs, including late-generation fluoroquinolones, were not used enough to adequately evaluate efficacy, but most experts and emerging evidence suggest that the efficacy of fluoroquinolones noted in adults should be similar in children (83,161).\nHarms. In our PS-matched IPDMA, grade 3 adverse events were recorded systematically in a subset of 1,962 patients from a cohort study of MDR-TB at 27 sites in nine countries. Permanent discontinuation of fluoroquinolones due to adverse events was uncommon. Among 150 patients treated with levofloxacin, the drug was stopped permanently because of adverse events in 6 (4.0%). Among 398 patients treated with moxifloxacin, the drug was stopped permanently in 14 (3.5%) patients. Among 1,167 patients treated with ofloxacin, the drug was stopped permanently in 56 (4.8%) patients. An analysis of 56 clinical trials comparing quinolones against placebo or against other antimicrobial agents found generally similar adverse event profiles (3). Seven studies reported more frequent adverse events and six studies reported fewer adverse events in fluoroquinolone-treated patients. The most frequent adverse effects reported are those of the gastrointestinal tract in 3% to 17% and CNS in 0.9% to 11% of patients (155,162). Allergic and other hypersensitivity reactions and other skin reactions occur in 0.5% to 2.8% of patients. Other adverse effects that occur in .1% of patients are cardiac (QT interval prolongation) and endocrine (hypoglycemia). Recently, FDA strengthened warnings in the prescribing information for the entire class of fluoroquinolones on risks of severe hypoglycemia, certain mental health side effects, and tendonitis, as well as risks of ruptures or tears in the aorta (163). Safety concerns persist for long-term pediatric use of fluoroquinolones, especially regarding arthropathy. However, several long-term prospective and retrospective studies in children have confirmed that severe adverse effects with the fluoroquinolones are rare, including musculoskeletal, neurological, and QT interval prolongation adverse effects (164)(165)(166).\nAdditional considerations. As latergeneration fluoroquinolones have become generic, their cost has decreased greatly and their use has expanded to many different indications, so procurement and availability have not been problematic, but resistance is more common than among aminoglycosides. Some foods or beverages and antacids high in content of divalent or AMERICAN THORACIC SOCIETY DOCUMENTS trivalent cations can reduce fluoroquinolone absorption (16,(167)(168)(169). When feasible, taking fluoroquinolones on an empty stomach minimizes the potential of delays in or reduction of fluoroquinolone absorption. Moxifloxacin and to a lesser extent levofloxacin prolong the QT interval. Moxifloxacin may necessitate ECG monitoring, especially if patients have a baseline QTc . 500 milliseconds or take other QT-prolonging drugs.\nPharmacokinetic modeling studies for levofloxacin and moxifloxacin use in children are ongoing: recent data suggest that for children, a levofloxacin dose of at least 15 to 20 mg/kg daily (170,171), and a moxifloxacin dose of 10 to 15 mg/kg/d are effective (based on data showing too low exposure at 7.5-10 mg/kg) (172). Although a modeling paper suggests a dose of 25 mg/kg/d for infants to 3 months of age and 20 mg/kg/d for toddlers, safety at these doses has not been verified (173).\nConclusions. In our PS-matched IPDMA, patients treated with moxifloxacin and levofloxacin had better outcomes than patients not treated with any fluoroquinolones, or compared with patients treated with ofloxacin, after adjustment for numerous covariates that in themselves were strong determinants of outcome, such as clinical characteristics, extent of drug resistance, and number of other effective drugs in the treatment regimen. Moxifloxacin or levofloxacin should be included in a regimen to achieve a total of five effective drugs for the treatment of patients with MDR-TB. Our recommendation for the use of moxifloxacin or levofloxacin is strong despite very low certainty in the evidence, because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment that includes these latergeneration fluoroquinolones (compared with no fluoroquinolones) as having a particularly favorable balance of benefits over harms. NCT01918397) and dosing regimens, as preliminary work suggests these drugs may be more effective at higher doses (174). The activity, safety, and tolerability of using higher doses of fluoroquinolones against isolates with modestly elevated MICs should also be explored. Modest increases in toxicity can be minimized and managed by clinicians and may still be preferable to treating MDR-TB without quinolones. Higher doses may also limit acquired resistance (175,176).\nInjectables: Amikacin, Capreomycin, Kanamycin, and Streptomycin\nThe term \"injectable drugs\" in general encompasses four drugs: the aminoglycoside antibiotics streptomycin, amikacin, and kanamycin; and the cyclic polypeptide antibiotic capreomycin (155,162,177). Aminoglycosides are highly cationic and water soluble, but insoluble in organic solvents and hydrophobic environments, explaining much about their pharmacology, limited ability to cross lipid membranes, poor absorption from the gastrointestinal tract, and poor penetration into the CNS. Consequently, they are administered parenterally through slow intravenous infusion or through intramuscular injection (177). Streptomycin's core ring structure differs from all other aminoglycosides, explaining in part why cross-resistance between streptomycin and other aminoglycosides is uncommon (155,177). These drugs block protein synthesis at the ribosomal level by binding to a highly conserved nucleotide sequence in the prokaryotic 16S ribosomal subunit, the mRNA decoding region, where translation of mRNA codon to aminoacyltransfer RNA anticodon normally takes place (155,177). Aminoglycosides share three important characteristics: 1) concentration-dependent killing, 2) a postantibiotic effect, and 3) synergism with other antibacterial drugs (155). These drugs kill bacteria in proportion to drug concentration, so a single daily dose is more effective than divided doses or a continuous infusion. Moreover, antibacterial activity continues many hours after serum levels become undetectable, the so-called \"postantibiotic\" effect (155).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PS-matched IPDMA, treatment outcomes for 613 patients who did not receive an injectable drug were compared with 1,554 patients treated with streptomycin, 4,330 treated with kanamycin, 2,275 treated PICO Question 12-Fluoroquinolones: In patients with MDR-TB, are outcomes safely improved when regimens include fluoroquinolones compared with regimens that do not include fluoroquinolones? Recommendation 12: We recommend including moxifloxacin or levofloxacin in a regimen for treatment of patients with MDR-TB (strong recommendation, low certainty in the evidence). Our recommendation for the use of moxifloxacin or levofloxacin is strong despite very low certainty in the evidence because we viewed the significant reduction in mortality, improved treatment success, and relatively few adverse effects associated with MDR-TB treatment that includes these latergeneration fluoroquinolones (compared with no fluoroquinolones) as having a particularly favorable balance of benefits over harms.\nPICO Question 13-Injectables: In patients with MDR-TB, are outcomes safely improved when regimens include an injectable compared with regimens that do not include an injectable? Recommendation 13: We suggest including amikacin or streptomycin in a regimen for treatment of patients with MDR-TB when susceptibility to these drugs is confirmed (conditional recommendation, very low certainty in the evidence). Because of their toxicity, these drugs should be used when more effective or less toxic therapies cannot otherwise be assembled to achieve a total of five effective drugs. We suggest NOT including kanamycin or capreomycin (conditional recommendation, very low certainty in the evidence).\nwith amikacin, and 2,401 treated with capreomycin. Patients who received two or more injectable drugs (n = 875) were excluded, because the outcome could not be ascribed to one of the drugs (3). The noinjectable comparison group had notably fewer AFB smear-positive patients and patients with cavitary disease. On the other hand, patients in this group had more past treatment with second-line drugs; more resistance to quinolones, injectables, and XDR TB; and much more treatment with linezolid. In these respects, the capreomycin group was similar (more past treatment with second-line drugs, worse pretreatment drug resistance) to the other three drugs. Analysis was based on patients whose isolates were susceptible to the drug they received, with exceptions noted below.\n# Benefits. INJECTABLE DRUGS COMPARED\nWITH NO INJECTABLE DRUG. Compared with 613 patients treated without an injectable drug, 1,554 streptomycin-treated patients had increased treatment success (aOR, 1.5; 95% CI, 1.1-2.1). In the subgroup with quinolone resistance (17.8% of the total), streptomycin-treated patients had increased treatment success (aOR, 3.0; 95% CI, 1.3-6.6). Compared with 613 patients not treated with injectable drugs, 2,275 amikacin-treated patients had increased treatment success (aOR, 2.0; 95% CI, 1.5-2.6). In the subgroup with quinolone resistance, amikacin was also associated with increased treatment success (aOR, 3.0; 1.6-5.6). Among patients with XDR-TB, amikacin was associated with reduced deaths (aOR, 0.4; 95% CI, 0.2-0.8). In contrast, neither kanamycin nor capreomycin was associated with any benefit on treatment success or death versus no injectable drug at all. To the contrary, kanamycin treatment was associated with fewer treatment successes (aOR, 0.5; 95% CI, 0.4-0.6). Capreomycin was associated with an increased risk of death (aOR, 1.4; 95% CI, 1.1-1.7). In XDR-TB, capreomycin was associated with increased deaths (aOR, 3.4; 95% CI, 2.7-4.3) when compared with regimens with no injectable drug.\nIn a pediatric IPDMA, the use of second-line injectable agents (amikacin, kanamycin, capreomycin) in children with confirmed MDR-TB was associated with more treatment success compared with those not receiving second-line injectable agents (aOR, 2.94; 95% CI, 1.05-8.28; P = 0.041) (113). However, a high proportion of children with less-severe disease who received no second-line injectable agents still did well; therefore, children may be able to be spared from injectables and the associated toxicities if newer, more-effective drugs can be included in an all-oral regimen (113).\n# INJECTABLE DRUGS COMPARED AGAINST\nEACH OTHER. Compared with streptomycintreated patients, patients treated with amikacin had increased treatment successes (aOR, 1.7; 95% CI, 1.3-2.2) but with no significant impact on death (aOR, 1.0; 95% CI, 0.8-1.2). Kanamycin and capreomycin were both significantly inferior to streptomycin in every respect. Amikacin was superior to kanamycin and capreomycin in every respect, with higher treatment success rates, lower death rates, or both. In the quinolone-resistant subgroup, on the other hand, use of amikacin did not have a significant effect on treatment success (aOR, 1.7; 95% CI, 0.9-3.4) or death (aOR, 1.2; 95% CI, 0.7-2.0) compared with use of streptomycin.\nHarms. All aminoglycosides and capreomycin share important toxicities, especially nephrotoxicity, ototoxicity, and electrolyte disturbances, as well as other less common toxicities (155,162,177). The ototoxicity can be vestibular, resulting in loss of balance, or cochlear, resulting in hearing loss. Because these drugs date back to the early years of antibiotic discovery and development, there is vast published experience with their toxicities. In the treatment of MDR-TB, the risk of toxicity is substantial, because the duration of treatment is many months. Ototoxicity may be severe and irreversible but with close monitoring can be minimized or prevented. Nephrotoxicity is often reversible when identified early and addressed appropriately; however, ototoxicity can progress even after the drug is stopped. Monitoring (measuring drug levels; monthly high-quality audiometry, electrolytes, and serum creatinine) and skilled management can prevent or mitigate these effects and are part of standard practice for MDR-TB experts. Risk of hearing loss increases with increasing duration of treatment. For aminoglycosides in general, the estimated frequency of nephrotoxicity is 5% to 15% and of ototoxicity 2% to 14%, including 2% to 10% cochlear and 3% to 14% vestibular (155). In a survey of clinical trials performed between 1975 and 1982 and totaling z10,000 patients, the incidence of amikacin nephrotoxicity was 8.7% (178). Cumulative dose and duration predicted toxicity; older age, dehydration/hypovolemia/hypotension, prior aminoglycoside treatment, coexisting hepatic or renal disease, and concomitant medications were important as well (155). Significant hearing impairment exceeds 50% in some reported series, renal dysfunction approaches 50%, and vestibular dysfunction as high as 20% has been reported (155,162,177). At the other extreme, series have been published with no significant or permanent toxicity, including with longer-term use (155,162,177). Direct comparisons of drug toxicity for the four drugs used in TB are scarce. Experience suggests streptomycin may be more ototoxic, but that may be a consequence of far longer and wider use of streptomycin. Observational studies suggest amikacin may be more ototoxic than the other drugs (179)(180)(181).\nIn children, ototoxicity (hearing loss) has been documented in up to 24% of cases in a retrospective study, which also brings serious implications for development of normal speech (182). Pain of intramuscular injections can be safely reduced by adding lidocaine to amikacin injections without interference of pharmacokinetics (183). Dose range of amikacin should be 15 to 20 mg/kg as single daily dose.\nAdditional considerations. When injectables are used, serum creatinine, electrolyte measurements, clinical assessment for vertigo and tinnitus, highquality audiometry (including hearing frequency of 6,000-8,000 Hz, as highfrequency hearing loss is seen initially), and clinical examinations should be conducted at least monthly, or more frequently if adverse effects occur. Limited data suggest there may be a genetic predisposition for hearing loss associated with specific mitochondrial gene mutations (184). Although routine genetic testing is not currently suggested, the provider should be aware of these genetic mutations and the risks of ototoxicity (185,186). Because bactericidal activity is concentration dependent, high peak levels and single daily dosing are preferred to divided doses. Because of the postantibiotic effect, toxicity can be minimized by allowing trough levels between doses to remain below detectable levels for many hours. Some experts take advantage of these AMERICAN THORACIC SOCIETY DOCUMENTS pharmacokinetic and pharmacodynamic properties with thrice-weekly dosing, especially after conversion of cultures to negative, decreasing healthcare system demands and the requirement for daily injections (16,177). Intramuscular injections are painful, and 6 months of injections can be traumatic, especially to younger patients. Patients' values may differ sharply from providers in this respect and should be considered when determining whether to use injectable agents.\nConclusions. In our PS-matched IPDMA, the use of amikacin and streptomycin when the patient's isolate was susceptible to these drugs was associated with an increase in treatment success when compared with the control group not receiving these injectables. However, because of their toxicity and modest efficacy compared with other drugs, which also are less toxic, these drugs should be reserved for when more-effective or lesstoxic therapies cannot be assembled to achieve a total of five effective drugs. In our analyses, amikacin and streptomycin had similar aORs for treatment success in a minority of patients with fluoroquinolone resistance. Kanamycin and capreomycin were ineffective. We recommend against using kanamycin or capreomycin. As is the case for adults, the use of amikacin and streptomycin for children should also be reserved to when more-effective or less-toxic therapies cannot be assembled to achieve a total of five effective drugs.\nResearch needs. N-acetylcysteine, a thiol-containing antioxidant, may limit the severity and irreversibility of aminoglycoside-induced ototoxicity (187,188), warranting additional research into this and other otoprotective measures that may improve the balance of benefits and harms for using these injectable agents.\n# Linezolid\nLinezolid is an oxazolidinone antibiotic that inhibits bacterial protein synthesis by preventing the fusion of 30S and 50S ribosomal subunits (189). It also binds to human mitochondria and inhibits protein synthesis, which is the mechanism of toxicity in clinical use (190,191). Linezolid was initially used off-label in the absence of consistent scientific evidence as part of the regimen for difficult-to-treat cases of MDR-and XDR-TB (192). The first large retrospective observational study suggested linezolid was effective, but with frequent and often severe adverse events (192). The same study suggested, for the first time, that reducing the daily dose from 1,200 mg to 600 mg per day might be associated with fewer adverse events and improved tolerability. Several systematic reviews, IPDMAs, and one controlled clinical trial have been published on linezolid for treatment of MDR-TB (87,(193)(194)(195)(196). The clinical trial confirmed previous observational findings and, in particular, the effectiveness of linezolid and its potential toxicity (195). A meta-analysis with 121 cases of patients with MDR-TB from 11 countries, treated with linezolid, confirmed linezolid effectiveness (culture conversion, 93.5%; treatment success, 81.8%) and that the 600mg daily dose was safer than the 1,200-mg dose (46.7% adverse events vs. 74.5%, respectively) without lowering its effectiveness (196). The clinical trial confirmed the efficacy, safety, and tolerability of linezolid in patients with XDR-TB (194). There are insufficient data regarding the effectiveness of initiating treatment with doses ,600 mg daily to recommend lower doses. Recently, the importance of therapeutic drug monitoring to reduce adverse events potentially due to linezolid has been emphasized (197,198).\nSummary of the evidence. Linezolid was used in regimens for MDR-and XDR-TB across 38 studies (3). The initial dose of linezolid was 1,200 mg/d for 91 patients in five studies, 600 mg/d for 784 patients in 28 studies, and 300 mg/d for 99 patients in five studies (3). Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B.\nBenefits. In our PS-matched IPDMA, patients who received linezolid-containing regimens were more likely to achieve treatment success (aOR, 3.4; 95% CI, 2.6-4.5) and to have a lower rate of death (aOR, 0.3; 95% CI, 0.2-0.3) than those who did not receive linezolid. The effect on treatment success was more pronounced when studies from only high-income countries were included (aOR, 3.9; 95% CI, 2.6-5.8). The greatest impact was found in patients with XDR-TB, where the aOR for successful treatment versus failure or relapse was 6.3 (95% CI, 3.9-10.1) and the aOR for death was 0.1 (95% CI, 0.1-0.2). When PS-matched pairs analyses were performed comparing the effects of bedaquiline and linezolid with those of no bedaquiline or linezolid, the combination of bedaquiline and linezolid was associated with an aOR of 2.7 (95% CI, 1.5-4.9) for success versus failure/relapse, and of 0.3 (95% CI, 0.2-0.4) for death versus success/failure/relapse. The efficacy of linezolid in children with TB has been shown in two studies of children ,18 years of age, albeit with few patients (199,200).\nHarms. Adverse effects associated with linezolid in patients with TB include neurotoxicity (i.e., peripheral neuropathy and optic neuritis), myelosuppression, hyperlactatemia, and diarrhea, all of which are presumably secondary to the inhibition of mitochondrial protein synthesis (190,201). A published systematic review of 12 studies conducted in 11 countries globally reported an adverse event rate of 58.9% (hematological, neurological, and gastrointestinal), predominantly noted in individuals treated with a dosages .600 mg/d (196). Hematological toxicity can occur quickly after starting treatment and can involve any cell line. Neurotoxicity, including optic neuritis and peripheral neuropathy, occur later, usually after 12 to 20 weeks of treatment. Toxicity has been associated with trough levels of .2.0 PICO Question 14-Linezolid: In patients with MDR-TB, are outcomes safely improved when regimens include linezolid compared with regimens that do not include linezolid?\nRecommendation 14: We suggest including linezolid in a regimen for the treatment of patients with MDR-TB (conditional recommendation, very low certainty in the evidence). This is a conditional recommendation despite linezolid-containing regimens showing large reduction in mortality and improved treatment success, similar to bedaquiline and later-generation fluoroquinolones, because linezolid had more adverse effects and the balance of benefits and harms was less favorable compared with those drugs. (202)(203)(204). Adverse effects, especially myelosuppression, are also noted to be common at the currently recommended dose of 10 mg/kg twice daily in children ,10 years of age.\nAdditional considerations. Although use of linezolid for the FDA-approved 28 days or less for non-TB indications is associated with an acceptable adverse effect profile (205), the data on the longer-term use necessary for MDR-TB are limited (3,195,200). Strict clinical monitoring for potential toxicity (in particular peripheral neuropathy, optic neuritis, anemia, and leukopenia) is necessary because of the risk of adverse events associated with the longterm use of linezolid (16). If optic neuritis occurs, many patients may be rechallenged successfully with linezolid once vision normalizes. Assessment for visual toxicity must continue after restarting linezolid. Some patients are able to be rechallenged with the full dose; others are able to avoid recurrent visual toxicity with a reduced dose of linezolid at 300 mg daily (195). Linezolid should generally not be administered to patients taking serotonergic agents, such as monoamine oxidase inhibitors, because of the potential for serious CNS reactions, such as serotonin syndrome. Because monoamine oxidase type A deaminates serotonin, and selective serotonin reuptake inhibitors potentiate the action of serotonin by inhibiting its neuronal reuptake, administration of linezolid concurrently with a selective serotonin reuptake inhibitor can lead to serious reactions, such as serotonin syndrome or neuroleptic malignant syndrome-like reactions (16). One randomized clinical trial demonstrated that lowering the dose from 600 mg/d to 300 mg/d after culture conversion reduced toxicity (195). For children, one modeling study reported that linezolid dose of 15 mg/kg in full-term neonates and infants aged <3 months and 10 mg/kg in toddlers, administered once daily, achieved cumulative fraction of response of >90%, with ,10% achieving linezolid area under the concentration-versus-time curve (AUC) of 0 to 24 associated with toxicity (173). On the basis of modeling of pharmacokinetic data from 48 children, WHO and Sentinel Project recommend pediatric doses of linezolid as 15 mg/kg once daily for children ,15 kg and 10 to 12 mg/kg once daily for those weighing .15 kg (7,17). It is common practice for patients on linezolid to be prescribed vitamin B6 (16).\nConclusions. In our PS-matched IPDMA, patients who received linezolidcontaining regimens were more likely to achieve treatment success and to have a lower rate of death than those who did not receive linezolid. We suggest including linezolid in a regimen for the treatment of patients with MDR-TB. This is a conditional recommendation despite linezolid-containing regimens showing large reduction in mortality and improved treatment success, similar to bedaquiline and later-generation fluoroquinolones, because linezolid had more adverse effects and the balance of benefits and harms was less favorable compared with those drugs.\nResearch needs. Clinical trials of combinations of new chemical entities plus linezolid, including when administered at different doses and durations to optimize its therapeutic effect while minimizing toxicity are underway (Nix-TB, ClinicalTrials.gov Identifier: NCT02333799; ZeNix [Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants with Pulmonary TB, XDR-TB, Pre-XDR-TB or Non-responsive/Intolerant MDR-TB], NCT03086486). Further linezolid pharmacokinetic and safety data are needed to find optimal dosing in adults and children.\n# Macrolides: Azithromycin and Clarithromycin\nThe macrolides azithromycin and clarithromycin have unclear efficacy and role in the treatment of MDR-TB (23). Macrolides are commonly used to treat upper and lower respiratory tract infections and have an essential role in the treatment of nontuberculous mycobacteria (206). They are believed to have immunomodulatory and antiinflammatory effects. M. tuberculosis has intrinsic, inducible resistance to clarithromycin (207,208), and in vivo murine TB models confirm the lack of activity of macrolides (209). Clarithromycin may increase linezolid serum exposure when used in combination (210), prompting some consideration of potential synergy between macrolides and other MDR-TB drugs (211). WHO does not recommend use of macrolides to treat MDR-TB (23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PSmatched IPDMA, patients who received macrolides (n = 1,067) were more likely to have been treated with second-line drugs and to have resistance to fluoroquinolones or any PICO Question 15-Macrolides: In patients with MDR-TB, are outcomes safely improved when regimens include macrolides compared with regimens that do not include macrolides? Recommendation 15: We recommend NOT including the macrolides azithromycin and clarithromycin in a treatment regimen for patients with MDR-TB (strong recommendation, very low certainty in the evidence). Our recommendation against the use of the macrolides azithromycin and clarithromycin in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug class as having a notably unfavorable balance of benefits to potential harms.\nPICO Question 16-p-Aminosalicylic Acid: In patients with MDR-TB, are outcomes safely improved when regimens include p-aminosalicylic acid compared with regimens that do not include p-aminosalicylic acid? Recommendation 16: We suggest NOT including p-aminosalicylic acid in a treatment regimen for patients with MDR-TB (conditional recommendation, very low certainty in the evidence). When the individualized treatment regimen for patients with MDR-TB contains newer-generation, more-effective drugs, the addition of p-aminosalicylic acid does not appear to provide a benefit.\n# AMERICAN THORACIC SOCIETY DOCUMENTS\nsecond-line injectable (3). Patients who received macrolides were more likely to receive later-generation fluoroquinolones, capreomycin, and linezolid. In adjusted analyses, patients who received macrolides were less likely to achieve treatment success (aOR, 0.6; 95% CI, 0.5-0.8) and had a higher rate of death (aOR, 1.6, 95% CI, 1.2-2.0) than patients who did not receive macrolides.\nBenefits. The available evidence does not support the use of macrolides in the treatment of MDR-TB.\nHarms. In our PS-matched IPDMA, patients who received macrolides were less likely to achieve treatment success (aOR, 0.6; 95% CI, 0.5-0.8) and had a higher rate of death (aOR, 1.6; 95% CI, 1.2-2.0) than patients who did not receive macrolides.\nConclusions. Macrolides, specifically azithromycin or clarithromycin, should not be included in a regimen for the treatment of patients with MDR-TB. Our recommendation against the use of the macrolides azithromycin and clarithromycin in MDR-TB treatment is strong despite the evidence being judged to be of very low certainty because we viewed the increased mortality and decreased likelihood of treatment success associated with the use of this drug class as having a notably unfavorable balance of benefits to potential harms.\nResearch needs. Further research may be warranted on newer-generation macrolides and to elucidate if there is potential synergy of macrolides with linezolid or other second-line agents.\n# p-Aminosalicylic Acid\nOne of the first agents found to be effective against TB (212), p-aminosalicylic acid has been widely used clinically, although its precise mode of action remains uncertain (213). With the discovery of other more potent drugs, including rifampin, p-aminosalicylic acid, initially used combined with streptomycin, was no longer considered in first-line regimens. It is now used as part of a treatment regimen for MDR-and XDR-TB, although the benefits of p-aminosalicylic acid are not clear and toxicity limits its use. Current guidance recommends that p-aminosalicylic acid be used to compose a regimen when five effective drugs cannot otherwise be assembled (16,23).\nSummary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PS-matched IPDMA, p-aminosalicylic acid was not associated with any benefit on treatment success (aOR, 0.8; 95% CI, 0.7-1.0) and was associated with increased death (aOR, 1.2; 95% CI, 1.1-1.4) (3). The potential to cause adverse events (12.2% in a previous meta-analysis) has also limited the tolerability of p-aminosalicylic acid (23).\nBenefits. No association with any benefit on treatment success was identified for p-aminosalicylic acid in our PS-matched IPDMA. In an IPDMA of children with MDR-TB, there was no benefit identified for the inclusion of p-aminosalicylic acid in regimens (aOR, 0.75; 95% CI, 0.25-1.96; P = 0.483) (113).\nHarms. Gastrointestinal distress is common with p-aminosalicylic acid but reported to occur less with the PASER formulation than with older preparations (16). Rare hepatotoxicity and thrombocytopenia have been reported, as has reversible hypothyroidism, particularly when used concomitantly with ethionamide (120). In the setting of hypothyroidism, some experts provide thyroid replacement therapy rather than discontinuing p-aminosalicylic acid. Clinical experience has shown paminosalicylic acid to be better tolerated regarding gastrointestinal disturbance in children than in adults, although hypothyroidism also remains common in children.\nAdditional considerations. Indirect comparison suggests that ethionamide may be better than p-aminosalicylic acid if a fifth drug is needed to construct a regimen with at least five effective drugs. Old studies have shown p-aminosalicylic acid to be a good companion drug to protect other drugs from developing resistance and also have shown efficacy in combination with first-line drugs (214,215). It has recently been suggested by pediatric DR-TB experts that in children p-aminosalicylic acid may replace an injectable agent in the absence of better drugs (83). When p-aminosalicylic acid is used, experts recommend monitoring thyroid-stimulating hormone, electrolytes, blood counts, and liver function tests.\nConclusions. When the individualized treatment regimen for patients with MDR-TB contains newer-generation, more-effective drugs, the addition of p-aminosalicylic acid does not appear to provide benefit.\nResearch needs. Given the limited armament of TB drugs available for treating MDR-TB, some experts have advocated for the evaluation of doseoptimized p-aminosalicylic acid to improve efficacy while minimizing toxicity (216). Research on whether p-aminosalicylic acid, among other agents, may offer protection against the acquisition of resistance to other drugs in the regimen would also be valuable.\n# Pyrazinamide\nPyrazinamide, a nicotinamide analog, is a prodrug that is converted in vivo into pyrazinoic acid, which interferes with mycobacterial fatty acid synthase. Pyrazinamide has demonstrated effectiveness against M. tuberculosis; it is included in standard regimens for treatment of drug-susceptible TB and also used in regimens for MDR-TB (11,16,23). However, recent population-based studies conducted as part of multicountry surveillance activities have shown that pyrazinamide resistance is highly associated with rifampin resistance (217,218). This finding, in conjunction with evidence that pyrazinamide efficacy is reduced in the setting of pncA gene mutations (219)(220)(221)(222), underscores the importance of documenting drug susceptibility to pyrazinamide by WGS, molecular tests, or traditional DST, if the drug is to be included as part of a regimen for MDR-TB. \n# AMERICAN THORACIC SOCIETY DOCUMENTS\nPyrazinamide has been demonstrated to have substantial sterilizing activity as part of combination regimens and has allowed for treatment shortening in drugsusceptible TB (223,224). Higher doses have been shown to be more effective in animal models and phase 2A studies, but doses of 40 to 70 mg/kg were found to be too toxic to be pursued further in human studies (224). Summary of the evidence. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. Our PS-matched IPDMA compared outcomes in 1,986 individuals with isolates susceptible to pyrazinamide who received the drug with 307 individuals with isolates susceptible to pyrazinamide who did not receive the drug (3). However, the groups were not balanced with regard to other effective drugs; in particular, the patients not receiving pyrazinamide were more likely to receive linezolid and a latergeneration fluoroquinolone. Thus, the ability to detect an effect of pyrazinamide might have been partially obscured. In a previous IPDMA, before linezolid and bedaquiline were more commonly used, administration of pyrazinamide among patients with susceptible isolates was associated with an aOR of 1.9 (95% CI, 1.3-2.9) for cure/complete versus failure/relapse and an aOR of 1.6 (95% CI, 1.3-2.1) for cure/complete versus failure/relapse/death, compared with patients receiving pyrazinamide whose isolates were resistant in vitro (6).\nBenefits. In our PS-matched IPDMA, treatment success was significantly less likely with regimens containing pyrazinamide (aOR, 0.7; 95% CI, 0.5-0.9), but death was also significantly less frequent (aOR, 0.7; 95% CI, 0.6-0.8). This paradox may be due to confounding in our PS-matched IPDMA, as patients who did not receive pyrazinamide were substantially more likely to receive linezolid. Moreover, our PS-matched IPDMA did not assess the potential ability of pyrazinamide to Levofloxacin doses of up to 1,250 mg have been used safely when needed to achieve therapeutic concentrations. A recent population pharmacokinetic study in South African children found that higher levofloxacin doses from 18 mg/kg/d for younger children, up to 40 mg/kg/d for older children, may be required to achieve adult-equivalent exposures (170). ‡ Higher moxifloxacin doses have been used safely when the isolate is resistant to ofloxacin and the minimum inhibitory concentration for levofloxacin or moxifloxacin suggests higher doses may overcome resistance. Higher doses also are used in cases of malabsorption.\nx Cycloserine doses can be divided if needed (typically twice daily). Doses .750 mg are difficult for many patients to tolerate. jj Cycloserine dose may be lowered if serum concentrations exceed 35 mg/ml, even if patient is not experiencing toxicity, to prevent central nervous system toxicity. ¶ Modified from adult intermittent dose of 25 mg/kg, and accounting for larger total body water content and faster clearance of injectable drugs in most children. Dosing can be guided by serum concentrations. **Ethionamide can be given at bedtime or with a meal to reduce nausea. Experienced clinicians suggest starting with 250 mg once daily and gradually increasing the dose over 1 week. Serum concentrations may be useful in determining the appropriate dose. Few patients tolerate 500 mg twice daily. † † Studies are ongoing evaluating meropenem at higher doses (ClinicalTrials.gov identifiers: NCT03174184 and NCT02349841). ‡ ‡ Some experts prescribe p-aminosalicylic acid at 6 g, and up to12 g, administered once daily (16,216).\nxx For children, some experts prescribe p-aminosalicylic acid at 200 mg/kg administered once daily (216). jjjj Isoniazid is tested at two concentrations. Some experts use these results (or resistance conferred through mutations in inhA) to select a higher dose when it tests resistant at the lower concentration and susceptible at the higher concentration. The higher dose may achieve in vivo concentrations sufficiently high to overcome low-level resistance (16,216).\nAMERICAN THORACIC SOCIETY DOCUMENTS e120 contribute to treatment shortening, as has been achieved in drug-susceptible TB. Because pyrazinamide is associated with increased success only when used to treat patients whose isolates are susceptible to the drug (144), whenever feasible, the decision to include pyrazinamide in a regimen should be based on pyrazinamide susceptibility results.\nIn an IPDMA of children with MDR-TB, the addition of pyrazinamide to a regimen showed no benefit in the treatment of confirmed MDR-TB cases (aOR, 1.63; 95% CI, 0.41-6.56; P = 0.484) (113). Pyrazinamide resistance was, however, not tested and improved selection of cases on the basis of resistance might change this outcome.\nHarms. Pyrazinamide has been used extensively in the treatment of TB, and toxicities are well documented (225). The most common is gastrointestinal upset or intolerance. In a recent review of the tolerability of TB drugs, pyrazinamide was associated with serious adverse events in 56 of 2,023 (2.8%) patients (226). This is consistent with previous reports of pyrazinamide toxicity (11,225,227). Hepatic enzyme elevations are common with pyrazinamide, and significant hepatotoxicity, although less common, can occur. Modest elevated serum uric acid levels are also expected, although the clinical significance of this is unclear. Nongouty polyarthralgias and hypersensitivity reactions can occur. Flares of clinical gout can also occur, especially in those with a history of prior gouty arthritis.\nAdditional considerations. All patients receiving pyrazinamide as part of an MDR-TB treatment regimen should be monitored carefully for signs or symptoms of hepatotoxicity and have their pyrazinamide dose held or decreased if such toxicity is detected. Isolated increases in uric acid without symptoms of gout are common and are not an indication to discontinue the drug. Recent population-based studies have found that pyrazinamide resistance is common in the setting of MDR with some regional variability, suggesting that pyrazinamide susceptibility should be confirmed or suspected if the drug is included in the regimen (217,228,229). Although there are known challenges related to accurately determining phenotypic DST for pyrazinamide, recent highly predictive DNA sequencing techniques show significant promise for newer genomic approaches (230).\nWhen included in the regimen, most experts use doses of 25 to 40 mg/kg/d orally. The recommended dose of pyrazinamide in children is 30 to 40 mg/kg daily.\nConclusions. We suggest including pyrazinamide in a regimen for the treatment of patients with MDR-TB, when the M. tuberculosis isolate has not been found resistant to pyrazinamide.\nResearch needs. Pyrazinamide is being evaluated as part of novel treatment regimens for both DS and MDR-TB in multiple clinical trials (56). Development of a reliable, simple molecular test for pyrazinamide susceptibility is a critically important research need. Dose optimization studies for pyrazinamide are warranted, as higher doses may be more efficacious but also may be more toxic.\n# Building a Treatment Regimen for MDR-TB\nThe guideline committee proposes a clinical strategy tool for building a treatment regimen for MDR-TB (Table 10). The clinical strategy tool incorporates the evidence-based review of the individual drugs, with consideration of the balance of benefits and harms for each drug, the experience of MDR-TB experts on the committee, as well as perspectives of patients. This clinical strategy tool encourages the building of all oral regimens with five effective drugs (to which the isolate is susceptible or has low likelihood of resistance) for the treatment of MDR-TB. In our PS-matched IPDMA, significant favorable synergies were identified with improved treatment success and reduced mortality when bedaquiline was used in combination with linezolid or clofazimine. As noted, amikacin and streptomycin show modest effectiveness when the patient's isolate is susceptible to these drugs; however, because of their significant toxicities, aminoglycosides should be reserved for when a more-effective or lesstoxic regimen cannot otherwise be assembled. The final choice of drugs and drug classes is contingent on many factors, including patient preferences, harms and benefits associated with agents, the capacity to appropriately monitor for significant adverse effects, consideration of drug-drug interactions, comorbidities, and drug availability. Final regimen development, therefore, is individualized and may differ substantially from the approach described in Table 10. Doses of the drugs for treating adults and children with MDR-TB are provided in Table 9, modified and updated from the 2016 ATS/CDC/IDSA Treatment of Drug-Susceptible TB Practice Guidelines (11).\n# Role of Therapeutic Drug Monitoring in Treatment of MDR-TB\nSpecific pharmacokinetic (PK)/ pharmacodynamic (PD) targets, especially the AUC divided by the MIC over 24 hours (AUC 0-24 /MIC), are being recognized as playing an important role in determining efficacy (231). This has been demonstrated most clearly in hollow fiber systems in vitro that isolate the activity of the drug against the organism (232,233). Further evidence has been provided by animal models (mouse, rabbit, nonhuman primates) and through human clinical trials (234)(235)(236)(237). Drug levels are usually chosen to be four to five times greater than the MIC. Because of the complexities of clinical disease, it is more challenging to isolate the PK/PD contribution of individual drugs, but studies have nonetheless been informative on the relationships between efficacy and drug exposure (238)(239)(240). In human TB, a combination of drugs is used, and each patient has his or her unique duration of disease, host genetics, and particular strain of M. tuberculosis. The general term for these PK/PD data is \"exposure-response\" data (i.e., for a given amount of drug exposure, how much response can you expect?). Much of the published data focus on the first-line TB drugs, with some emerging data becoming available for second-line drugs (241)(242)(243).\nIn clinical practice, the actual MIC for each drug often is not available. Epidemiological cut-off values or \"critical concentrations\" that separate wild-type from more resistant isolates can be used for selecting what drugs to include in a regimen (244). These in vitro cut-offs are based on patterns of susceptibility compared with achievable concentrations within humans. An organism is not just \"susceptible\" as an inherent property; it is susceptible to inhibition or killing by specific, tested concentrations of the AMERICAN THORACIC SOCIETY DOCUMENTS drugs. Individual MIC values might be preferred; however, in practice, there are technical and financial barriers to such individualized data. Following standardized dosing, clinical experience over the past 3 decades clearly shows that some patients have low drug concentrations, leading to clinical failures (11,231,241,242,244).\nMany MDR-TB experts use therapeutic drug monitoring (TDM) to identify patients with problems with drug absorption, thereby informing dose adjustments.\nIndividuals who have poor response to TB treatment despite adherence may benefit from TDM (11). Patients with TB with gastrointestinal problems that increase risk of malabsorption, concurrent HIV infection, impaired renal clearance, or diabetes should be prioritized for TDM (11). Furthermore, some experts use TDM for all patients being treated for MDR or XDR-TB early in treatment, rather than waiting for a poor response. TDM should be used and interpreted in consultation with an expert in MDR-TB.\nTDM also provides patient-specific information that may help limit toxicity due to certain drugs, including the injectable drugs cycloserine and linezolid (245)(246)(247). In particular, linezolid toxicity is associated with elevated trough values (202)(203)(204). \"Target\" ranges for the injectable drugs and cycloserine have been proposed, and research continues on refining these. Fluoroquinolones display concentrationdependent efficacy, and higher doses of moxifloxacin and levofloxacin are being studied (174,248). Currently, Table 10. Clinical Strategy to Build an Individualized Treatment Regimen for MDR-TB d Build a regimen using five or more drugs to which the isolate is susceptible (or has low likelihood of resistance), preferably with drugs that have not been used to treat the patient previously. d Choice of drugs is contingent on capacity to appropriately monitor for significant adverse effects, patient comorbidities, and preferences/values (choices therefore subject to program and patient safety limitations). d In children with TB disease who are contacts of infectious MDR-TB source cases, the source case's isolate DST result should be used if an isolate is not obtained from the child. d TB expert medical consultation is recommended (ungraded good practice statement).\nStep 1: Choose one later-generation fluoroquinolone Levofloxacin Moxifloxacin\nStep 2: Choose both of these prioritized drugs Bedaquiline Linezolid\nStep 3: Choose both of these prioritized drugs Clofazimine Cycloserine/terizidone\nStep 4: If a regimen cannot be assembled with five effective oral drugs, and the isolate is susceptible, use one of these injectable agents* Amikacin Streptomycin\nStep 5: If needed or if oral agents preferred over injectable agents in Step 4, use the following drugs † Delamanid ‡ Pyrazinamide Ethambutol\nStep 6: If limited options and cannot assemble a regimen of five effective drugs, consider use of the following drugs Ethionamide or prothionamide x Imipenem-cilastatin/clavulanate or meropenem/clavulanate jj p-Aminosalicylic acid ¶ High-dose isoniazid**\nThe following drugs are no longer recommended for inclusion in MDR-TB regimens:\nCapreomycin and kanamycin Amoxicillin/clavulanate (when used without a carbapenem) Azithromycin and clarithromycin Definition of abbreviations: DST = drug susceptibility testing; INH = isoniazid; IPDMA = individual patient data meta-analyses; MDR = multidrug-resistant; PS = propensity score; TB = tuberculosis. *Amikacin and streptomycin should be used only when the patient's isolate is susceptible to these drugs. Because of their toxicity, these drugs should be reserved for when more-effective or less-toxic therapies cannot be assembled to achieve a total of five effective drugs. † Patient preferences in terms of the harms and benefits associated with injectables (the use of which is no longer obligatory), the capacity to appropriately monitor for significant adverse effects, consideration of drug-drug interactions, and patient comorbidities should be considered in selecting Step 5 agents over injectables. Ethambutol and pyrazinamide had mixed/marginal performance on outcomes assessed in our PS-matched IPDMA; however, some experts may prefer these drugs over injectable agents to build a regimen of at least five effective oral drugs. Use pyrazinamide and ethambutol only when the isolate is documented as susceptible. ‡ Data on dosing and safety of delamanid are available in children >3 years of age.\nx Mutations in the inhA region of the Mycobacterium tuberculosis genome can confer resistance to ethionamide/prothionamide as well as to INH. In this situation, ethionamide/prothionamide may not be a good choice unless the isolate is shown to be susceptible with in vitro testing. jj Divided daily intravenous dosing limits feasibility. Optimal duration of use not defined. ¶ Fair/poor tolerability and low performance. Adverse effects reported to be less common in children. **Data not reviewed in our PS-matched IPDMA, but high-dose isoniazid can be considered despite low-level isoniazid resistance but not with high-level INH resistance.\nAMERICAN THORACIC SOCIETY DOCUMENTS e122 avoiding low serum concentrations seems advisable.\nA common clinical practice is to collect samples at 2 and 6 hours after drug administration to measure concentrations that may distinguish normal drug absorption (a 2-h value within the normal range) from delayed absorption (a 6-h value greater than the 2-h value, approaching the normal range) and malabsorption (both values are below the normal range). This approach also works for injectable drugs. Furthermore, trough values for linezolid can be helpful (11,231,241,242,244). Although it is clearly possible to cure patients without TDM and even in the setting of lower serum drug concentrations, the available data suggest that the probability of cure decreases with decreasing drug concentrations (231)(232)(233)(234)(235)(236)(237)(238)(239)(240)(241). Given the incomplete information currently available, many expert clinicians use in vitro susceptibility data and TDM as available tools for optimizing the treatment of patients with MDR-and XDR-TB. For all patients, but in particular those receiving outpatient treatment, TDM should be coordinated and conducted using patientcentered approaches.\nShorter-Course, Standardized, 9-to 12-Month Regimen for MDR-TB A randomized, phase 3, noninferiority trial, STREAM Stage 1 (ClinicalTrials.gov identifier: NCT02409290) was recently conducted to assess a shorter-course regimen composed of existing drugs for MDR-TB (8). This regimen had achieved success rates of 83% (95% CI, 71.0-90.3%) in cohort studies (249,250). The shortercourse regimen is standardized and composed of kanamycin, moxifloxacin (in place of gatifloxacin, which was the fluoroquinolone originally used in the \"Bangladesh\" regimen), prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol for an initial period (4-6 mo) and moxifloxacin, clofazimine, pyrazinamide, and ethambutol for the continuation phase (5 mo) (23). The total duration of therapy is between 9 and 11 months, compared with an individualized regimen of 18 to 24 months of therapy. The medication costs of the shorter regimen are believed to be less than that of conventional regimens, currently undergoing a formal economic evaluation as part of the STREAM trials (251).\n# Summary of the Evidence\nIn the STREAM Stage 1 clinical trial, of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population (8). Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group-a difference, with adjustment for HIV status, of 1.0 percentage point (95% CI, 27.5 to 9.5). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population. Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. In our PS-matched IPDMA of 12,030 patients (n = 50 studies), 169 (n = 33 studies) were eligible for analysis of death and 1,369 (n = 33 studies) were eligible for analysis of treatment success (249) once the criteria used for the shorter-course regimen were applied (249). There were data from 532 individuals (n = 3 studies) on the shorter regimen available for analysis of death and 498 (n = 3 studies) for analysis of treatment success. After using PS matching to adjust for age, sex, HIV, smear status, past TB treatment with first-line drugs, and number of effective drugs, there were no statistically significant associations for the shorter regimen with treatment success (aOR, 0.5; 95% CI, 0.02-13), or deaths (aOR, 1.7; 95% CI, 0.6-4.6), compared with individualized regimens.\n# Benefits\nThe shorter regimen allows for a significantly shorter duration of therapy compared with the individualized regimen and consequently less pill burden, medication cost, and associated provider administration costs. The burden on patients of lost productivity or lost wages and out-of-pocket costs is considerably less with a shorter regimen. From preliminary results of the STREAM Stage 1 trial, there was a documented reduction in costs to patients due to less time away from work, fewer clinic visits, and less spending on supplementary food (252).\n# Harms\nIn the STREAM Stage 1 clinical trial, an adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group (8). Prolongation of either the QT interval or the QTc to 500 milliseconds occurred in 11.0% of participants in the short-regimen group, compared with 6.4% in the long-regimen group (P = 0.14). Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. Among the participants who had HIV coinfection at baseline, 18 of 103 (17.5%) in the short-regimen group died, compared with 4 of 50 (8.0%) in the PICO Question 18-Shorter-course, standardized regimen: In patients with MDR-TB, does treatment with a standardized MDR-TB regimen for <12 months lead to better outcomes than treatment with an MDR-TB regimen for 18-24 months? Recommendation 18: The shorter-course regimen is standardized with the use of kanamycin (which the committee recommends against using) and includes drugs for which there is documented or high likelihood of resistance (e.g., isoniazid, ethionamide, pyrazinamide). Although the STREAM Stage 1 randomized trial found the shorter-course regimen to be noninferior to longer injectable-containing regimens with respect to the primary efficacy outcome (8), the guideline committee cannot make a recommendation either for or against this standardized shorter-course regimen, compared with longer individualized all-oral regimens that can be composed in accordance with the recommendations in this practice guideline. We make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is documented or highly likely.\nAMERICAN THORACIC SOCIETY DOCUMENTS long-regimen group (HR in a post hoc analysis, 2.23; 95% CI, 0.76-6.60) (8). Similarly, in a recently published IPDMA, a greater proportion of individuals who received the shorter regimen had less treatment success and more death (249). In the IPDMA, other adverse effects were also statistically insignificant with the shorter regimen, including deafness and ototoxicity (relative risk, 1.5; 95% CI, 0.6-4.0), liver injury (relative risk, 2.2; 95% CI, 0.5-10.3), hepatitis (relative risk, 2.5; 95% CI, 0.3-21.2), and renal impairment (relative risk, 4.5; 95% CI, 0.6-35.2). One of the most concerning adverse effects of the shorter regimen is hearing loss, with 7.1% reported in the African study and between 0% and 23% in the meta-analysis (249,250). The STREAM Stage 1 trial found that ear and labyrinth disorders occurred in 7.4% participants on the shorter regimen, compared with 5.7% with the longer regimen, which was not statistically significant (8); the frequency may have been lower than in cohort studies because hearing loss was not monitored by audiometry in STREAM Stage 1.\n# Additional Considerations\nWhen applying the eligibility criteria from WHO for using the shorter-course, standardized regimen to the population included in our PS-matched IPDMA (7,253), .15% of individuals would have been eligible for the standardized, shorter regimen. In Europe, patient eligibility for the shorter-course regimen has ranged from 7.9% (48 of 612 new cases) in a study performed at TB reference centers (254) to 16.9% in a surveillance-based study performed by the European Centre for Disease Prevention and Control (ECDC) (93,107,255). In the United States, .15% of patients with MDR-TB would be eligible for the shorter-course MDR-TB regimen (256). Data from California showed either 14.6% or 20.5% eligibility, based on whether high-dose isoniazid or ethionamide would be determined effective on the basis of genetic katG or inhA mutations, respectively (257). The availability of molecular and growth-based DST is key to determining the potential eligibility of shorter-course regimen use. The combined use of both modalities can better inform drug resistance and potential treatment regimens. High-dose isoniazid is likely to be active against organisms with low-level isoniazid resistance, commonly associated with a mutation in the inhA gene that also confers resistance to ethionamide (257). Ethionamide is more likely to be active against M. tuberculosis organisms with high-level resistance to isoniazid, associated with a mutation in katG and which are less commonly resistant to ethionamide (257). Global data have shown that katG is present in 64.3% of the cases tested and inhA in 19.2%, with some regional differences (258). The shorter regimen includes both ethionamide and high-dose isoniazid and therefore is likely to be effective against both of these common MDR-TB resistance patterns (257,259). There is uncertainty regarding the diagnostic accuracy and reproducibility of ethambutol and pyrazinamide growthbased DST assays (260). For ethambutol, the ECDC has reported that the growth-based DST when performed on Mycobacteria Growth Indicator Tube (MGIT) is reliable (107), whereas Model Performance Evaluation Program data have identified variability in detecting ethambutol resistance, with the majority of laboratories having disagreement on one to several strains with ethambutol resistance (261). Alternatively, molecular testing for pncA mutations as a method for determining pyrazinamide resistance may be more reliable, because on average 85% of TB strains resistant to pyrazinamide will have such a mutation (217,221,222). In limited-resourced settings, testing all the drugs composing the shorter-course regimen may not be possible (106,108). In contrast, in Europe, DST for ethambutol (93,107) and pyrazinamide ( 106) is well studied, but katG and inhA genetic mutations are not. In the United States, growth-based DST data are available for ethambutol, pyrazinamide, high-and lowlevel isoniazid, and ethionamide, and molecular testing is available through some state public health laboratories and through the CDC's MDDR service (257). Therefore, considering patients with either katG or inhA (but not both) mutations to be eligible for the shorter regimen might be rational. Last, the rate of cross-resistance between ofloxacin and moxifloxacin is likely not complete. Data from the ECDC showed that 81% of M. tuberculosis isolates that were resistant to ofloxacin were also resistant to moxifloxacin. However, other settings (e.g., Bangladesh and Pakistan) have shown cross-resistance as low as 7% (107).\n# Conclusions\nThe shorter-course regimen was judged by the guidelines committee to have minimal desirable effects (on treatment success, mortality, and culture conversions) and small to moderate undesirable effects (adverse events, limited applicability, and the use of kanamycin as part of the standardized regimen), and includes drugs for which there is documented or high likelihood of resistance (e.g., isoniazid, ethionamide, and pyrazinamide). Although the WHO's STREAM Stage 1 randomized trial found the shorter-course regimen to be noninferior to a long regimen with respect to the primary efficacy outcome (8), the guideline committee cannot make a recommendation either for or against this standardized shorter-course regimen compared PICO Question 19-Surgery for MDR-TB: Should elective lung resection surgery (i.e., lobectomy or pneumonectomy) be used as an adjunctive therapeutic option in combination with antimicrobial therapy, versus medical therapy alone, for adults with MDR-TB? Recommendation 19a: We suggest elective partial lung resection (e.g., lobectomy or wedge resection), rather than medical therapy alone, for adults with MDR-TB receiving antimicrobial-based therapy (conditional recommendation, very low certainty in the evidence). The writing committee believes this option would be beneficial for patients for whom clinical judgement, supported by bacteriological and radiographic data, suggests a strong risk of treatment failure or relapse with medical therapy alone.\nRecommendation 19b: We suggest medical therapy alone, rather than including elective total lung resection (pneumonectomy), for adults with MDR-TB receiving antimicrobial therapy (conditional recommendation, very low certainty in the evidence).\nwith longer individualized regimens. We instead make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is confirmed or deemed to be highly likely. If this shorter-course regimen is used, we recommend obtaining DST for all medications in the regimen, with the exception of clofazimine, for which reliable testing is not available, and recommend careful side effect monitoring, including high-quality audiometry, monthly microbiologic monitoring, and close case management, especially in persons with HIV.\n# Research Needs\nWe make a research recommendation for the conduct of randomized clinical trials evaluating the efficacy, safety, and tolerability of modified shorter-course regimens that include newer oral agents, exclude injectables, and include drugs for which susceptibility is confirmed or deemed to be highly likely. Further research is needed on medications such as linezolid, bedaquiline, and other medications currently in clinical trials as substitutions in the regimen if patients experience adverse effects or resistance develops to any of the medications in the regimen (262). Research on modified shorter-course regimens for pediatric patients and in individuals living with HIV is also needed. Until more data regarding the use and outcomes of the shorter-course regimens in patients with HIV are available, this treatment approach should preferentially be considered only within a research study. Current trials are underway to help answer some these questions (262).\n# Role of Surgery in MDR-TB\nSurgery was one of the first therapeutic approaches for treating TB. It was replaced by chemotherapy between 1960 and 1975. However, several scientific societies and national and international organizations suggest consideration of surgery as an adjunctive therapy for MDR-TB. This is based on the results of observational retrospective studies. Selected indications are highlighted, including failure of drug therapy, relapse, localized (e.g., an isolated cavity) or extensive pulmonary TB, and clinical complications (e.g., hemoptysis or empyema) (23,(263)(264)(265)(266)(267)(268)(269)(270).\n# Summary of the Evidence\nSystematic reviews and meta-analyses have been performed on the role of surgery in patients with MDR-and XDR-TB (263,271,272). The main limitation of systematic reviews of surgery in MDR and XDR-TB that summarize results of observational studies combining study-level data is the tremendous variability in patient characteristics, background chemotherapy regimens, and types of surgical procedures (263,271,272). An IPDMA of surgery in MDR-TB was designed to address those shortcomings (271). Procedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B.\nThe IPDMA identified 67 cohort studies, of which 45 could not be used because either individual patient data were not available or the surgical status of patients was not known. Twenty-six studies comprising 6,431 patients with MDR-TB were included (271). We used data from this IPDMA to generate the evidence profiles. Despite the analytic advantages of an IPDMA, which allows for adjustment on baseline imbalance in many prognostic factors, there was a substantial residual risk of bias in the results. There is no information about the impact of surgery on adverse effects or quality of life.\n# Benefits\nPatients with partial lung resection had a higher probability of treatment success, as opposed to treatment failure, relapse, or death (aOR, 3.0; 95% CI, 1.5-5.9). However, the estimate is very uncertain because of the limitations of individual studies and lack of precision in results.\n# Harms\nIn the published IPDMA, a substantially higher proportion of patients who had a pneumonectomy died (8.5%) compared with those who had a partial resection (2.2%), but the authors could not establish whether patients died as a result of surgical complications or of their TB (271). The estimates of the effects of pneumonectomy on risk of death (aOR, 1.8; 95% CI, 0.6-5.1) and treatment success (aOR, 0.8; 95% CI, 0.1-6.0) were not statistically significant. As for partial lung resection, both estimates are very uncertain. Treatment success in patients with XDR-TB was noted to be lower when patients underwent surgery compared with patients who did not (aOR, PICO Question 20-Treatment of isoniazid-resistant TB: PICO Question 20a: Should patients with isoniazid-resistant TB be treated with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 months compared with rifampin, ethambutol, and pyrazinamide (without a fluoroquinolone) for 6 months? PICO Question 20b: Should patients with isoniazid-resistant TB be treated with a regimen composed of fluoroquinolone, rifampin, and ethambutol for 6 months and pyrazinamide for the first 2 months compared with a regimen composed of a fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 months? Recommendation 20a: We suggest adding a later-generation fluoroquinolone to a 6-month regimen of daily rifampin, ethambutol, and pyrazinamide for patients with isoniazid-resistant TB (conditional recommendation, very low certainty in the evidence).\n# Recommendation 20b:\nIn patients with isoniazid-resistant TB treated with a daily regimen of a later-generation fluoroquinolone, rifampin, ethambutol, and pyrazinamide, we suggest that the duration of pyrazinamide can be shortened to 2 months in selected situations (i.e., noncavitary and lower-burden disease or toxicity from pyrazinamide) (conditional recommendation, very low certainty in the evidence).\nAMERICAN THORACIC SOCIETY DOCUMENTS 0.4; 95% CI, 0.2-0.9), an effect that was heterogeneous across studies and may also be confounded by factors that predisposed to poor outcomes in these patients (271). Alternatively, patients who were healthy enough to withstand surgery may have intrinsically lower mortality, so it is difficult to predict the direction of potential bias.\n# Additional Considerations\nIn the MDR-TB treatment guidelines updated in 2016, WHO recommended elective partial surgery as an intervention complementary to chemotherapy in specifically selected individuals (23). The committee acknowledged there is significant uncertainty, with a paucity of publications and data regarding patient preferences, acceptability by surgical personnel, cost, and feasibility of performing elective surgery as an intervention for MDR-TB.\n# Conclusions\nOn the basis of the limited evidence that is available, there appears to be a net benefit from an elective partial lung resection (e.g., lobectomy or wedge resection) when offered together with a recommended MDR-TB regimen, compared with medical therapy alone. Committee members believed that this therapeutic option would probably be more beneficial when clinical judgement, supported by bacteriological and radiographic data, suggests a strong risk of relapse or treatment failure with medical regimen alone. We found no currently available evidence that pneumonectomy would be beneficial for patients with MDR TB receiving a background drug regimen.\n# Research Needs\nRigorously designed and conducted studies, ideally well-done randomized trials that measure and report benefits but also adverse effects and quality of life, are needed to clarify the role of surgery in the management of patients with MDR-TB. The following specific issues need to be addressed: the optimal timing for surgery, the optimal drug regimens and their duration before and after surgery, the role of surgery in special populations and patients with comorbid conditions (e.g., those living with HIV), the optimal surgical approaches, the optimal infection control measures to be implemented perioperatively, and the role of pulmonary rehabilitation (263,267,270,273).\n# Treatment of Isoniazid-Resistant TB\nIsoniazid is an important first-line agent for the treatment of TB, possessing potent early bactericidal activity against M. tuberculosis. However, monoresistance to isoniazid is frequent worldwide, with an estimated prevalence of 8% (range, 5-11%) of TB cases (12). A recent systematic review and metaanalysis compared the treatment outcomes of isoniazid-resistant TB to outcomes of drugsusceptible TB and found that treatment of isoniazid-resistant TB with first-line drugs resulted in suboptimal outcomes, with higher treatment failure (11% vs. 1%) and relapse (10% vs. 5%) (274). In addition, the study found that standardized empirical treatment of new isoniazid-resistant TB cases may be contributing to higher rates of acquired drug resistance (8% vs. 0.3%). Prior ATS, CDC, and IDSA guidelines recommended treatment with a standard four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) for 6 months, with discontinuation of isoniazid after the results of DST are known and if isoniazid resistance was found (275).\n# Summary of the Evidence\nProcedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. An IPDMA of 33 datasets with 6,424 patients, of whom 3,923 patients in 23 studies received regimens related to isoniazid-resistant TB, was used as the evidence (276). Regimens of interest for our analyses (all with or without isoniazid) were 1) rifampin, ethambutol, and pyrazinamide; and 2) rifampin, ethambutol, and pyrazinamide, plus a fluoroquinolone. For these analyses, isoniazid-resistant TB was defined based on phenotypic resistance to isoniazid and susceptibility to rifampicin, with or without additional resistance to pyrazinamide, ethambutol, or streptomycin. Critical concentrations of 0.1 mg/ml or 0.2 mg/ml were used in 21 out of 23 centers for the definition of resistance to isoniazid (276). For PICO Question 20a, we found few studies that used regimens of 6 months of rifampin, ethambutol, and pyrazinamide, plus a fluoroquinolone, but several that used regimens of 8 to 9 months of this regimen; hence, we combined 6 with .6 months for this PICO. For the comparator of rifampin, ethambutol, pyrazinamide with or without isoniazid, we similarly combined regimens of 6 and .6 months' duration regimens, after comparison between these durations showed outcomes were not significantly different. For PICO Question 20b, few patients received regimens that had a fluoroquinolone, rifampin, ethambutol, and a shorter duration of pyrazinamide. A total of 118 patients received 1 to 3 months of pyrazinamide in conjunction with 6 and .6 months' durations of rifampin, ethambutol, and fluoroquinolone-containing regimen and were available for analyses.\n# Benefits\nCompared with 6 months of daily rifampin, ethambutol, and pyrazinamide (with or without isoniazid), adding a fluoroquinolone to this regimen was associated with significantly greater treatment success (aOR, 2.8; 95% CI, 1.1-7.3) but with no significant effect on mortality (aOR, 0.7; 95% CI, 0.4-1.1) or acquired rifampicin resistance (aOR, 0.1; 95% CI, 0.0-1.2). When evaluating the impact of shortening the duration of pyrazinamide (ranging from 1-3 mo) in a regimen that contains a fluoroquinolone, the treatment success was very high, with 117 of 118 patients achieving treatment success. On the other hand, comparisons of shorter pyrazinamide regimens to regimens including both a fluoroquinolone and pyrazinamide for >6 months did not show significantly different results (aOR, 5.2; 95% CI, 0.6-46.7). Similar results were obtained when the comparisons were restricted to patients receiving latergeneration fluoroquinolones, namely moxifloxacin, levofloxacin, and gatifloxacin (data not shown).\n# Harms\nThe outcome of adverse events from TB drugs was intended to be assessed in the IPDMA but could not be analyzed because these outcomes were either not reported or reported with very different definitions. The adverse events associated with TB drugs, especially pyrazinamide, are well established (227,277).\n# Additional Considerations\nWe note that the estimates of effect were imprecise from the IPDMA because of the small number of patients who received the AMERICAN THORACIC SOCIETY DOCUMENTS e126 regimens of interest. Given that pyrazinamide is the most toxic of the present first-line drugs, a key potential advantage of adding a fluoroquinolone would be to shorten the duration of pyrazinamide to the initial 2 months of treatment. Although the IPDMA only had 118 patients receiving fluoroquinolone-containing regimens with shorter durations of pyrazinamide, it is noted that treatment success was very high in this group (117 of 118). On the basis of the efficacy signals seen and the known toxicities of prolonged pyrazinamide, the committee viewed the balance of benefits and harms to favor shortening the duration of x Increases in serum creatinine via decrease in renal tubular creatinine excretion are commonly seen with cobicistat and dolutegravir usage. This is not a toxicity. jj Indirect hyperbilirubinemia is expected with atazanavir and indinavir. This is not a toxicity.\n# AMERICAN THORACIC SOCIETY DOCUMENTS\npyrazinamide when a later-generation fluoroquinolone is included in the regimen in patients in whom there is toxicity anticipated or experienced because of pyrazinamide or when the patient has noncavitary, lower burden of disease. Finally, plasma peak concentration and exposure to moxifloxacin have been shown to decrease by approximately 30% when coadministered with rifampin (278,279). The impact of these decreased exposures on outcomes has not been established. However, some experts opt to use levofloxacin when combined with rifampin.\n# Conclusions\nWe conclude that in patients with isoniazidresistant TB, the addition of a later-generation fluoroquinolone to 6 months of daily rifampin, ethambutol, and pyrazinamide improves treatment success rates. In patients in whom toxicity from pyrazinamide is anticipated or experienced, or in patients with active TB with lower burden of disease (i.e., noncavitary), the committee viewed the balance of benefits and harms to favor shortening the duration of pyrazinamide when a later-generation fluoroquinolone is included in the regimen, acknowledging that the certainty in the evidence is very low and more research is needed.\n# Research Needs\nAll but 2 of the 23 studies included in the IPDMA were observational. Moreover, the analyzed population included only 37 children, 119 patients with diabetes, and 249 patients with HIV infection. Given the burden of isoniazid-resistant TB worldwide, clinical trials that include these special populations and evaluate new regimens, including the evaluation of the efficacy, safety, and tolerability of shorter versus longer durations of pyrazinamide, are urgently needed.\n# Treatment of MDR-TB in Special Situations\n\n# HIV Infection\nAmong patients with HIV and TB, rifampin resistance has been identified more often compared with those without HIV (280,281).\nPatients with MDR-TB and HIV have up to a fourfold higher risk of mortality compared with patients with MDR-TB without HIV (282). Low CD4 cell counts (e.g., <50 cells/ml) in patients with HIV and MDR-TB further correlate with higher mortality (283,284). Numerous practice guidelines recommend HIV testing of people with suspected or confirmed TB (11,20,34,285), regardless of drug resistance. Because of their high risk for mortality early in the course of TB disease, people with HIV in whom TB is suspected are recommended to receive rapid testing for TB using nucleic acid amplification tests coupled with molecular diagnostic DST for rifampin (with or without isoniazid) (13,20). For patients with HIV receiving therapy for drug-susceptible TB, studies found significantly lower mortality among patients receiving concurrent antiretroviral therapy (ART) compared with those not receiving ART (286)(287)(288). U.S. practice guidelines recommend starting ART within 2 weeks of initiating treatment for drug-susceptible non-CNS TB for patients with CD4 cell counts ,50 cells/ml and by 8 to 12 weeks for patients with higher CD4 cell counts (11,289). Although the optimal timing for starting ART to reduce patient mortality has not yet been adequately determined for patients with MDR-TB, lower mortality rates have been shown in multiple studies among patients with MDR-TB receiving concurrent ART compared with those not receiving ART (283,(290)(291)(292)(293)(294)(295)(296)(297), especially among patients with TB with CD4 counts ,50 cells/ml (283,292). The decreased mortality seen in patients treated for MDR-TB who concurrently receive ART, especially among those with CD4 cell counts ,50 cells/ml, supports a similar ART management approach as recommended for drugsusceptible TB.\nMDR-TB of the CNS in patients with HIV presents additional challenges. TB meningitis with isoniazid-resistant TB, RR-TB, or MDR-TB can be associated with higher mortality compared with drugsusceptible disease (298)(299)(300). Starting ART early in patients with TB is associated with a higher incidence of immune reconstitution inflammatory syndrome (286,288,301), and this can be even more problematic in CNS disease. A recent study in Vietnam of patients with advanced AIDS found a higher incidence of potentially lifethreatening (grade 4) adverse events among patients with TB meningitis starting ART early compared with those delaying ART until after 2 months of standardized firstline TB treatment and did not show a survival benefit of starting ART early (302). It has been recommended to delay starting ART by 8 weeks in patients with CNS TB and HIV (11); however, there is a paucity of data in patients with MDR-TB of the CNS. The optimal approach for initiation of ART in patients with this medical condition remains uncertain, and close clinical monitoring is warranted.\nDrug interactions between antiretroviral and anti-TB agents are common in the management of patients with HIV and TB, particularly with rifamycins. Because the rifamycins (with the possible exception of rifabutin) are not used for treatment of MDR-TB, interactions of other TB medication classes with ART should be considered. Bedaquiline and/or delamanid might be considered for use in patients with HIV. Although efavirenz can produce a decrease in serum bedaquiline concentrations and this combination is avoided, other ART drugs, including the protease inhibitors and cobicistat, can result in increased serum bedaquiline levels. The current WHO recommendations for the use of delamanid apply to patients living with HIV (7). Drug-drug interaction studies in healthy volunteers of delamanid with tenofovir, efavirenz, and lopinavir/ritonavir show that no dose adjustments were needed (303). Nonetheless, when delamanid is included in the regimen for MDR-TB in HIVinfected patients, the design of their PICO Question 21-Treatment of Contacts Exposed to MDR-TB: Should contacts exposed to an infectious patient with MDR-TB be offered LTBI treatment versus followed with observation alone? Recommendation 21: For contacts with presumed MDR LTBI due to exposure to an infectious patient with MDR-TB, we suggest offering treatment for LTBI (conditional recommendation, very low certainty in the evidence). We suggest 6 to 12 months of treatment with a later-generation fluoroquinolone alone or with a second drug, on the basis of drug susceptibility of the source-case M. tuberculosis isolate. On the basis of evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug.\nOn the basis of recent modeling studies, it is estimated that there are about 1 million incident cases of TB in children annually and 230,000 deaths caused by the disease (306,307). About 35,000 cases of MDR-and XDR-TB occur in children annually (308,309). Our PS-matched IPDMA did not include sufficient numbers of children to allow the formulations of GRADE-based recommendations. Nonetheless, on the basis of a recent IPDMA of 975 children with MDR-TB from 18 countries, recent pharmacokinetic studies in children, and several observational studies showing good outcomes, the recommendations noted on choice of drugs, composition of regimens, and durations of treatment for adults can also be applied to children with MDR-TB (113,119,124,161,165,170,200,310).\nThere are some special considerations for formulating effective regimens for children of various ages and adolescents. The bacterial burden in young children with TB is much smaller than that in most adults with TB. As a result, most drug resistance in children was present when the organism was inhaled (primary resistance), and further development of resistance while on therapy (secondary resistance) is much less common in children. However, the paucibacillary nature of childhood TB also makes microbiologic confirmation much more difficult. The only way to determine drug susceptibility in cases that meet clinical definitions of TB disease (i.e., microbiologic confirmation is not available) is by linking the child to a specific source case for whom the drug susceptibilities of the organism are known. Linking the child and a specific case is more feasible in lowburden settings to which these guidelines apply but can be difficult in high-burden settings when there may be more than one possible source case. Also, standard definitions of relapse and treatment failure for pediatric TB trials are inconsistent because the low burden of organisms in children makes microbiologic confirmation of these outcomes difficult.\nThere are several technical factors that can affect the outcome of treatment for MDR-and XDR-TB in children. The two age extremes of childhood have been somewhat neglected in studies of MDR-and XDR-TB. Little is known about the pharmacokinetics, safety, and tolerability of the drugs used to treat drug-resistant TB in neonates, infants, and toddlers (115). Children, especially those ,2 years of age, are more prone to developing disseminated TB, including meningitis. Drugs that penetrate well into the CSF, such as linezolid, might have an advantage over drugs that appear to have less penetration, such as ethambutol and bedaquiline. Adolescents can develop TB similar to that found either in adults or in young children. However, adolescent patients often have been excluded from TB treatment trials. Most of the oral drugs used to treat MDRand XDR-TB are not licensed for children. Although the Global Drug Facility has pediatric dispersible tablets available (http://stoptb.org/gdf/drugsupply/drugs_ available.asp), these formulations are not registered with FDA or the European Medicines Agency, which has limited commercial availability of child-friendly dosage forms. As a result, for younger children, the medication often has to be crushed or put into suspension or capsules once opened, and the pharmacokinetics and pharmacodynamics of these various preparations are unknown. HIV-infected children may be exposed to lower concentrations of certain orally administered drugs than HIV-uninfected children given the same bodyweight dose. Unfortunately, the pharmacokinetics in HIV-infected children of drugs used to treat MDR-and XDR-TB are largely unstudied. Children generally have a more difficult time tolerating injectable medications because of pain and the fact that many children with TB are malnourished and have diminished muscle mass. With the recent development of new oral drugs, it is hoped that injectable drugs can be avoided in children whenever possible. Fortunately, children generally tolerate the oral TB drugs better than adults, with fewer serious adverse events resulting in fewer breaks in therapy. Also, most children with TB have not developed the common chronic diseases of adulthood and will not suffer complications of them during treatment. However, drug adverse effects can be difficult to assess in children and likely are underreported. In general, the same schedules used to monitor adverse events and laboratory abnormalities in adult patients treated for MDR-or XDR-TB also should be used for children.\n# Outcomes of MDR-TB treatment in children.\nA recently published systematic review (33 studies) and IPDMA (28 of the studies) described treatment outcomes for 975 children with MDR-TB using random effects multivariate logistical regression adjusted for age, sex, HIV infection, malnutrition, severe extrapulmonary disease, and severe pulmonary disease on chest radiograph (113). Overall, 78% had a successful treatment outcome, including 75% of the microbiologically confirmed cases. However, treatment was successful in only 56% of HIV-infected children who did not also receive ART during TB treatment compared with an 82% success rate in those also treated with ART. In children with confirmed MDR-TB, the use of injectable agents and high-dose isoniazid was associated with treatment success. Unfortunately, limitations of this study included that the vast majority of patients AMERICAN THORACIC SOCIETY DOCUMENTS came from one site (Cape Town, South Africa), difficulty in estimating the treatment effects of individual drugs within multidrug regimens, the availability of only observational cohort studies, and that treatment decisions were based on the clinician's perception of illness, with resulting potential for bias.\nConclusions. Excellent treatment outcomes have been demonstrated in both trials and extensive clinical experience for children with MDR-and XDR-TB using individualized treatment regimens with the currently available drugs. Microbiologic cure and probable cure rates in children can reach 80% to 90% with early recognition of drug resistance and adequate treatment (311). The greatest difficulties have been recognizing that the child has MDR-TB and the ability of the child to tolerate injectable drugs; fortunately, with expanded knowledge of and experience with the newer oral drugs, such as bedaquiline and delamanid, pediatricians with expertise in MDR-TB believe that the majority of children with MDR-TB likely can be cured with an all-oral drug regimen.\n# Pregnant Women\nUntreated MDR-TB during pregnancy can be associated with adverse maternal and fetal outcomes. Crucial gaps exist in the literature on treatment of MDR-TB in pregnant women, including the effectiveness, safety, and tolerability of available treatment regimens, as well as timing and duration of second-line drugs. In support of these guidelines, we conducted a systematic literature review with a focus on pregnant women with MDR-TB and included all original research reporting MDR-TB treatment outcomes during pregnancy, including case reports and case series, in all languages. We excluded animal studies, review articles, letters to the editor, and articles without documentation of MDR-TB treatment during pregnancy. Fulltext review and data extraction were conducted by three reviewers. Our initial search yielded 280 publications, of which 16 met inclusion criteria for full-text review (312)(313)(314)(315)(316)(317)(318)(319)(320)(321)(322)(323)(324)(325)(326)(327); however, 3 publications were eventually excluded because of lack of data on medications or outcomes (315,325,327). The remaining 13 articles were observational case reviews without any comparison groups. Treatment regimens reported were individualized according to drug susceptibility and tolerability of drugs.\nSummary of the evidence. Of the 65 pregnant women for whom MDR-TB treatment outcome data were available, 49% (n = 32) were cured and 20% (n = 13) completed treatment for a treatment success proportion of 69%. Fourteen percent (n = 9) of the women died. Treatment failure was reported in 9% (n = 6), and 3% (n = 2) were lost to followup. Across these studies, four women were still receiving treatment at the time of publication. Fetal outcomes included 78.5% (n = 51) healthy births, with eight children being born premature or having low birth weight. Medical abortions were obtained by 12% of the patients (n = 8), and 3% (n = 2) underwent spontaneous abortions. Stillbirth was reported for one child (1.5%), 3% (n = 2) of children were born with HIV, and 1.5% (n = 1) had TB/HIV coinfection.\nConclusions. On the basis of the limited data available, we conclude that there is evidence to support treatment of MDR-TB during pregnancy, including the prescription of second-line drugs. Most of the second-line drugs are pregnancy category C per the U.S. Food and Drug Administration, with the exception of bedaquiline and meropenem, which are classified as category B (according to the previous FDA letter-based classification system, currently undergoing revision [328]), and aminoglycosides, which are category D (71,320,329). Despite low cure rates reported in the literature, we believe that the benefits of treatment to mother, child, and the community outweigh the harms. There is no evidence to support one particular regimen; however, most MDR-TB experts avoid aminoglycosides and ethionamide in pregnant women if alternative agents can be used for an effective treatment regimen.\nResearch needs. Global registries aimed at collecting data on the efficacy, safety, and tolerability, and maternal and fetal outcomes associated with MDR-TB regimens in pregnant women are urgently needed. Furthermore, given the significant morbidity and mortality associated with MDR-TB, a reconsideration of the current approach of assumed exclusion of pregnant women from MDR-TB clinical trials is warranted. A recent consensus statement from an international expert panel advocated for allowing pregnant and lactating women to remain eligible for phase III MDR-TB trials, unless there is a compelling reason for exclusion (330).\n# Treatment of Contacts Exposed to MDR-TB\nIn 1992 and 2000, ATS and CDC advised: 1) no treatment for MDR LTBI for persons not at high risk for progression to TB disease, but provision of clinical follow-up for TB disease signs and symptoms; 2) 6 to 12 months of treatment with two or more medications to which the isolate of the source case is susceptible (331,332).\n# Summary of the Evidence\nProcedures and methodology to assemble and rank the certainty in the evidence are reported in APPENDIX A, with evidence profiles for PICO questions reported in APPENDIX B. A systematic review of 21 published observational studies that examined outcomes of TB incidence, treatment completion, adverse effects, and cost effectiveness was used as the evidence (333). Six articles compared TB incidence among contacts receiving MDR LTBI treatment versus untreated contacts: 10 presented TB incidence only for contacts who received MDR LTBI treatment, and 5 presented TB incidence only for untreated contacts.\n# Benefits\nUsing data from five non-registry-matched comparison studies included in the systematic review of 21 published observational studies, MDR-TB incidence occurred in 2 of 190 (1.1%) patients treated for MDR LTBI, compared with 18 of 126 (14.3%) in those who received no MDR LTBI treatment (290). The estimated MDR-TB incidence reduction was 90% (9-99%), using a negative binomial model controlling for person time and overdispersion (333).\n# Harms\nFrom 11 studies having data by regimen on treatment discontinuation due to adverse effects, there was high (51%) treatment discontinuation among patients taking pyrazinamide-containing regimens (333). About one-third of patients taking fluoroquinolone-containing regimens, without pyrazinamide, had adverse effects, but only 2% discontinued treatment. For children <15 years of age regardless of regimen, treatment discontinuation due to adverse effects was substantially less (5% vs. 33%) (333). \n# Additional Considerations\nModeled cost-effectiveness studies have shown greatest benefit using a fluoroquinolone-based MDR LTBI treatment. In one study, the most costeffective regimen was fluoroquinolone/ethambutol, followed by fluoroquinolone alone, then by pyrazinamide/ethambutol (333). A pyrazinamide/fluoroquinolone regimen was particularly toxic, as measured by treatment discontinuation, and prevented about half as many TB cases as the most cost-effective option (333). An expert panel generated a policy brief on this topic recently, acknowledged that further evidence is urgently needed, but still endorsed the immediate implementation of postexposure management of household contacts of MDR-TB, endorsing the approach as being effective, feasible, and cost efficient (334). The Curry International TB Center Drug Resistant TB: Clinician's Survival Guide suggests an LTBI regimen of levofloxacin or moxifloxacin alone or combined with a second medication to which the isolate of the infectious source patient is susceptible (16).\nAmong those with presumed MDR LTBI, there is probable effectiveness of preventing TB through MDR LTBI treatment. From systematic reviews of studies reporting incidence for both treated and untreated contacts, TB incidence was significantly lower with MDR LTBI treatment (333,(335)(336)(337)(338)(339). In studies that published outcomes by regimen, there were high treatment discontinuation rates due to adverse effects and toxicity in persons taking pyrazinamide-containing MDR-LTBI regimens (336,337,(339)(340)(341)(342). There were low treatment discontinuation rates due to adverse effects and toxicity in persons taking fluoroquinolone-containing MDR-LTBI regimens. Finally, children are at high risk for developing MDR-TB if infected with MDR LTBI and generally experience fewer adverse effects than adults. Given the uncertainties above, many TB experts and programs provide extended post-treatment completion follow-up for patients treated for presumed MDR LTBI.\n# Conclusions\nFor contacts with presumed MDR LTBI due to exposure to an infectious patient with MDR-TB, we suggest offering treatment for LTBI versus following with observation alone. For treatment of MDR LTBI, we suggest 6 to 12 months' treatment with a fluoroquinolone alone or with a second drug, on the basis of source-case isolate DST. On the basis of evidence of increased toxicity, adverse events, and discontinuations, pyrazinamide should not be routinely used as the second drug. In lieu of fluoroquinolone-based treatment, there are few data for the use of other secondline medications and, because of toxicity, they are not recommended by experts. For contacts to fluoroquinolone-resistant, pre-XDR-TB, pyrazinamide/ethambutol may be an effective option, if source-case isolate DST shows susceptibility to these drugs. In children, TB drugs are generally better tolerated, and levofloxacin is preferred because of the availability of an oral suspension formulation. ): 6 months of daily delamanid versus 6 months of isoniazid. In addition, more information is needed on the cost effectiveness of treating contacts with presumed DR-TB infection using these newer MDR LTBI regimens.\n# Summary of Key Differences between ATS/CDC/ERS/IDSA and WHO 2019 Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment\nThe 2019 WHO Consolidated Guidelines on Drug-Resistant Tuberculosis Treatment guidelines were based on a modified set of data that expanded on the initial individual patient dataset used for these ATS/CDC/ERS/IDSA guidelines (3). For the 2019 WHO update, data from 625 patients were included by WHO from eight other datasets received in 2018 (Australia, Belarus, Brazil, France, Latvia, Republic of Korea, Russian Federation, and the EndTB project), as well as a sample of 3,626 patients receiving treatment in South Africa, including 1,210 cases started on bedaquiline in 2015. With these newer data added, the WHO individual patient dataset removed 3,367 records because of incomplete DST documentation (7). Despite the changes in the datasets described, WHO and ATS/CDC/ERS/IDSA recommendations are largely concordant, as they were derived concurrently, using a similar approach (GRADE methodology and a multidisciplinary Guideline Development Group), and were informed by an individual patient data meta-analysis that overlapped substantially. The main differences are highlighted below. This official clinical practice guideline was prepared by an ad hoc subcommittee of the ATS, CDC, ERS, and IDSA.\nMembers of the subcommittee are as follows:\n# \nART regimens should be developed in consultation with HIV and ART experts. A thorough review of all patients' medications should be performed, in consultation with MDR-TB experts, to select individualized regimens with less potential for overlapping ART/TB drug toxicities (Table 11). Useful webpages regarding drug interactions (TB/HIV and other) are available from AIDSinfo (https://aidsinfo.nih.gov/guidelines), CDC (http://www.cdc.gov/tb/publications/ guidelines/TB_HIV_Drugs/default.htm), University of California San Francisco (http:// hivinsite.ucsf.edu/insite?page=ar-00-02), University of Liverpool (http://www.hivdruginteractions.org/), and Indiana University (http://medicine.iupui.edu/ clinpharm/ddis/).\nThe management of MDR-TB is more complex among patients with HIV infection. The higher pill burden of combined ART with expanded TB drug therapy, potential drug-drug interactions, the management of immune reconstitution inflammatory syndrome, and other concurrent HIV-associated opportunistic diseases all pose unique challenges in the care of these patients. The management of patients with HIV and MDR-TB can best be performed by a multidisciplinary care team composed of health providers experienced in MDR-TB, HIV, and public health case management (304,305 "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":294,"cells":{"id":{"kind":"string","value":"342bf9187b6ba9baa1bc61dee0dc78a0f3f235e0"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"F o r - « le by th e S u p e rin te n d e n t of D o c u m e n ts, U .S . G o vem m en t P rin tin g O ffic e , W ash in g to n , D .C . 20402 HEW Publication No. (NIOSH) 76-138 PREFACE The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers exposed to an ever-increasing number of potential hazards at their workplace. The National Institute for Occupational Safety and Health has projected a formal system of research, with priorities determined on the basis of specified indices, to provide relevant data from which valid criteria for effective standards can be derived. Recommended standards for occupational exposure, which are the result of this work, are based on the health effects of exposure. The Secretary of Labor will weigh these recommen dations along with other considerations such as feasibility and means of implementation in developing regulatory standards. It is intended to present successive reports as research and epide miologic studies are completed and as sampling and analytical methods are developed. Criteria and standards will be reviewed periodically to ensure continuing protection of the worker. I am pleased to acknowledge the contributions to this report on methylene chloride by members of my staff and the valuable constructive comments by the Review Consultants on methylene chloride, by the ad hoc committees of the American Industrial Hygiene Association and the American Academy of Occupational Medicine, by Robert B. O'Connor, M.D., NIOSH consultant in occupational medicine, and by William M. Pierce on respiratory protection and work practices. The NIOSH recommendations for standards are not necessarily a consensus of all the consultants and pro fessional societies that reviewed this criteria document on methylene chloride. Lists of the NIOSH Review Committee members and of the Review Consultants appear on the following pages.# CRITERIA DOCUMENT:\n\n# RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR METHYLENE CHLORIDE\n\"Occupational exposure to methylene chloride\" is defined as exposure above one-half the daily time-weighted average (TWA) exposure limit, except when there is also exposure to carbon monoxide (CO) at more than 9 ppm.\nBecause the toxicities of CO and methylene chloride are additive, the appropriate environmental limit and action level of methylene chloride must be reduced in the presence of CO. When CO levels are more than 9 ppm \"occupational exposure to methylene chloride\" shall be determined from the (3) Only appropriate respirators as described in Table 1- Less than or equal 1) Any supplied air respirator, to 3,750 ppm (50X) with full facepiece, helmet or hood. 2) Any self-contained breathing apparatus with full facepiece.\n3,750 ppm or more 1) Self-contained breathing apparatus, pressure demand mode (positive pressure), in full facepiece.\nCombination supplied air respira tor, pressure demand mode, with auxiliary self-contained air supply.\nEvacuation or escape 1) Any escape-type, self-contained (no concentration breathing apparatus. limit)\n2) Any escape--type gas mask providing protection against methylene chloride (C)\nThe employer shall provide respirators in accordance with (E) Respirators specified in Table 1- However, records which form the basis for concluding that the exposures are below one-half the limit shall be maintained and exposure surveys shall be made when any process change indicates the need for réévaluation or at the discretion of the compliance officer.\n\n# (b)\nWhere exposure concentrations have not been determined, they shall be determined within 6 months of the promulgation of a standard incorporating these recommendations.\n(c) Where it has been determined that environmental concentrations result in TWA workday exposures above one-half the limit, employers shall maintain records of environmental exposures to methylene chloride based upon the following sampling and recording schedules:\n(1) Samples shall be collected at least every 6 months in accordance with Appendix I for the evaluation of the work environment with respect to the recommended standard.\n(2) Environmental samples shall be taken when a new process is installed or when process changes are made which may cause an increase in environmental concentrations. Increased production, relocation of existing operations, and increased overtime also requires resampling.\n(3) In all monitoring, samples shall be collected which are representative of breathing-zone exposures characteristic of each job or specific operation in each work area. The method of analysis was not given.\nThe hands and arms of the chemist were also exposed to liquid methylene chloride when the salt was removed from the distillation apparatus.\nAfter A disadvantage of the method is the indirect system of measurement requiring collection and desorption prior to analysis.\n( The Czechoslovak Committee of MAC listed standards for Hungary (6 ppm), Great Britain (500 ppm) and GDR (141 ppm).\n The Czechoslovak Committee considered that contamination of methylene chloride with methyl chloride was the reason for the low USSR standard.\nThe 1969 ANSI Z-37 standard was adopted as the federal standard, 29 CFR 1910.1000, Table G2. This standard is a TWA of 500 ppm for an 8 hour/day, a ceiling concentration of 1,000 ppm, and a maximum peak of 2,000 ppm for no more than 5 minutes in any 2 h o u r s . Human male subjects (nonsmokers) exposed experimentally to methylene chloride for 7.5 hours daily on 5 consecutive days attained average peak COHb percentages of 2.9% at 50 ppm methylene chloride, 5.7% at 100 ppm methylene chloride, and 9.6% at 250 ppm methylene chloride.\n\n# Basis for Recommended Environmental\nIn each case, the peaks were attained on the 5th day of exposure.\nThe date and time of sample collection.\n(2) Sampling duration.\n(3) Total sample volume.\n(4) Location of sampling.\n\n# MATERIAL SAFETY DATA SHEET\n\n# PRODUCT IDENTIFICATION\n\n# U N U S U A L F IR E A N D E X P L O S IO N H A Z A R D V HEALTH HAZARD INFORMATION H E A L T H H A Z A R O D A T A R O U T E S O F E X P O SU R E IN H A L A T IO N S K IN C O N T A C T S K IN A B S O R P T IO N E Y E C O N T A C T IN G E S T IO N E F F E C T S OF O V E R E X P O S U R E A C U T E O V E R E X P O S U R E C H R O N IC O V E R E X P O S U R E E M E R G E N C Y A N D F IR ST"},"raw_text":{"kind":"string","value":"F o r * « le by th e S u p e rin te n d e n t of D o c u m e n ts, U .S . G o vem m en t P rin tin g O ffic e , W ash in g to n , D .C . 20402 HEW Publication No. (NIOSH) 76-138 PREFACE The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers exposed to an ever-increasing number of potential hazards at their workplace. The National Institute for Occupational Safety and Health has projected a formal system of research, with priorities determined on the basis of specified indices, to provide relevant data from which valid criteria for effective standards can be derived. Recommended standards for occupational exposure, which are the result of this work, are based on the health effects of exposure. The Secretary of Labor will weigh these recommen dations along with other considerations such as feasibility and means of implementation in developing regulatory standards. It is intended to present successive reports as research and epide miologic studies are completed and as sampling and analytical methods are developed. Criteria and standards will be reviewed periodically to ensure continuing protection of the worker. I am pleased to acknowledge the contributions to this report on methylene chloride by members of my staff and the valuable constructive comments by the Review Consultants on methylene chloride, by the ad hoc committees of the American Industrial Hygiene Association and the American Academy of Occupational Medicine, by Robert B. O'Connor, M.D., NIOSH consultant in occupational medicine, and by William M. Pierce on respiratory protection and work practices. The NIOSH recommendations for standards are not necessarily a consensus of all the consultants and pro fessional societies that reviewed this criteria document on methylene chloride. Lists of the NIOSH Review Committee members and of the Review Consultants appear on the following pages.# CRITERIA DOCUMENT:\n\n# RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR METHYLENE CHLORIDE\n\"Occupational exposure to methylene chloride\" is defined as exposure above one-half the daily time-weighted average (TWA) exposure limit, except when there is also exposure to carbon monoxide (CO) at more than 9 ppm.\nBecause the toxicities of CO and methylene chloride are additive, the appropriate environmental limit and action level of methylene chloride must be reduced in the presence of CO. When CO levels are more than 9 ppm \"occupational exposure to methylene chloride\" shall be determined from the (3) Only appropriate respirators as described in Table 1- Less than or equal 1) Any supplied air respirator, to 3,750 ppm (50X) with full facepiece, helmet or hood. 2) Any self-contained breathing apparatus with full facepiece.\n3,750 ppm or more 1) Self-contained breathing apparatus, pressure demand mode (positive pressure), in full facepiece.\n# 2)\nCombination supplied air respira tor, pressure demand mode, with auxiliary self-contained air supply.\nEvacuation or escape 1) Any escape-type, self-contained (no concentration breathing apparatus. limit)\n2) Any escape--type gas mask providing protection against methylene chloride (C)\nThe employer shall provide respirators in accordance with (E) Respirators specified in Table 1- However, records which form the basis for concluding that the exposures are below one-half the limit shall be maintained and exposure surveys shall be made when any process change indicates the need for réévaluation or at the discretion of the compliance officer.\n# (b)\nWhere exposure concentrations have not been determined, they shall be determined within 6 months of the promulgation of a standard incorporating these recommendations.\n(c) Where it has been determined that environmental concentrations result in TWA workday exposures above one-half the limit, employers shall maintain records of environmental exposures to methylene chloride based upon the following sampling and recording schedules:\n(1) Samples shall be collected at least every 6 months in accordance with Appendix I for the evaluation of the work environment with respect to the recommended standard.\n(2) Environmental samples shall be taken when a new process is installed or when process changes are made which may cause an increase in environmental concentrations. Increased production, relocation of existing operations, and increased overtime also requires resampling.\n(3) In all monitoring, samples shall be collected which are representative of breathing-zone exposures characteristic of each job or specific operation in each work area. The method of analysis was not given.\n[58]\nThe hands and arms of the chemist were also exposed to liquid methylene chloride when the salt was removed from the distillation apparatus.\nAfter A disadvantage of the method is the indirect system of measurement requiring collection and desorption prior to analysis.\n( The Czechoslovak Committee of MAC listed standards for Hungary (6 ppm), Great Britain (500 ppm) and GDR (141 ppm).\n[133] The Czechoslovak Committee considered that contamination of methylene chloride with methyl chloride was the reason for the low USSR standard.\nThe 1969 ANSI Z-37 standard [5] was adopted as the federal standard, 29 CFR 1910.1000, Table G2. This standard is a TWA of 500 ppm for an 8 hour/day, a ceiling concentration of 1,000 ppm, and a maximum peak of 2,000 ppm for no more than 5 minutes in any 2 h o u r s . Human male subjects (nonsmokers) exposed experimentally to methylene chloride for 7.5 hours daily on 5 consecutive days attained average peak COHb percentages of 2.9% at 50 ppm methylene chloride, 5.7% at 100 ppm methylene chloride, and 9.6% at 250 ppm methylene chloride.\n# Basis for Recommended Environmental\nIn each case, the peaks were attained on the 5th day of exposure. \n# \n(1)\nThe date and time of sample collection.\n(2) Sampling duration.\n(3) Total sample volume.\n(4) Location of sampling.\n( \n# MATERIAL SAFETY DATA SHEET\n\n# PRODUCT IDENTIFICATION\n\n# U N U S U A L F IR E A N D E X P L O S IO N H A Z A R D V HEALTH HAZARD INFORMATION H E A L T H H A Z A R O D A T A R O U T E S O F E X P O SU R E IN H A L A T IO N S K IN C O N T A C T S K IN A B S O R P T IO N E Y E C O N T A C T IN G E S T IO N E F F E C T S OF O V E R E X P O S U R E A C U T E O V E R E X P O S U R E C H R O N IC O V E R E X P O S U R E E M E R G E N C Y A N D F IR ST\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":295,"cells":{"id":{"kind":"string","value":"0b698e0e189e28d0bd9597fafb6eb34f799adea1"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Disclosure of Relationship CDC, our planners, and our content experts wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. This document will not include any discussion of the unlabeled use of a product or a product under investigational use, with the exception that some of the recommendations in this document might be inconsistent with package labeling.# Introduction\nUnintended pregnancy rates remain high in the United States; approximately 45% of all pregnancies are unintended, with higher proportions among adolescent and young women, women who are racial/ethnic minorities, and women with lower levels of education and income (1). Unintended pregnancies increase the risk for poor maternal and infant outcomes (2) and in 2010, resulted in U.S. government health care expenditures of $21 billion (3). Approximately half of unintended pregnancies are among women who were not using contraception at the time they became pregnant; the other half are among women who became pregnant despite reported use of contraception (4). Strategies to prevent unintended pregnancy include assisting women at risk for unintended pregnancy and their partners with choosing appropriate contraceptive methods and helping them use methods correctly and consistently to prevent pregnancy.\nIn 2013, CDC published the first U.S. Selected Practice Recommendations for Contraceptive Use (U.S. SPR), adapted from global guidance developed by the World Health Organization (WHO SPR), which provided evidence-based guidance on how to use contraceptive methods safely and effectively once they are deemed to be medically appropriate.\n\n# U.S. SPR is a companion document to U.S. Medical Eligibility\nCriteria for Contraceptive Use (U.S. MEC) (. gov/reproductivehealth/unintendedpregnancy/usmec.htm), which provides recommendations on safe use of contraceptive methods for women with various medical conditions and other characteristics (5). WHO intended for the global guidance to be used by local or national policy makers, family planning program managers, and the scientific community as a reference when they develop family planning guidance at the country or program level. During 2012-2013, CDC went through a formal process to adapt the global guidance for best implementation in the United States, which included rigorous identification and critical appraisal of the scientific evidence through systematic reviews, and input from national experts on how to translate that evidence into recommendations for U.S. health care providers (6). At that time, CDC committed to keeping this guidance up to date and based on the best available evidence, with full review every few years (6).\nThis document updates the 2013 U.S. SPR (6) with new evidence and input from experts. Major updates include 1) revised recommendations for starting regular contraception after the use of emergency contraceptive pills and 2) new recommendations for the use of medications to ease insertion of intrauterine devices (IUDs). Recommendations are provided for health care providers on the safe and effective use of contraceptive methods and address provision of contraceptive methods and management of side effects and other problems with contraceptive method use, within the framework of removing unnecessary medical barriers to accessing and using contraception. These recommendations are meant to serve as a source of clinical guidance for health care providers; health care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients, who should seek advice from their health care providers when considering family planning options.\n\n# Summary of Changes from the 2013 U.S. SPR Updated Recommendations\nRecommendations have been updated regarding when to start regular contraception after ulipristal acetate (UPA) emergency contraceptive pills:\n- Advise the woman to start or resume hormonal contraception no sooner than 5 days after use of UPA, and provide or prescribe the regular contraceptive method as needed. For methods requiring a visit to a health care provider, such as depo-medroxyprogesterone acetate (DMPA), implants, and IUDs, starting the method at the time of UPA use may be considered; the risk that the regular contraceptive method might decrease the effectiveness of UPA must be weighed against the risk of not starting a regular hormonal contraceptive method. - The woman needs to abstain from sexual intercourse or use barrier contraception for the next 7 days after starting or resuming regular contraception or until her next menses, whichever comes first. - Any nonhormonal contraceptive method can be started immediately after the use of UPA. - Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks.\n\n# New Recommendations\nNew recommendations have been made for medications to ease IUD insertion:\n- Misoprostol is not recommended for routine use before IUD insertion. Misoprostol might be helpful in select circumstances (e.g., in women with a recent failed insertion). - Paracervical block with lidocaine might reduce patient pain during IUD insertion.\n\n# Methods\nSince publication of the 2013 U.S. SPR, CDC has monitored the literature for new evidence relevant to the recommendations through the WHO/CDC continuous identification of research evidence (CIRE) system (7). This system identifies new evidence as it is published and allows WHO and CDC to update systematic reviews and facilitate updates to recommendations as new evidence warrants. Automated searches are run in PubMed weekly, and the results are reviewed. Abstracts that meet specific criteria are added to the web-based CIRE system, which facilitates coordination and peer review of systematic reviews for both WHO and CDC. In 2014, CDC reviewed all of the existing recommendations in the 2013 U.S. SPR for new evidence identified by CIRE that had the potential to lead to a changed recommendation. During August 27-28, 2014, CDC held a meeting in Atlanta, Georgia, of 11 family planning experts and representatives from partner organizations to solicit their input on the scope of and process for updating both the 2010 U.S. MEC and the 2013 U.S. SPR. The participants were experts in family planning and represented different provider types and organizations that represent health care providers. A list of participants is provided at the end of this report. The meeting related to topics to be addressed in the update of U.S. SPR based on new scientific evidence published since 2013 (identified though the CIRE system), topics addressed at a 2014 WHO meeting to update global guidance, and suggestions CDC received from providers for the addition of recommendations not included in the 2013 U.S. SPR (e.g., from provider feedback through e-mail, public inquiry, and questions received at conferences). CDC identified one topic to consider adding to the guidance: the use of medications to ease IUD insertion (evidence question: \"Among women of reproductive age, does use of medications before IUD insertion improve the safety or effectiveness of the procedure or affect patient outcomes compared with nonuse of these medications?\"). CDC also identified one topic for which new evidence warranted a review of an existing recommendation: initiation of regular contraception after emergency contraceptive pills (evidence question: \"Does ulipristal acetate for emergency contraception interact with regular use of hormonal contraception leading to decreased effectiveness of either contraceptive method?\"). CDC determined that all other recommendations in the 2013 U.S. SPR were up to date and consistent with the current body of evidence for that recommendation.\nIn preparation for a subsequent expert meeting August 2015, to review the scientific evidence\n\n# Maintaining Updated Guidance\nAs with any evidence-based guidance document, a key challenge is keeping the recommendations up to date as new scientific evidence becomes available. Working with WHO, CDC uses the CIRE system to ensure that WHO and CDC guidance is based on the best available evidence and that a mechanism is in place to update guidance when new evidence becomes available (7). CDC will continue to work with WHO to identify and assess all new relevant evidence and determine whether changes in the recommendations are warranted. In most cases, U.S. SPR will follow any updates in the WHO guidance, which typically occurs every 5 years (or sooner if warranted by new data). In addition, CDC will review any interim WHO updates for their application in the United States. CDC also will identify and assess any new literature for the recommendations that are not included in the WHO guidance and will completely review U.S. SPR every 5 years. Updates to the guidance can be found on the U.S. SPR website (/ UnintendedPregnancy/USSPR.htm).\n\n# How To Use This Document\nThe recommendations in this report are intended to help health care providers address issues related to use of contraceptives, such as how to help a woman initiate use of a contraceptive method, which examinations and tests are needed before initiating use of a contraceptive method, what regular follow-up is needed, and how to address problems that often arise during use, including missed pills and side effects such as unscheduled bleeding. Each recommendation addresses what a woman or health care provider can do in specific situations. For situations in which certain groups of women might be medically ineligible to follow the recommendations, comments and reference to U.S. MEC are provided (5). The full U.S. MEC recommendations and the evidence supporting those recommendations have been updated in 2016 (5) and are summarized (Appendix A).\nThe information in this document is organized by contraceptive method, and the methods generally are presented in order of effectiveness, from highest to lowest. However, the recommendations are not intended to provide guidance on every aspect of provision and management of contraceptive method use. Instead, they incorporate the best available evidence to address specific issues regarding common, yet sometimes complex, clinical issues. Each contraceptive method section generally includes information about initiation of the method, regular follow-up, and management of problems with use (e.g., usage errors and side effects). Each section first provides the recommendation and then includes comments and a brief summary of the scientific evidence on which the recommendation is based. The level of evidence from the systematic reviews for each evidence summary are provided based on the U.S. Preventive Services Task Force system, which includes ratings for study design (I: randomized controlled trials; II-1: controlled trials without randomization; II-2: observational studies; and II-3: multiple time series or descriptive studies), ratings for internal validity (good, fair, or poor), and categorization of the evidence as direct or indirect for the specific review question (10).\nRecommendations in this document are provided for permanent methods of contraception, such as vasectomy and female sterilization, as well as for reversible methods of contraception, including the copper-containing intrauterine device (Cu-IUD); levonorgestrel-releasing IUDs (LNG-IUDs); the etonogestrel implant; progestin-only injectables; progestinonly pills (POPs); combined hormonal contraceptive methods that contain both estrogen and a progestin, including combined oral contraceptives (COCs), a transdermal contraceptive patch, and a vaginal contraceptive ring; and the standard days method (SDM). Recommendations also are provided for emergency use of the Cu-IUD and emergency contraceptive pills (ECPs).\nFor each contraceptive method, recommendations are provided on the timing for initiation of the method and indications for when and for how long additional contraception, or a back-up method, is needed. Many of these recommendations include guidance that a woman can start a contraceptive method at any time during her menstrual cycle if it is reasonably certain that she is not pregnant. Guidance for health care providers on how to be reasonably certain that a woman is not pregnant also is provided.\nFor each contraceptive method, recommendations include the examinations and tests needed before initiation of the method. These recommendations apply to persons who are presumed to be healthy. Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Most women need no or very few examinations or tests before initiating a contraceptive method although they might be needed to address other noncontraceptive health needs (12). Any additional screening needed for preventive health care can be performed at the time of contraception initiation, and initiation should not be delayed for test results. The following classification system was developed by WHO and adopted by CDC to categorize the applicability of the various examinations or tests before initiation of contraceptive methods (13): Class A: These tests and examinations are essential and mandatory in all circumstances for safe and effective use of the contraceptive method.\nClass B: These tests and examinations contribute substantially to safe and effective use, although implementation can be considered within the public health context, service context, or both. The risk for not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: These tests and examinations do not contribute substantially to safe and effective use of the contraceptive method.\nThese classifications focus on the relation of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. Systematic reviews were conducted for several different types of examinations and tests to assess whether a screening test was associated with safe use of contraceptive methods. Because no single convention exists for screening panels for certain diseases, including diabetes, lipid disorders, and liver diseases, the search strategies included broad terms for the tests and diseases of interest.\nSummary charts and clinical algorithms that summarize the guidance for the various contraceptive methods have been developed for many of the recommendations, including when to start using specific contraceptive methods (Appendix B), examinations and tests needed before initiating the various contraceptive methods (Appendix C), routine follow-up after initiating contraception (Appendix D), management of bleeding irregularities (Appendix E), and management of IUDs when users are found to have pelvic inflammatory disease (PID) (Appendix F). These summaries might be helpful to health care providers when managing family planning patients. Additional tools are available on the U.S. SPR website (. gov/reproductivehealth/UnintendedPregnancy/USSPR.htm).\n\n# Contraceptive Method Choice\nMany elements need to be considered individually by a woman, man, or couple when choosing the most appropriate contraceptive method. Some of these elements include safety, effectiveness, availability (including accessibility and affordability), and acceptability. Although most contraceptive methods are safe for use by most women, U.S. MEC provides recommendations on the safety of specific contraceptive methods for women with certain characteristics and medical conditions (5); a U.S. MEC summary (Appendix A) and the categories of medical eligibility criteria for contraceptive use (Box 1) are provided.\nVoluntary informed choice of contraceptive methods is an essential guiding principle, and contraceptive counseling, where applicable, might be an important contributor to the successful use of contraceptive methods.\nContraceptive method effectiveness is critically important in minimizing the risk for unintended pregnancy, particularly among women for whom an unintended pregnancy would pose additional health risks. The effectiveness of contraceptive methods depends both on the inherent effectiveness of the method itself and on how consistently and correctly it is used (Figure 1). Both consistent and correct use can vary greatly with characteristics such as age, income, desire to prevent or delay pregnancy, and culture. Methods that depend on consistent and correct use by clients have a wide range of effectiveness between typical use (actual use, including incorrect or inconsistent use) and perfect use (correct and consistent use according to directions) (14). IUDs and implants are considered longacting, reversible contraception (LARC); these methods are highly effective because they do not depend on regular compliance from the user. LARC methods are appropriate for most women, including adolescents and nulliparous women. All women should be counseled about the full range and effectiveness of contraceptive options for which they are medically eligible so that they can identify the optimal method.\nIn choosing a method of contraception, dual protection from the simultaneous risk for human immunodeficiency virus (HIV) and other sexually transmitted diseases (STDs) also should be considered. Although hormonal contraceptives and IUDs are highly effective at preventing pregnancy, they do not protect against STDs, including HIV. Consistent and correct use of the male latex condom reduces the risk for HIV infection and other STDs, including chlamydial infection, gonococcal infection, and trichomoniasis (15). Although evidence is limited, use of female condoms can provide protection from acquisition and transmission of STDs (15). All patients, regardless of contraceptive choice, should be counseled about the use of condoms and the risk for STDs, including HIV infection (15). Additional information about prevention and treatment of STDs is available from the CDC Sexually Transmitted Diseases Treatment Guidelines (. cdc.gov/std/treatment) (15).\nWomen, men, and couples have increasing numbers of safe and effective choices for contraceptive methods, including LARC methods such as IUDs and implants, to reduce the risk for unintended pregnancy. However, with these expanded options comes the need for evidence-based guidance to help health care providers offer quality family planning care to their patients, including assistance in choosing the most appropriate contraceptive method for individual circumstances and using that method correctly, consistently, and continuously to maximize effectiveness. Removing unnecessary barriers can help patients access and successfully use contraceptive methods. Several medical barriers to initiating and continuing contraceptive methods might exist, such as unnecessary screening examinations and tests before starting the method (e.g., a pelvic examination before initiation of COCs), inability to receive the contraceptive on the same day as the visit (e.g., waiting for test results that might not be needed or waiting until the woman's next menstrual cycle to start use), and difficulty obtaining continued contraceptive supplies (e.g., restrictions on number of pill packs dispensed at one time). Removing unnecessary steps, such as providing prophylactic antibiotics at the time of IUD insertion or requiring unnecessary follow-up procedures, also can help patients access and successfully use contraception.\n\n# How To Be Reasonably Certain that a Woman Is Not Pregnant\nIn most cases, a detailed history provides the most accurate assessment of pregnancy risk in a woman who is about to start using a contraceptive method. Several criteria for assessing pregnancy risk are listed in the recommendation that follows. These criteria are highly accurate (i.e., a negative predictive value of 99%-100%) in ruling out pregnancy among women who are not pregnant (16)(17)(18)(19). Therefore, CDC recommends that health care providers use these criteria to assess pregnancy status in a woman who is about to start using contraceptives (Box 2). If a woman meets one of these criteria (and therefore the health care provider can be reasonably certain that she is not pregnant), a urine pregnancy BOX 1. Categories of medical eligibility criteria for contraceptive use - U.S. MEC 1 = A condition for which there is no restriction for the use of the contraceptive method. - U.S. MEC 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. - U.S. MEC 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. - U.S. MEC 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. test might be considered in addition to these criteria (based on clinical judgment), bearing in mind the limitations of the accuracy of pregnancy testing. If a woman does not meet any of these criteria, then the health care provider cannot be reasonably certain that she is not pregnant, even with a negative pregnancy test. Routine pregnancy testing for every woman is not necessary. On the basis of clinical judgment, health care providers might consider the addition of a urine pregnancy test; however, they should be aware of the limitations, including accuracy of the test relative to the time of last sexual intercourse, recent delivery, or spontaneous or induced abortion. Routine pregnancy testing for every woman is not necessary. If a woman has had recent (i.e., within the last 5 days) unprotected sexual intercourse, consider offering emergency contraception (either a Cu-IUD or ECPs) if pregnancy is not desired.\nComments and Evidence Summary. The criteria for determining whether a woman is pregnant depend on the assurance that she has not ovulated within a certain amount of time after her last menses, spontaneous or induced abortion, or delivery. Among menstruating women, the timing of ovulation can vary widely. During an average 28-day cycle, ovulation generally occurs during days 9-20 (20). In addition, the likelihood of ovulation is low from days 1-7 of the menstrual cycle (21). After a spontaneous or an induced abortion, ovulation can occur within 2-3 weeks and has been found to occur as early as 8-13 days after the end of the pregnancy. Therefore, the likelihood of ovulation is low ≤7 days after\n\n# JANUARY\n\n# S p e r m i c i d e\n\n# Spermicide\n\n# How to make your method most e ective\n\n# Vasectomy and hysteroscopic sterilization:\nAfter procedure, little or nothing to do or remember.\nUse another method for rst 3 months.\nInjectable: Get repeat injections on time.\nPills: Take a pill each day.\n\n# Least E ective\n\n# Most E ective\nLess than 1 pregnancy 6-12 pregnancies per 100 women in a year per 100 women in a year 18 or more pregnancies per 100 women in a year\n\n# CONDOMS SHOULD ALWAYS BE USED TO REDUCE THE RISK OF SEXUALLY TRANSMITTED INFECTIONS.\nOther Methods of Contraception Lactational Amenorrhea Method: LAM is a highly e ective, temporary method of contraception. Emergency Contraception: Emergency contraceptive pills or a copper IUD after unprotected intercourse substantially reduces risk of pregnancy. an abortion (22)(23)(24). A systematic review reported that the mean day of first ovulation among postpartum nonlactating women occurred 45-94 days after delivery (25). In one study, the earliest ovulation was reported at 25 days after delivery. Among women who are within 6 months postpartum, are fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority of feeds are breastfeeds), and are amenorrheic, the risk for pregnancy is <2% (26,27).\nAlthough pregnancy tests often are performed before initiating contraception, the accuracy of qualitative urine pregnancy tests varies depending on the timing of the test relative to missed menses, recent sexual intercourse, or recent pregnancy. The sensitivity of a pregnancy test is defined as the concentration of human chorionic gonadotropin (hCG) at which 95% of tests are positive. Most qualitative pregnancy tests approved by the U.S. Food and Drug Administration (FDA) report a sensitivity of 20-25 mIU/mL in urine (28)(29)(30)(31). However, pregnancy detection rates can vary widely because of differences in test sensitivity and the timing of testing relative to missed menses (30,32). Some studies have shown that an additional 11 days past the day of expected menses are needed to detect 100% of pregnancies using qualitative tests (29). In addition, pregnancy tests cannot detect a pregnancy resulting from recent sexual intercourse. Qualitative tests also might have positive results for several weeks after termination of pregnancy because hCG can be present for several weeks after delivery or abortion (spontaneous or induced) (33)(34)(35).\nFor contraceptive methods other than IUDs, the benefits of starting to use a contraceptive method likely exceed any risk, even in situations in which the health care provider is uncertain whether the woman is pregnant. Therefore, the health care provider can consider having patients start using contraceptive methods other than IUDs at any time, with a follow-up pregnancy test in 2-4 weeks. The risks of not starting to use contraception should be weighed against the risks of initiating contraception use in a woman who might be already pregnant. Most studies have shown no increased risk for adverse outcomes, including congenital anomalies or neonatal or infant death, among infants exposed in utero to COCs (36)(37)(38). Studies also have shown no increased risk for neonatal or infant death or developmental abnormalities among infants exposed in utero to DMPA (37,39,40).\nIn contrast, for women who want to begin using an IUD (Cu-IUD or LNG-IUD), in situations in which the health care provider is uncertain whether the woman is pregnant, the woman should be provided with another contraceptive method to use until the health care provider is reasonably certain that she is not pregnant and can insert the IUD. Pregnancies among women with IUDs are at higher risk for complications such as spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis (41).\nA systematic review identified four analyses of data from three diagnostic accuracy studies that evaluated the performance of the listed criteria (Box 2) through use of a pregnancy checklist compared with a urine pregnancy test conducted concurrently (42). The performance of the checklist to diagnose or exclude pregnancy varied, with sensitivity of 55%-100% and specificity of 39%-89%. The negative predictive value was consistent across studies at 99%-100%; the pregnancy checklist correctly ruled out women who were not pregnant. One of the studies assessed the added usefulness of signs and symptoms of pregnancy and found that these criteria did not substantially improve the performance of the pregnancy checklist, although the number of women with signs and symptoms was small (16) (Level of evidence: Diagnostic accuracy studies, fair, direct).\n\n# Intrauterine Contraception\nFour IUDs are available in the United States, the coppercontaining IUD and three levonorgestrel-releasing IUDs (containing a total of either 13.5 mg or 52 mg levonorgestrel). Fewer than 1 woman out of 100 becomes pregnant in the first year of using IUDs (with typical use) (14). IUDs are long-acting, are reversible, and can be used by women of all ages, including adolescents, and by parous and nulliparous women. IUDs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# BOX 2. How to be reasonably certain that a woman is not pregnant\nA health care provider can be reasonably certain that a woman is not pregnant if she has no symptoms or signs of pregnancy and meets any one of the following criteria: - is ≤7 days after the start of normal menses - has not had sexual intercourse since the start of last normal menses. - has been correctly and consistently using a reliable method of contraception - is ≤7 days after spontaneous or induced abortion - is within 4 weeks postpartum - is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority of feeds are breastfeeds), amenorrheic, and <6 months postpartum\n\n# Initiation of Cu-IUDs Timing\n- The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). - The Cu-IUD also can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. If the day of ovulation can be estimated, the Cu-IUD also can be inserted >5 days after sexual intercourse as long as insertion does not occur >5 days after ovulation.\n\n# Need for Back-Up Contraception\n- No additional contraceptive protection is needed after Cu-IUD insertion.\n\n# Special Considerations\nAmenorrhea (Not Postpartum)\n- Timing: The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). - Need for back-up contraception: No additional contraceptive protection is needed.\n\n# Postpartum (Including After Cesarean Delivery)\n- Timing: The Cu-IUD can be inserted at any time postpartum, including immediately postpartum (U.S. MEC 1 or 2) (Box 1), if it is reasonably certain that the woman is not pregnant (Box 2). The Cu-IUD should not be inserted in a woman with postpartum sepsis (e.g., chorioamnionitis or endometritis) (U.S. MEC 4). - Need for back-up contraception: No additional contraceptive protection is needed.\n\n# Postabortion (Spontaneous or Induced)\n- Timing: The Cu-IUD can be inserted within the first 7 days, including immediately postabortion (U.S. MEC 1 for first-trimester abortion and U.S. MEC 2 for secondtrimester abortion). The Cu-IUD should not be inserted immediately after a septic abortion (U.S. MEC 4). - Need for back-up contraception: No additional contraceptive protection is needed.\n\n# Switching from Another Contraceptive Method\n- Timing: The Cu-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. - Need for back-up contraception: No additional contraceptive protection is needed.\nComments and Evidence Summary. In situations in which the health care provider is not reasonably certain that the woman is not pregnant, the woman should be provided with another contraceptive method to use until the health care provider can be reasonably certain that she is not pregnant and can insert the Cu-IUD.\nA systematic review identified eight studies that suggested that timing of Cu-IUD insertion in relation to the menstrual cycle in non-postpartum women had little effect on longterm outcomes (rates of continuation, removal, expulsion, or pregnancy) or on short-term outcomes (pain at insertion, bleeding at insertion, or immediate expulsion) (43) (Level of evidence: II-2, fair, direct).\n\n# Initiation of LNG-IUDs\n\n# Timing of LNG-IUD Insertion\n- The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n\n# Need for Back-Up Contraception\n- If the LNG-IUD is inserted within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. - If the LNG-IUD is inserted >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Special Considerations\nAmenorrhea (Not Postpartum)\n- Timing: The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Postpartum (Including After Cesarean Delivery)\n\n# Switching from Another Contraceptive Method\n- Timing: The LNG-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. - Need for back-up contraception: If it has been >7 days since menstrual bleeding began, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. - Switching from a Cu-IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider providing any type of ECPs at the time of LNG-IUD insertion. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the woman should be provided with another contraceptive method to use until the health care provider can be reasonably certain that she is not pregnant and can insert the LNG-IUD. If a woman needs to use additional contraceptive protection when switching to an LNG-IUD from another contraceptive method, consider continuing her previous method for 7 days after LNG-IUD insertion. No direct evidence was found regarding the effects of inserting LNG-IUDs on different days of the cycle on short-or longterm outcomes (43).\n\n# Examinations and Tests Needed Before Initiation of a Cu-IUD or an LNG-IUD\nAmong healthy women, few examinations or tests are needed before initiation of an IUD (Table 1). Bimanual examination and cervical inspection are necessary before IUD insertion. A baseline weight and BMI measurement might be useful for monitoring IUD users over time. If a woman has not been screened for STDs according to STD screening guidelines, screening can be performed at the time of insertion. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use IUDs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of IUDs. However, measuring weight and calculating - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § Most women do not require additional STD screening at the time of IUD insertion.\nIf a woman with risk factors for STDs has not been screened for gonorrhea and chlamydia according to CDC's STD Treatment Guidelines (/ treatment), screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with current purulent cervicitis or chlamydial infection or gonococcal infection should not undergo IUD insertion (U.S. MEC 4).\n\n# BMI (weight / height \n) at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Bimanual examination and cervical inspection are necessary before IUD insertion to assess uterine size and position and to detect any cervical or uterine abnormalities that might indicate infection or otherwise prevent IUD insertion (44,45).\nSTDs: Women should be routinely screened for chlamydial infection and gonorrhea according to national screening guidelines. The CDC Sexually Transmitted Diseases Treatment Guidelines provide information on screening eligibility, timing, and frequency of screening and on screening for persons with risk factors (15) (). If STD screening guidelines have been followed, most women do not need additional STD screening at the time of IUD insertion, and insertion should not be delayed. If a woman with risk factors for STDs has not been screened for gonorrhea and chlamydia according to CDC STD treatment guidelines, screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with current purulent cervicitis or chlamydial infection or gonococcal infection should not undergo IUD insertion (U.S. MEC 4). A systematic review identified two studies that demonstrated no differences in PID rates among women who screened positive for gonorrhea or chlamydia and underwent concurrent IUD insertion compared with women who screened positive and initiated other contraceptive methods (46). Indirect evidence demonstrates women who undergo same-day STD screening and IUD insertion have similar PID rates compared with women who have delayed IUD insertion. Women who undergo same-day STD screening and IUD insertion have low incidence rates of PID. Algorithms for predicting PID among women with risk factors for STDs have poor predictive value. Risk for PID among women with risk factors for STDs is low (15,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57). Although women with STDs at the time of IUD insertion have a higher risk for PID, the overall rate of PID among all IUD users is low (51,54).\nHemoglobin: Women with iron-deficiency anemia can use the LNG-IUD (U.S. MEC 1) (5); therefore, screening for anemia is not necessary for safe initiation of the LNG-IUD. Women with iron-deficiency anemia generally can use Cu-IUDs (U.S. MEC 2) (5). Measurement of hemoglobin before initiation of Cu-IUDs is not necessary because of the minimal change in hemoglobin among women with and without anemia using Cu-IUDs. A systematic review identified four studies that provided direct evidence for changes in hemoglobin among women with anemia who received Cu-IUDs (58). Evidence from one randomized trial (59) and one prospective cohort study (60) showed no significant changes in hemoglobin among Cu-IUD users with anemia, whereas two prospective cohort studies (61,62) showed a statistically significant decrease in hemoglobin levels during 12 months of follow-up; however, the magnitude of the decrease was small and most likely not clinically significant. The systematic review also identified 21 studies that provided indirect evidence by examining changes in hemoglobin among healthy women receiving Cu-IUDs (63-83), which generally showed no clinically significant changes in hemoglobin levels with up to 5 years of follow up (Level of evidence: I to II-2, fair, direct).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of Cu-IUD or LNG-IUD because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results about the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Women with liver disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for liver disease is not necessary for the safe initiation of the Cu-IUD. Although women with certain liver diseases generally should not use the LNG-IUD (U.S. MEC 3) (5), screening for liver disease before initiation of the LNG-IUD is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptive use (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited, and no evidence exists for the LNG-IUD.\nClinical breast examination: Women with breast disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for breast disease is not necessary for the safe initiation of the Cu-IUD. Although women with current breast cancer should not use the LNG-IUD (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before inserting an IUD is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nCervical cytology: Although women with cervical cancer should not undergo IUD insertion (U.S. MEC 4) (5), screening asymptomatic women with cervical cytology before IUD insertion is not necessary because of the high rates of cervical screening, low incidence of cervical cancer in the United States, and high likelihood that a woman with cervical cancer already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with cervical cytology before initiation of IUDs (57). Cervical cancer is rare in the United States, with an incidence rate of 9.8 per 100,000 women during 2012 (96). The incidence and mortality rates from cervical cancer have declined dramatically in the United States, largely because of cervical cytology screening (97). Overall screening rates for cervical cancer in the United States are high; in 2013 among women aged 18-44 years, approximately 77% reported having cervical cytology screening within the last 3 years (98).\nHIV screening: Women with HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) IUDs (5). Therefore, HIV screening is not necessary before IUD insertion. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened for HIV infection before IUD insertion (57). Limited evidence suggests that IUDs are not associated with disease progression, increased infection, or other adverse health effects among women with HIV infection (99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114).\nOther screening: Women with hypertension, diabetes, or thrombogenic mutations can use (U.S. MEC 1) or generally can use (U.S. MEC 2) IUDs (5). Therefore, screening for these conditions is not necessary for the safe initiation of IUDs.\n\n# Provision of Medications to Ease\nIUD Insertion\n- Misoprostol is not recommended for routine use before IUD insertion. Misoprostol might be helpful in select circumstances (e.g., in women with a recent failed insertion). - Paracervical block with lidocaine might reduce patient pain during IUD insertion. Comments and Evidence Summary. Potential barriers to IUD use include anticipated pain with insertion and provider concerns about difficult insertion. Identifying effective approaches to ease IUD insertion might increase IUD initiation.\nEvidence for misoprostol from two systematic reviews, including a total of 10 randomized controlled trials, suggests that misoprostol does not improve provider ease of insertion, reduce the need for adjunctive insertion measures, or improve insertion success (Level of evidence: I, good to fair, direct) and might increase patient pain and side effects (Level of evidence: I, high quality) (115,116). However, one randomized controlled trial examined women with a recent failed IUD insertion and found significantly higher insertion success with second insertion attempt among women pretreated with misoprostol versus placebo (Level of evidence: I, good, direct) (117).\nLimited evidence for paracervical block with lidocaine from one systematic review suggests that it might reduce patient pain (115). In this review, two randomized controlled trials found significantly reduced pain at either tenaculum placement or IUD insertion among women receiving paracervical block with 1% lidocaine 3-5 minutes before IUD insertion (118,119). Neither trial found differences in side effects among women receiving paracervical block compared with controls (Level of evidence: I, moderate to low quality) (118,119).\nLimited evidence on nonsteroidal antiinflammatory drugs (NSAIDs) and nitric oxide donors generally suggested no positive effect; evidence on lidocaine with administration other than paracervical block was limited and inconclusive (Level of evidence for provider ease of insertion: I, good to poor, direct; Level of evidence for need for adjunctive insertion measures: I, fair, direct; Level of evidence for patient pain: I, high to low quality; Level of evidence for side effects: I, high to low quality) (115,116).\n\n# Provision of Prophylactic Antibiotics at the Time of IUD Insertion\n- Prophylactic antibiotics are generally not recommended for Cu-IUD or LNG-IUD insertion. Comments and Evidence Summary. Theoretically, IUD insertion could induce bacterial spread and lead to complications such as PID or infective endocarditis. A metaanalysis was conducted of randomized controlled trials examining antibiotic prophylaxis versus placebo or no treatment for IUD insertion (120). Use of prophylaxis reduced the frequency of unscheduled return visits but did not significantly reduce the incidence of PID or premature IUD discontinuation. Although the risk for PID was higher within the first 20 days after insertion, the incidence of PID was low among all women who had IUDs inserted (51). In addition, the American Heart Association recommends that the use of prophylactic antibiotics solely to prevent infective endocarditis is not needed for genitourinary procedures (121). Studies have not demonstrated a conclusive link between genitourinary procedures and infective endocarditis or a preventive benefit of prophylactic antibiotics during such procedures (121).\n\n# Routine Follow-Up After IUD Insertion\nThese recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, persons with certain medical conditions or characteristics, and persons with multiple medical conditions.\n- Advise the woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. - At other routine visits, health care providers who see IUD users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the IUD for safe and effective continued use on the basis of U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider performing an examination to check for the presence of the IUD strings. -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. Evidence from a systematic review about the effect of a specific follow-up visit schedule on IUD continuation is very limited and of poor quality. The evidence did not suggest that greater frequency of visits or earlier timing of the first follow-up visit after insertion improves continuation of use ( 122) (Level of evidence: II-2, poor, direct). Evidence from four studies from a systematic review on the incidence of PID among IUD initiators, or IUD removal as a result of PID, suggested that the incidence of PID did not differ between women using Cu-IUDs and those using DMPA, COCs, or LNG-IUDs (123) (Level of evidence: I to II-2, good, indirect). Evidence on the timing of PID after IUD insertion is mixed. Although the rate of PID generally was low, the largest study suggested that the rate of PID was significantly higher in the first 20 days after insertion (51) (Level of evidence: I to II-3, good to poor, indirect).\n\n# Bleeding Irregularities with Cu-IUD Use\n- Before Cu-IUD insertion, provide counseling about potential changes in bleeding patterns during Cu-IUD use. Unscheduled spotting or light bleeding, as well as heavy or prolonged bleeding, is common during the first 3-6 months of Cu-IUD use, is generally not harmful, and decreases with continued Cu-IUD use. - If clinically indicated, consider an underlying gynecological problem, such as Cu-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids), especially in women who have already been using the Cu-IUD for a few months or longer and who have developed a new onset of heavy or prolonged bleeding. If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecological problem is not found and the woman requests treatment, the following treatment option can be considered during days of bleeding: -NSAIDs for short-term treatment (5-7 days) - If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the Cu-IUD, information about common side effects such as unscheduled spotting or light bleeding or heavy or prolonged menstrual bleeding, especially during the first 3-6 months of use, should be discussed (64). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other contraceptives (i.e., DMPA) (124,125).\nEvidence is limited on specific drugs, doses, and durations of use for effective treatments for bleeding irregularities with Cu-IUD use. Therefore, although this report includes general recommendations for treatments to consider, evidence for specific regimens is lacking.\nA systematic review identified 11 studies that examined various therapeutic treatments for heavy menstrual bleeding, prolonged menstrual bleeding, or both among women using Cu-IUDs (126). Nine studies examined the use of various oral NSAIDs for the treatment of heavy or prolonged menstrual bleeding among Cu-IUD users and compared them with either a placebo or a baseline cycle. Three of these trials examined the use of indomethacin (127)(128)(129), three examined mefenamic acid (130)(131)(132), and three examined flufenamic acid (127,128,133). Other NSAIDs used in the reported trials included alclofenac (127,128), suprofen (134), and diclofenac sodium (135). All but one NSAID study ( 131) demonstrated statistically significant or notable reductions in mean total menstrual blood loss with NSAID use. One study among 19 Cu-IUD users with heavy bleeding suggested that treatment with oral tranexamic acid can significantly reduce mean blood loss during treatment compared with placebo (135). Data regarding the overall safety of tranexamic acid are limited; an FDA warning states that tranexamic acid is contraindicated in women with active thromboembolic disease or with a history or intrinsic risk for thrombosis or thromboembolism (136,137). Treatment with aspirin demonstrated no statistically significant change in mean blood loss among women whose pretreatment menstrual blood loss was >80 ml or 60-80 mL; treatment resulted in a significant increase among women whose pretreatment menstrual blood loss was <60 mL (138). One study examined the use of a synthetic form of vasopressin, intranasal desmopressin (300 µg/day), for the first 5 days of menses for three treatment cycles and found a significant reduction in mean blood loss compared with baseline (130) (Level of evidence: I to II-3, poor to fair, direct). Only one small study examined treatment of spotting with three separate NSAIDs and did not observe improvements in spotting in any of the groups (127) (Level of evidence: I, poor, direct).\n\n# Bleeding Irregularities (Including Amenorrhea) with LNG-IUD Use\n- Before LNG-IUD insertion, provide counseling about potential changes in bleeding patterns during LNG-IUD use. Unscheduled spotting or light bleeding is expected during the first 3-6 months of LNG-IUD use, is generally not harmful, and decreases with continued LNG-IUD use. Over time, bleeding generally decreases with LNG-IUD use, and many women experience only light menstrual bleeding or amenorrhea. Heavy or prolonged bleeding, either unscheduled or menstrual, is uncommon during LNG-IUD use.\n\n# Irregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding)\n- If clinically indicated, consider an underlying gynecological problem, such as LNG-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired.\n\n# Amenorrhea\n- Amenorrhea does not require any medical treatment. Provide reassurance.\n-If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. - If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired Comments and Evidence Summary. During contraceptive counseling and before insertion of the LNG-IUD, information about common side effects such as unscheduled spotting or light bleeding, especially during the first 3-6 months of use, should be discussed. Approximately half of LNG-IUD users are likely to experience amenorrhea or oligomenorrhea by 2 years of use (139). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (124,125). No direct evidence was found regarding therapeutic treatments for bleeding irregularities during LNG-IUD use.\n\n# Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Have PID\n- Treat the PID according to the CDC Sexually Transmitted Diseases Treatment Guidelines (15). - Provide comprehensive management for STDs, including counseling about condom use. - The IUD does not need to be removed immediately if the woman needs ongoing contraception. - Reassess the woman in 48-72 hours. If no clinical improvement occurs, continue antibiotics and consider removal of the IUD. - If the woman wants to discontinue use, remove the IUD sometime after antibiotics have been started to avoid the potential risk for bacterial spread resulting from the removal procedure. - If the IUD is removed, consider ECPs if appropriate.\nCounsel the woman on alternative contraceptive methods, and offer another method if it is desired. - A summary of IUD management in women with PID is provided (Appendix F). Comments and Evidence Summary. Treatment outcomes do not generally differ between women with PID who retain the IUD and those who have the IUD removed; however, appropriate antibiotic treatment and close clinical follow-up are necessary.\nA systematic review identified four studies that included women using copper or nonhormonal IUDs who developed PID and compared outcomes between women who had the IUD removed or did not (140). One randomized trial showed that women with IUDs removed had longer hospitalizations than those who did not, although no differences in PID recurrences or subsequent pregnancies were observed (141). Another randomized trial showed no differences in laboratory findings among women who removed the IUD compared with those who did not (142). One prospective cohort study showed no differences in clinical or laboratory findings during hospitalization; however, the IUD removal group had longer hospitalizations (143). One randomized trial showed that the rate of recovery for most clinical signs and symptoms was higher among women who had the IUD removed than among women who did not (144). No evidence was found regarding women using LNG-IUDs (Level of evidence: I to II-2, fair, direct.)\n\n# Management of the IUD when a Cu-IUD or an LNG-IUD User is Found To Be Pregnant\n- Evaluate for possible ectopic pregnancy.\n- Advise the woman that she has an increased risk for spontaneous abortion (including septic abortion that might be life threatening) and for preterm delivery if the IUD is left in place. The removal of the IUD reduces these risks but might not decrease the risk to the baseline level of a pregnancy without an IUD.\n-If she does not want to continue the pregnancy, counsel her about options. -If she wants to continue the pregnancy, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever.\n\n# IUD Strings Are Visible or Can Be Retrieved Safely from the Cervical Canal\n- Advise the woman that the IUD should be removed as soon as possible.\n-If the IUD is to be removed, remove it by pulling on the strings gently. -Advise the woman that she should return promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. - If she chooses to keep the IUD, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever.\n\n# IUD Strings Are Not Visible and Cannot Be Safely Retrieved\n- If ultrasonography is available, consider performing or referring for ultrasound examination to determine the location of the IUD. If the IUD cannot be located, it might have been expelled or have perforated the uterine wall. - If ultrasonography is not possible or the IUD is determined by ultrasound to be inside the uterus, advise the woman to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. Comments and Evidence Summary. Removing the IUD improves the pregnancy outcome if the IUD strings are visible or the device can be retrieved safely from the cervical canal. Risks for spontaneous abortion, preterm delivery, and infection are substantial if the IUD is left in place.\nTheoretically, the fetus might be affected by hormonal exposure from an LNG-IUD. However, whether this exposure increases the risk for fetal abnormalities is unknown.\nA systematic review identified nine studies suggesting that women who did not remove their IUDs during pregnancy were at greater risk for adverse pregnancy outcomes (including spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis) compared with women who had their IUDs removed or who did not have an IUD (41). Cu-IUD removal decreased risks but not to the baseline risk for pregnancies without an IUD. One case series examined LNG-IUDs. When they were not removed, 8 out of 10 pregnancies ended in spontaneous abortions (Level of evidence: II-2, fair, direct).\n\n# Implants\nThe etonogestrel implant, a single rod with 68 mg of etonogestrel, is available in the United States. Fewer than 1 woman out of 100 become pregnant in the first year of use of the etonogestrel implant with typical use (14). The implant is long acting, is reversible, and can be used by women of all ages, including adolescents. The implant does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# Initiation of Implants Timing\n- The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n\n# Need for Back-Up Contraception\n- If the implant is inserted within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. - If the implant is inserted >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Special Considerations\nAmenorrhea (Not Postpartum)\n- Timing: The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Postpartum (Breastfeeding)\n\n# Postabortion (Spontaneous or Induced)\n- Timing: The implant can be inserted within the first 7 days, including immediately after the abortion (U.S. MEC 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the implant is placed at the time of a surgical abortion.\n\n# Switching from Another Contraceptive Method\n- Timing: The implant can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. - Need for back-up contraception: If it has been >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days after insertion. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options:\n-Advise the woman to retain the IUD for at least 7 days after the implant is inserted and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs (with the exception of UPA) at the time of IUD removal. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting the implant likely exceed any risk; therefore, starting the implant should be considered at any time, with a follow-up pregnancy test in 2-4 weeks.\nIf a woman needs to use additional contraceptive protection when switching to an implant from another contraceptive method, consider continuing her previous method for 7 days after implant insertion. No direct evidence was found regarding the effects of starting the etonogestrel implant at different times of the cycle.\n\n# Examinations and Tests Needed Before Implant Insertion\nAmong healthy women, no examinations or tests are needed before initiation of an implant, although a baseline weight and BMI measurement might be useful for monitoring implant users over time (Table 2). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use implants (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of implants. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nBimanual examination and cervical inspection: A pelvic examination is not necessary before initiation of implants because it would not facilitate detection of conditions for which implant use would be unsafe. Women with current breast cancer should not use implants (U.S. MEC 4); women with certain liver diseases generally should not (U.S. MEC 3) use implants (5). However, none of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed. No evidence was found regarding implants (Level of evidence: II-2 fair, direct).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of implants because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/ dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results regarding the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases generally should not use implants (U.S. MEC 3) (5), screening for liver disease before initiation of implants is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, the percentage of U.S. women with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for implants.\nClinical breast examination: Although women with current breast cancer should not use implants (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. examination before initiation of implants is not necessary because of the low prevalence of breast cancer among women of reproductive age (15-49 years). A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with hypertension, diabetes, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) implants (5); therefore, screening for these conditions is not necessary for the safe initiation of implants.\n\n# Routine Follow-Up After Implant Insertion\nThese recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n- Advise the woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. - At other routine visits, health care providers seeing implant users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the implant for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. A systematic review did not identify any evidence regarding whether a routine follow-up visit after initiating an implant improves correct or continued use (122).\n\n# Bleeding Irregularities (Including Amenorrhea) During Implant Use\n- Before implant insertion, provide counseling about potential changes in bleeding patterns during implant use. Unscheduled spotting or light bleeding is common with implant use, and some women experience amenorrhea. These bleeding changes are generally not harmful and might or might not decrease with continued implant use. Heavy or prolonged bleeding, unscheduled or menstrual, is uncommon during implant use.\nIrregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding)\n- If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) - If irregular bleeding persists and the woman finds it unacceptable, counsel her on alternative methods, and offer another method if it is desired.\n\n# Amenorrhea\n- Amenorrhea does not require any medical treatment. Provide reassurance.\n-If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. - If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the implant, information about common side effects, such as unscheduled spotting or light bleeding and amenorrhea, especially during the first year of use, should be discussed. A pooled analysis of data from 11 clinical trials indicates that a significant proportion of etonogestrel implant users had relatively little bleeding: 22% of women experienced amenorrhea and 34% experienced infrequent spotting, although 7% reported frequent bleeding and 18% reported prolonged bleeding (146). Unscheduled bleeding or amenorrhea is generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (124,125).\nA systematic review and four newly published studies examined several medications for the treatment of bleeding irregularities with primarily levonorgestrel contraceptive implants (147)(148)(149)(150)(151). Two small studies found significant cessation of bleeding within 7 days of start of treatment among women taking oral celecoxib (200 mg) daily for 5 days or oral mefenamic acid (500 mg) 3 times daily for 5 days compared with placebo (149,150). Differences in bleeding cessation were not found among women with etonogestrel implants taking mifepristone but were found when women with the implants combined mifepristone with either ethinyl estradiol or doxycycline (151,152). Doxycycline alone or in combination with ethinyl estradiol did not improve bleeding cessation among etonogestrel implant users (151). Among LNG implant users, mifepristone reduced the number of bleeding or spotting days but only after 6 months of treatment (153). Evidence also suggests that estrogen (154)(155)(156), daily COCs (154), LNG pills (155), tamoxifen (157), or tranexamic acid (158) can reduce the number of bleeding or spotting days during treatment among LNG implant users. In one small study, vitamin E was found to significantly reduce the mean number of bleeding days after the first treatment cycle; however, another larger study reported no significant differences in length of bleeding and spotting episodes with vitamin E treatment (159,160). Use of aspirin did not result in a significant difference in median length of bleeding or bleeding and spotting episodes after treatment (159). One study among implant users reported a reduction in number of bleeding days after initiating ibuprofen; however, another trial did not demonstrate any significant differences in the number of spotting and bleeding episodes with ibuprofen compared with placebo (148,155).\n\n# Injectables\nProgestin-only injectable contraceptives (DMPA, 150 mg intramuscularly or 104 mg subcutaneously) are available in the United States; the only difference between these two formulations is the route of administration. Approximately 6 out of 100 women will become pregnant in the first year of use of DMPA with typical use (14). DMPA is reversible and can be used by women of all ages, including adolescents. DMPA does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# Initiation of Injectables Timing\n- The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n\n# Need for Back-Up Contraception\n- If DMPA is started within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. - If DMPA is started >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Special Considerations\nAmenorrhea (Not Postpartum)\n- Timing: The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 2). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Postpartum (Breastfeeding)\n- Postabortion (Spontaneous or Induced)\n- Timing: The first DMPA injection can be given within the first 7 days, including immediately after the abortion (U.S. MEC 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the injection is given at the time of a surgical abortion.\n\n# Switching from Another Contraceptive Method\n- Timing: The first DMPA injection can be given immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. - Need for back-up contraception: If it has been >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after the injection and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs (with the exception of UPA) at the time of IUD removal. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting DMPA likely exceed any risk; therefore, starting DMPA should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to DMPA from another contraceptive method, consider continuing her previous method for 7 days after DMPA injection.\nA systematic review identified eight articles examining DMPA initiation on different days of the menstrual cycle (161). Evidence from two studies with small sample sizes indicated that DMPA injections given up to day 7 of the menstrual cycle inhibited ovulation; when DMPA was administered after day 7, ovulation occurred in some women. Cervical mucus was of poor quality (i.e., not favorable for sperm penetration) in 90% of women within 24 hours of the injection (Level of evidence: II-2, fair) (162)(163)(164). Studies found that use of another contraceptive method until DMPA could be initiated (bridging option) did not help women initiate DMPA and was associated with more unintended pregnancies than immediate receipt of DMPA (165-169) (Level of evidence: I to II-3, fair to poor, indirect).\n\n# Examinations and Tests Needed Before Initiation of an Injectable\nAmong healthy women, no examinations or tests are needed before initiation of DMPA, although a baseline weight and BMI measurement might be useful to monitor DMPA users over time (Table 3). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for obesity is not necessary for the safe initiation of DMPA. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. (See guidance on follow-up for DMPA users for evidence on weight gain with DMPA use).\nBimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of DMPA because it does not facilitate detection of conditions for which DMPA would be unsafe. Although women with current breast cancer should not use DMPA (U.S. MEC 4), and women with severe hypertension, heart disease, vascular disease, or certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), none of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two casecontrol studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed (Level of evidence: II-2, fair, direct).\nBlood pressure: Women with hypertension generally can use DMPA (U.S. MEC 2), with the exception of women with severe hypertension or vascular disease, who generally should not use DMPA (U.S. MEC 3) (5). Screening for hypertension before initiation of DMPA is not necessary because of the low prevalence of undiagnosed severe hypertension and the high likelihood that women with these conditions already would have had them diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a blood pressure measurement before initiation of progestin-only contraceptives (170). The prevalence of undiagnosed hypertension among women of reproductive age is low. During 2009-2012 among women aged 20-44 years in the United States, the prevalence of hypertension was 8.7% (84). During 1999-2008, the percentage of women aged 20-44 years with undiagnosed hypertension was 1.9% (85).\nGlucose: Although women with complicated diabetes generally should not use DMPA (U.S. MEC 3) (5), screening for diabetes before initiation of DMPA is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes would already have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (57). The prevalence of diabetes among women of reproductive age is low. During 2009-2012 among women aged 20-44 years in the United States, the prevalence of diabetes was 3.3% (84). During 1999-2008, the percentage of women aged 20-44 years with undiagnosed diabetes was 0.5% (85).\nAlthough hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (171)(172)(173)(174)(175)(176)(177).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of injectables because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results about the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), screening for liver disease before initiation of DMPA is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for DMPA. - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\n\n# Clinical breast examination:\nAlthough women with current breast cancer should not use DMPA (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating DMPA is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for these conditions is not necessary for the safe initiation of DMPA.\n\n# Routine Follow-Up After Injectable Initiation\nThese recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n- Advise the woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time for reinjection.\nNo routine follow-up visit is required. - At other routine visits, health care providers seeing injectable users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the injectable for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. Although no evidence exists regarding whether a routine follow-up visit after initiating DMPA improves correct or continued use, monitoring weight or BMI change over time is important for DMPA users.\nA systematic review identified a limited body of evidence that examined whether weight gain in the few months after DMPA initiation predicted future weight gain (123). Two studies found significant differences in weight gain or BMI at follow-up periods ranging from 12 to 36 months between early weight gainers (i.e., those who gained >5% of their baseline body weight within 6 months after initiation) and those who were not early weight gainers (178,179). The differences between groups were more pronounced at 18, 24, and 36 months than at 12 months. One study found that most adolescent DMPA users who had gained >5% of their baseline weight by 3 months gained even more weight by 12 months (180) (Level of evidence: II-2, fair, to II-3, fair, direct).\n\n# Timing of Repeat Injections Reinjection Interval\n- Provide repeat DMPA injections every 3 months (13 weeks).\n\n# Special Considerations Early Injection\n- The repeat DMPA injection can be given early when necessary.\n\n# Late Injection\n- The repeat DMPA injection can be given up to 2 weeks late (15 weeks from the last injection) without requiring additional contraceptive protection. - If the woman is >2 weeks late (>15 weeks from the last injection) for a repeat DMPA injection, she can have the injection if it is reasonably certain that she is not pregnant (Box 2). She needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. She might consider the use of emergency contraception (with the exception of UPA) if appropriate. Comments and Evidence Summary. No time limits exist for early injections; injections can be given when necessary (e.g., when a woman cannot return at the routine interval). WHO has extended the time that a woman can have a late reinjection (i.e., grace period) for DMPA use from 2 weeks to 4 weeks on the basis of data from one study showing low pregnancy rates through 4 weeks; however, the CDC expert group did not consider the data to be generalizable to the United States because a large proportion of women in the study were breastfeeding. Therefore, U.S. SPR recommends a grace period of 2 weeks.\nA systematic review identified 12 studies evaluating time to pregnancy or ovulation after the last injection of DMPA (181). Although pregnancy rates were low during the 2-week interval following the reinjection date and for 4 weeks following the reinjection date, data were sparse, and one study included a large proportion of breastfeeding women (182)(183)(184). Studies also indicated a wide variation in time to ovulation after the last DMPA injection, with the majority ranging from 15 to 49 weeks from the last injection (185)(186)(187)(188)(189)(190)(191)(192)(193)\n\n# Unscheduled Spotting or Light Bleeding\n- If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment option during days of bleeding can be considered: -NSAIDs for short-term treatment (5-7 days) - If unscheduled spotting or light bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired.\n\n# Heavy or Prolonged Bleeding\n- If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (such as fibroids or polyps). If an underlying gynecologic problem is identified, treat the condition or refer for care. - If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) - If heavy or prolonged bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired.\n\n# Amenorrhea\n- Amenorrhea does not require any medical treatment. Provide reassurance.\n-If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. - If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiation of DMPA, information about common side effects such as irregular bleeding should be discussed. Unscheduled bleeding or spotting is common with DMPA use (194). In addition, amenorrhea is common after ≥1 years of continuous use (194,195). These bleeding irregularities are generally not harmful. Enhanced counseling among DMPA users detailing expected bleeding patterns and reassurance that these irregularities generally are not harmful has been shown to reduce DMPA discontinuation in clinical trials (124,125).\nA systematic review, as well as two additional studies, examined the treatment of bleeding irregularities during DMPA use (195)(196)(197). Two small studies found significant cessation of bleeding within 7 days of starting treatment among women taking valdecoxib for 5 days or mefenamic acid for 5 days compared with placebo (198,199). Treatment with ethinyl estradiol was found to stop bleeding better than placebo during the treatment period, although rates of discontinuation were high and safety outcomes were not examined (200). In one small study among DMPA users who had been experiencing amenorrhea for 2 months, treatment with COCs was found to alleviate amenorrhea better than placebo (201). No studies examined the effects of aspirin on bleeding irregularities among DMPA users.\n\n# Combined Hormonal Contraceptives\nCombined hormonal contraceptives contain both estrogen and a progestin and include 1) COCs (various formulations), 2) a transdermal contraceptive patch (which releases 150 µg of norelgestromin and 20 µg ethinyl estradiol daily), and 3) a vaginal contraceptive ring (which releases 120 µg etonogestrel and 15 µg ethinyl estradiol daily). Approximately 9 out of 100 women become pregnant in the first year of use with combined hormonal contraceptives with typical use (14). These methods are reversible and can be used by women of all ages. Combined hormonal contraceptives are generally used for US Department of Health and Human Services/Centers for Disease Control and Prevention 21-24 consecutive days, followed by 4-7 hormone-free days (either no use or placebo pills). These methods are sometimes used for an extended period with infrequent or no hormonefree days. Combined hormonal contraceptives do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# Initiation of Combined Hormonal Contraceptives Timing\n- Combined hormonal contraceptives can be initiated at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n\n# Need for Back-Up Contraception\n- If combined hormonal contraceptives are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. - If combined hormonal contraceptives are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Special Considerations\nAmenorrhea (Not Postpartum)\n- Timing: Combined hormonal contraceptives can be started at any time if it is reasonably certain that the woman is not pregnant (Box 2). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n\n# Postpartum (Breastfeeding)\n- Timing: Combined hormonal contraceptives can be started when the woman is medically eligible to use the method (5) and if it is reasonably certain that she is not pregnant. (\n\n# Postabortion (Spontaneous or Induced)\n- Timing: Combined hormonal contraceptives can be started within the first 7 days following first-trimester or second-trimester abortion, including immediately postabortion (U.S. MEC 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless combined hormonal contraceptives are started at the time of a surgical abortion.\n\n# Switching from Another Contraceptive Method\n- Timing: Combined hormonal contraceptives can be started immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. - Need for back-up contraception: If it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after combined hormonal contraceptives are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs at the time of IUD removal. Combined hormonal contraceptives can be started immediately after use of ECPs (with the exception of UPA). Combined hormonal contraceptives can be started no sooner than 5 days after use of UPA. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting combined hormonal contraceptives likely exceed any risk; therefore, starting combined hormonal contraceptives should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to combined hormonal contraceptives from another contraceptive method, consider continuing her previous method for 7 days after starting combined hormonal contraceptives.\nA systematic review of 18 studies examined the effects of starting combined hormonal contraceptives on different days of the menstrual cycle (202). Overall, the evidence suggested that pregnancy rates did not differ by the timing of combined hormonal contraceptive initiation (169,(203)(204)(205) (Level of evidence: I to II-3, fair, indirect). The more follicular activity that occurred before starting COCs, the more likely ovulation was to occur; however, no ovulations occurred when COCs were started at a follicle diameter of 10 mm (mean cycle day 7.6) or when the ring was started at 13 mm (median cycle day 11) (206-215) (Level of evidence: I to II-3, fair, indirect). Bleeding patterns and other side effects did not vary with the timing of combined hormonal contraceptive initiation (204,205,(216)(217)(218)(219)(220) (Level of evidence: I to II-2, good to poor, direct). Although continuation rates of combined hormonal contraceptives were initially improved by the \"quick start\" approach (i.e., starting on the day of the visit), the advantage disappeared over time (203,204,(216)(217)(218)(219)(220)(221) (Level of evidence: I to II-2, good to poor, direct).\n\n# Examinations and Test Needed Before Initiation of Combined Hormonal Contraceptives\nAmong healthy women, few examinations or tests are needed before initiation of combined hormonal contraceptives (Table 4). Blood pressure should be measured before initiation of combined hormonal contraceptives. Baseline weight and BMI measurements might be useful for monitoring combined hormonal contraceptive users over time. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Blood pressure: Women who have more severe hypertension (systolic pressure of ≥160 mmHg or diastolic pressure of ≥100 mm Hg) or vascular disease should not use combined hormonal contraceptives (U.S. MEC 4), and women who have less severe hypertension (systolic pressure of 140-159 mm Hg or diastolic pressure of 90-99 mm Hg) or adequately controlled hypertension generally should not use combined hormonal contraceptives (U.S. MEC 3) (5). Therefore, blood pressure should be evaluated before initiating combined hormonal contraceptives. In instances in which blood pressure cannot be measured by a provider, blood pressure measured in other settings can be reported by the woman to her provider. Evidence suggests that cardiovascular outcomes are worse among women who did not have their blood pressure measured before initiating COCs. A systematic review identified six articles from three studies that reported cardiovascular outcomes among women who had blood pressure measurements and women who did not have blood pressure measurements before initiating COCs (170). Three case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for acute myocardial infarction than women who did have blood pressure measurements (222)(223)(224). Two case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for ischemic stroke than women who did have blood pressure measurements (225,226). One case-control study showed no difference in the risk for hemorrhagic stroke among women who initiated COCs regardless of whether their blood pressure was measured (227). Studies that examined hormonal contraceptive methods other than COCs were not identified (Level of evidence: II-2, fair, direct).\n\n# Weight (BMI):\nObese women generally can use combined hormonal contraceptives (U.S. MEC 2) (5); therefore, screening for obesity is not necessary for the safe initiation of combined hormonal contraceptives. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nBimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of combined hormonal contraceptives because it does not facilitate detection of conditions for which hormonal contraceptives would be unsafe. Women with certain conditions such as current breast cancer, severe hypertension or vascular disease, heart disease, migraine headaches with aura, and certain liver diseases, as well as women aged ≥35 years and who smoke ≥15 cigarettes per day, should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5); however, none of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were found (Level of evidence: Level II-2 fair, direct).\nGlucose: Although women with complicated diabetes should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives, depending on the severity of the condition (5), screening for diabetes before initiation of hormonal contraceptives is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (57). The prevalence of diabetes among women of reproductive age is low. During 2009-2012 among women aged 20-44 years in the United States, the prevalence of diabetes was 3.3% (84). During 1999-2008, the percentage of women aged 20-44 years with undiagnosed diabetes was 0.5% (85). Although hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (171)(172)(173)(174)(175)(176)(177).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of combined hormonal contraceptives because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). A systematic review identified few studies, all of poor quality, that suggest that women with known dyslipidemias using combined hormonal contraceptives might be at increased risk for myocardial infarction, cerebrovascular accident, or venous thromboembolism compared with women without dyslipidemias; no studies were identified that examined risk for pancreatitis among women with known dyslipidemias using combined hormonal contraceptives (89). Studies have shown mixed results regarding the effects of hormonal contraceptives on lipid levels among both healthy women and women with - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † In instances in which blood pressure cannot be measured by a provider, blood pressure measured in other settings can be reported by the woman to her provider. § Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nbaseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5), screening for liver disease before initiation of combined hormonal contraceptives is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited; no evidence exists for other types of combined hormonal contraceptives.\nThrombogenic mutations: Women with thrombogenic mutations should not use combined hormonal contraceptives (U.S. MEC 4) (5) because of the increased risk for venous thromboembolism (228). However, studies have shown that universal screening for thrombogenic mutations before initiating COCs is not cost-effective because of the rarity of the conditions and the high cost of screening (229)(230)(231).\nClinical breast examination: Although women with current breast cancer should not use combined hormonal contraceptives (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating combined hormonal contraceptives is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with anemia, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) combined hormonal contraceptives (5); therefore, screening for these conditions is not necessary for the safe initiation of combined hormonal contraceptives.\n\n# Number of Pill Packs that Should Be Provided at Initial and Return Visits\n- At the initial and return visits, provide or prescribe up to a 1-year supply of COCs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. - A woman should be able to obtain COCs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy.\nA systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (232). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (233)(234)(235). However, one study found no difference in continuation when patients were provided one and then three packs versus four packs all at once (236). In addition to continuation, a greater number of pills packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (i.e., 13 packs versus three packs) also was associated with increased pill wastage in one study (234) (Level of evidence: I to II-2, fair, direct).\n\n# Routine Follow-Up After Combined Hormonal Contraceptive Initiation\nThese recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n- Advise the woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. - At other routine visits, health care providers seeing combined hormonal contraceptive users should do the following:\n-Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of combined hormonal contraceptives for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Assess blood pressure.\n-Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence exists regarding whether a routine follow-up visit after initiating combined hormonal contraceptives improves correct or continued use. Monitoring blood pressure is important for combined hormonal contraceptive users. Health care providers might consider recommending women obtain blood pressure measurements in other settings.\nA systematic review identified five studies that examined the incidence of hypertension among women who began using a COC versus those who started a nonhormonal method of contraception or a placebo (123). Few women developed hypertension after initiating COCs, and studies examining increases in blood pressure after COC initiation found mixed results. No studies were identified that examined changes in blood pressure among patch or vaginal ring users (Level of evidence: I, fair, to II-2, fair, indirect).\n\n# Late or Missed Doses and Side Effects from Combined Hormonal Contraceptive Use\nFor the following recommendations, a dose is considered late when <24 hours have elapsed since the dose should have been taken. A dose is considered missed if ≥24 hours have elapsed since the dose should have been taken. For example, if a COC pill was supposed to have been taken on Monday at 9:00 a.m. and is taken at 11:00 a.m., the pill is late; however, by Tuesday morning at 11:00 a.m., Monday's 9:00 a.m. pill has been missed and Tuesday's 9:00 a.m. pill is late. For COCs, the recommendations only apply to late or missed hormonally active pills and not to placebo pills. Recommendations are provided for late or missed pills (Figure 2), the patch (Figure 3), and the ring (Figure 4).\nComments and Evidence Summary. Inconsistent or incorrect use of combined hormonal contraceptives is a major cause of combined hormonal contraceptive failure. Extending the hormone-free interval is considered to be a particularly risky time to miss combined hormonal contraceptives. Seven days of continuous combined hormonal contraceptive use is deemed necessary to reliably prevent ovulation. The recommendations reflect a balance between simplicity and precision of science. Women who frequently miss COCs or experience other usage errors with combined hormonal patch or combined vaginal ring should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable).\nA systematic review identified 36 studies that examined measures of contraceptive effectiveness of combined hormonal contraceptives during cycles with extended hormone-free intervals, shortened hormone-free intervals, or deliberate nonadherence on days not adjacent to the hormone-free interval (237). Most of the studies examined COCs (215,, two examined the combined hormonal patch (259,266), and six examined the combined vaginal ring (211,(267)(268)(269)(270)(271). No direct evidence on the effect of missed pills on the risk for pregnancy was found. Studies of women deliberately extending the hormone-free interval up to 14 days found wide variability in the amount of follicular development and occurrence of ovulation (241,244,246,247,249,250,(252)(253)(254)(255); in general, the risk for ovulation was low, and among women who did ovulate, cycles were usually abnormal. In studies of women who deliberately missed pills on various days during the cycle not adjacent to the hormone-free interval, ovulation occurred infrequently (239,(245)(246)(247)255,256,258,259). Studies comparing 7-day hormone-free intervals with shorter hormone-free intervals found lower rates of pregnancy (238,242,251,257) and significantly greater suppression of ovulation (240,250,(261)(262)(263)265) among women with shorter intervals in all but one study (260), which found no difference. Two studies that compared 30-µg ethinyl estradiol pills with 20-µg ethinyl estradiol pills showed more follicular activity when 20-µg ethinyl estradiol pills were missed (241,244). In studies examining the combined vaginal ring, three studies found that nondeliberate extension of the hormone-free interval for 24 to <48 hours from the scheduled period did not increase the risk for pregnancy (267,268,270); one study found that ring insertion after a deliberately extended hormone-free interval that allowed a 13-mm follicle to develop interrupted ovarian function and further follicular growth (211); and one study found that inhibition of ovulation was maintained after deliberately forgetting to remove the ring for up to 2 weeks after normal ring use (271). In studies examining the combined hormonal patch, one study found that missing 1-3 consecutive days before patch replacement (either wearing one patch 3 days longer before replacement or going 3 days without a patch before replacing the next patch) on days not adjacent to the patch-free interval resulted in little follicular activity and low risk for ovulation (259), and one pharmacokinetic study found that serum levels of If one hormonal pill is late: (<24 hours since a pill should have been taken) If one hormonal pill has been missed: (24 to <48 hours since a pill should have been taken) If two or more consecutive hormonal pills have been missed: (≥48 hours since a pill should have been taken)\n- Take the late or missed pill as soon as possible.\n- Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day).\n- No additional contraceptive protection is needed. - Emergency contraception is not usually needed but can be considered (with the exception of UPA) if hormonal pills were missed earlier in the cycle or in the last week of the previous cycle.\n- Take the most recent missed pill as soon as possible. (Any other missed pills should be discarded.) - Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day).\n- Use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills have been taken for 7 consecutive days. - If pills were missed in the last week of hormonal pills (e.g., days 15-21 for 28-day pill packs):\n- Omit the hormone-free interval by nishing the hormonal pills in the current pack and starting a new pack the next day. o If unable to start a new pack immediately, use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills from a new pack have been taken for 7 consecutive days. - Emergency contraception should be considered (with the exception of UPA) if hormonal pills were missed during the rst week and unprotected sexual intercourse occurred in the previous 5 days. - Emergency contraception may also be considered (with the exception of UPA) at other times as appropriate. ethinyl estradiol and progestin norelgestromin remained within reference ranges after extending patch wear for 3 days (266).\nNo studies were found on extending the patch-free interval. In studies that provide indirect evidence on the effects of missed combined hormonal contraception on surrogate measures of pregnancy, how differences in surrogate measures correspond to pregnancy risk is unclear (Level of evidence: I, good, indirect to II-3, poor, direct).\n\n# Vomiting or Severe Diarrhea While Using COCs\nCertain steps should be taken by women who experience vomiting or severe diarrhea while using COCs (Figure 5).\nComments and Evidence Summary. Theoretically, the contraceptive effectiveness of COCs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence that addresses vomiting or severe diarrhea while using COCs, these recommendations are based on the recommendations for missed COCs. No evidence was found on the effects of vomiting or diarrhea on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality.\n\n# Unscheduled Bleeding with Extended or Continuous Use of Combined Hormonal Contraceptives\n- Before initiation of combined hormonal contraceptives, provide counseling about potential changes in bleeding patterns during extended or continuous combined hormonal contraceptive use. (Extended contraceptive use is defined as a planned hormone-free interval after at least two contiguous cycles. Continuous contraceptive use is defined as uninterrupted use of hormonal contraception without a hormone-free interval) (272). - Unscheduled spotting or bleeding is common during the first 3-6 months of extended or continuous combined hormonal contraceptive use. It is generally not harmful and decreases with continued combined hormonal contraceptive use. - If clinically indicated, consider an underlying gynecological problem, such as inconsistent use, interactions with other medications, cigarette smoking, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. - If an underlying gynecological problem is not found and the woman wants treatment, the following treatment option can be considered:\nDelayed insertion of a new ring or delayed reinsertion of a current ring for <48 hours since a ring should have been inserted\nDelayed insertion of a new ring or delayed reinsertion for ≥48 hours since a ring should have been inserted\n- Insert ring as soon as possible.\n- Keep the ring in until the scheduled ring removal day.\n- No additional contraceptive protection is needed.\n- Emergency contraception is not usually needed but can be considered (with the exception of UPA) if delayed insertion or reinsertion occurred earlier in the cycle or in the last week of the previous cycle.\n- Insert ring as soon as possible.\n- Keep the ring in until the scheduled ring removal day.\n- Use back-up contraception (e.g., condoms) or avoid sexual intercourse until a ring has been worn for 7 consecutive days. - Emergency contraception may also be considered (with the exception of UPA) at other times as appropriate.\n\n# FIGURE 4. Recommended actions after delayed insertion or reinsertion- with combined vaginal ring\nAbbreviation: UPA = ulipristal acetate. - If removal takes place but the woman is unsure of how long the ring has been removed, consider the ring to have been removed for ≥48 hours since a ring should have been inserted or reinserted.\n-Advise the woman to discontinue combined hormonal contraceptive use (i.e., a hormone-free interval) for 3-4 consecutive days; a hormone-free interval is not recommended during the first 21 days of using the continuous or extended combined hormonal contraceptive method. A hormone-free interval also is not recommended more than once per month because contraceptive effectiveness might be reduced. - If unscheduled spotting or bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiating extended or continuous combined hormonal contraceptives, information about common side effects such as unscheduled spotting or bleeding, especially during the first 3-6 months of use, should be discussed (273). These bleeding irregularities are generally not harmful and usually improve with persistent use of the hormonal method. To avoid unscheduled spotting or bleeding, counseling should emphasize the importance of correct use and timing; for users of contraceptive pills, emphasize consistent pill use. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with DMPA (124,125,274).\nA systematic review identified three studies with small study populations that addressed treatments for unscheduled bleeding among women using extended or continuous combined hormonal contraceptives (275). In two separate randomized clinical trials in which women were taking either contraceptive pills or using the contraceptive ring continuously for 168 days, women assigned to a hormone-free interval of 3 or 4 days reported improved bleeding. Although they noted an initial increase in flow, this was followed by an abrupt decrease 7-8 days later with eventual cessation of flow 11-12 days later. These findings were compared with women who continued to use their method without a hormonefree interval, in which a greater proportion reported either treatment failure or fewer days of amenorrhea (276,277). In another randomized trial of 66 women with unscheduled bleeding among women using 84 days of hormonally active contraceptive pills, oral doxycycline (100 mg twice daily) initiated the first day of bleeding and taken for 5 days did not result in any improvement in bleeding compared with placebo (278) (Level of evidence: I, fair, direct).\nVomiting or diarrhea (for any reason, for any duration), that occurs within 24 hours after taking a hormonal pill Vomiting or diarrhea, for any reason, continuing for 24 to <48 hours after taking any hormonal pill Vomiting or diarrhea, for any reason, continuing for ≥48 hours after taking any hormonal pill - Taking another hormonal pill (redose) is unnecessary.\n- Continue taking pills daily at the usual time (if possible, despite discomfort). - No additional contraceptive protection is needed. - Emergency contraception is not usually needed but can be considered (with the exception of UPA) as appropriate.\n- Continue taking pills daily at the usual time (if possible, despite discomfort). - Use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills have been taken for 7 consecutive days after vomiting or diarrhea has resolved.\n\n# Progestin-Only Pills\nPOPs contain only a progestin and no estrogen and are available in the United States. Approximately 9 out of 100 women become pregnant in the first year of use with POPs with typical use (14). POPs are reversible and can be used by women of all ages. POPs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# Initiation of POPs Timing\n- POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n\n# Need for Back-Up Contraception\n- If POPs are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. - If POPs are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n\n# Special Considerations\nAmenorrhea (Not Postpartum)\n- Timing: POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 2). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n\n# Postpartum (Breastfeeding)\n- Timing: POPs can be started at any time, including immediately postpartum (U.S. MEC 2 if 5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n\n# Postpartum (Not Breastfeeding)\n- Timing: POPs can be started at any time, including immediately postpartum (U.S. MEC 1), if it is reasonably certain that the woman is not pregnant (Box 2). - Need for back-up contraception: If a woman is 5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n\n# Postabortion (Spontaneous or Induced)\n- Timing: POPs can be started within the first 7 days, including immediately postabortion (U.S. MEC 1). - Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days unless POPs are started at the time of a surgical abortion.\n\n# Switching from Another Contraceptive Method\n- Timing: POPs can be started immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. - Need for back-up contraception: If it has been >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. - Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options: -Advise the women to retain the IUD for at least 2 days after POPs are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs at the time of IUD removal. POPs can be started immediately after use of ECPs (with the exception of UPA). POPs can be started no sooner than 5 days after use of UPA. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting POPs likely exceed any risk; therefore, starting POPs should be considered at any time, with a follow-up pregnancy test in 2-4 weeks.\nUnlike COCs, POPs inhibit ovulation in about half of cycles, although the rates vary widely by individual (279). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (279). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use has been deemed necessary to achieve the contraceptive effects on cervical mucus (279). If a woman needs to use additional contraceptive protection when switching to POPs from another contraceptive method, consider continuing her previous method for 2 days after starting POPs. No direct evidence was found regarding the effects of starting POPs at different times of the cycle.\n\n# Examinations and Tests Needed Before Initiation of POPs\nAmong healthy women, no examinations or tests are needed before initiation of POPs, although a baseline weight and BMI measurement might be useful for monitoring POP users over time (Table 5). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. The U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use POPs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of POPs. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nBimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of POPs because it does not facilitate detection of conditions for which POPs would be unsafe. Women with current breast cancer should not use POPs (U.S. MEC 4), and women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5); however, neither of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two casecontrol studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal findings from wet mounts were observed (Level of evidence: II-2 fair, direct).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of POPs because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results about the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5), screening for liver disease before initiation of POPs is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would - Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nhave had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94).\nClinical breast examination: Although women with current breast cancer should not use POPs (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating POPs is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with hypertension, diabetes, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) POPs (5); therefore, screening for these conditions is not necessary for the safe initiation of POPs.\n\n# Number of Pill Packs that Should Be Provided at Initial and Return Visits\n- At the initial and return visit, provide or prescribe up to a 1-year supply of POPs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. - A woman should be able to obtain POPs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy.\nA systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (232). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (233)(234)(235). However, one study found no difference in continuation when patients were provided one and then three packs versus four packs all at once (236). In addition to continuation, a greater number of pill packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (13 packs versus three packs) also was associated with increased pill wastage in one study (234) (Level of evidence: I to II-2, fair, direct).\n\n# Routine Follow-Up After POP Initiation\nThese recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n- Advise the woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. - At other routine visits, health care providers seeing POP users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of POPs for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence was found regarding whether a routine follow-up visit after initiating POPs improves correct and continued use.\n\n# Missed POPs\nFor the following recommendations, a dose is considered missed if it has been >3 hours since it should have been taken.\n- Take one pill as soon as possible.\n- Continue taking pills daily, one each day, at the same time each day, even if it means taking two pills on the same day. - Use back-up contraception (e.g., condoms) or avoid sexual intercourse until pills have been taken correctly, on time, for 2 consecutive days.\n- Emergency contraception should be considered (with the exception of UPA) if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Inconsistent or incorrect use of oral contraceptive pills is a major reason for oral contraceptive failure. Unlike COCs, POPs inhibit ovulation in about half of cycles, although this rate varies widely by individual (279). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (279). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use was deemed necessary to achieve the contraceptive effects on cervical mucus (279). Women who frequently miss POPs should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable). No evidence was found regarding the effects of missed POPs available in the United States on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality.\n\n# Vomiting or Diarrhea (for any Reason or Duration) that Occurs Within 3 Hours After\nTaking a Pill\n- Take another pill as soon as possible (if possible, despite discomfort). - Continue taking pills daily, one each day, at the same time each day. - Use back-up contraception (e.g., condoms) or avoid sexual intercourse until 2 days after vomiting or diarrhea has resolved. - Emergency contraception should be considered (with the exception of UPA) if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Theoretically, the contraceptive effectiveness of POPs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence to address this question, these recommendations are based on the recommendations for missed POPs. No evidence was found regarding the effects of vomiting or diarrhea on measures of contraceptive effectiveness, including pregnancy, follicular development, hormone levels, or cervical mucus quality.\n\n# Standard Days Method\nSDM is a method based on fertility awareness; users must avoid unprotected sexual intercourse on days 8-19 of the menstrual cycle (280). Approximately 5 out of 100 women become pregnant in the first year of use with perfect (i.e., correct and consistent) use of SDM (280); effectiveness based on typical use is not available for this method but is expected to be lower than that for perfect use. SDM is reversible and can be used by women of all ages. SDM does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# Use of SDM Among Women with Various Durations of the Menstrual Cycle Menstrual Cycles of 26-32 Days\n- The woman may use the method.\n- Provide a barrier method of contraception for protection on days 8-19 if she wants one. - If she has unprotected sexual intercourse during days 8-19, consider the use of emergency contraception if appropriate.\n\n# Two or More Cycles of 32 Days Within Any 1 Year of SDM Use\n- Advise the woman that the method might not be appropriate for her because of a higher risk for pregnancy. Help her consider another method. Comments and Evidence Summary. The probability of pregnancy is increased when the menstrual cycle is outside the range of 26-32 days, even if unprotected sexual intercourse is avoided on days 8-19. A study of 7,600 menstrual cycles, including information on cycle length and signs of ovulation, concluded that the theoretical effectiveness of SDM is greatest for women with cycles of 26-32 days, that the method is still effective for women who occasionally have a cycle outside this range, and that it is less effective for women who consistently have cycles outside this range. Information from daily hormonal measurements shows that the timing of the 6-day fertile window varies greatly, even among women with regular cycles (21,281,282).\n\n# Emergency Contraception\nEmergency contraception consists of methods that can be used by women after sexual intercourse to prevent pregnancy. Emergency contraception methods have varying ranges of effectiveness depending on the method and timing of administration. Four options are available in the United States: the Cu-IUD and three types of ECPs.\n\n# Types of Emergency Contraception Intrauterine Device\n- Cu-IUD\n\n# ECPs\n- UPA in a single dose (30 mg) - Levonorgestrel in a single dose (1.5 mg) or as a split dose (1 dose of 0.75 mg of levonorgestrel followed by a second dose of 0.75 mg of levonorgestrel 12 hours later) - Combined estrogen and progestin in 2 doses (Yuzpe regimen: 1 dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel followed by a second dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel 12 hours later)\n\n# Initiation of Emergency Contraception\nTiming Cu-IUD\n- The Cu-IUD can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. - In addition, when the day of ovulation can be estimated, the Cu-IUD can be inserted beyond 5 days after sexual intercourse, as long as insertion does not occur >5 days after ovulation.\n\n# ECPs\n- ECPs should be taken as soon as possible within 5 days of unprotected sexual intercourse. Comments and Evidence Summary. Cu-IUDs are highly effective as emergency contraception (283) and can be continued as regular contraception. UPA and levonorgestrel ECPs have similar effectiveness when taken within 3 days after unprotected sexual intercourse; however, UPA has been shown to be more effective than the levonorgestrel formulation 3-5 days after unprotected sexual intercourse (284). The combined estrogen and progestin regimen is less effective than UPA or levonorgestrel and also is associated with more frequent occurrence of side effects (nausea and vomiting) (285). The levonorgestrel formulation might be less effective than UPA among obese women (286).\nTwo studies of UPA use found consistent decreases in pregnancy rates when administered within 120 hours of unprotected sexual intercourse (284,287). Five studies found that the levonorgestrel and combined regimens decreased risk for pregnancy through the fifth day after unprotected sexual intercourse; however, rates of pregnancy were slightly higher when ECPs were taken after 3 days (288)(289)(290)(291)(292). A meta-analysis of levonorgestrel ECPs found that pregnancy rates were low when administered within 4 days after unprotected sexual intercourse but increased at 4-5 days (293) (Level of evidence: I to II-2, good to poor, direct).\n\n# Advance Provision of ECPs\n- An advance supply of ECPs may be provided so that ECPs will be available when needed and can be taken as soon as possible after unprotected sexual intercourse. Comments and Evidence Summary. A systematic review identified 17 studies that reported on safety or effectiveness of advance ECPs in adult or adolescent women (294). Any use of ECPs was two to seven times greater among women who received an advance supply of ECPs. However, a summary estimate (relative risk = 0.97; 95% confidence interval = 0.77-1.22) of five randomized controlled trials did not indicate a significant reduction in unintended pregnancies at 12 months with advance provision of ECPs. In the majority of studies among adults or adolescents, patterns of regular contraceptive use, pregnancy rates, and incidence of STDs did not vary between those who received advance ECPs and those who did not. Although available evidence supports the safety of advance provision of ECPs, effectiveness of advance provision of ECPs in reducing pregnancy rates at the population level has not been demonstrated (Level of evidence: I to II-3, good to poor, direct).\n\n# Initiation of Regular Contraception After ECPs\n\n# UPA\n- Advise the woman to start or resume hormonal contraception no sooner than 5 days after use of UPA, and provide or prescribe the regular contraceptive method as needed. For methods requiring a visit to a health care provider, such as DMPA, implants, and IUDs, starting the method at the time of UPA use may be considered; the risk that the regular contraceptive method might decrease the effectiveness of UPA must be weighed against the risk of not starting a regular hormonal contraceptive method. - The woman needs to abstain from sexual intercourse or use barrier contraception for the next 7 days after starting or resuming regular contraception or until her next menses, whichever comes first. - Any nonhormonal contraceptive method can be started immediately after the use of UPA. - Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks.\n\n# Levonorgestrel and Combined Estrogen and Progestin ECPs\n- Any regular contraceptive method can be started immediately after the use of levonorgestrel or combined estrogen and progestin ECPs. - The woman needs to abstain from sexual intercourse or use barrier contraception for 7 days. - Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks. Comments and Evidence Summary. The resumption or initiation of regular hormonal contraception after ECP use involves consideration of the risk for pregnancy if ECPs fail and the risks for unintended pregnancy if contraception initiation is delayed until the subsequent menstrual cycle. A health care provider may provide or prescribe pills, the patch, or the ring for a woman to start no sooner than 5 days after use of UPA. For methods requiring a visit to a health care provider, such as DMPA, implants, and IUDs, starting the method at the time of UPA use may be considered; the risk that the regular contraceptive method might decrease the effectiveness of UPA must be weighed against the risk of not starting a regular hormonal contraceptive method.\nData on when a woman can start regular contraception after ECPs are limited to pharmacodynamic data and expert opinion (295)(296)(297). In one pharmacodynamic study of women who were randomly assigned to either UPA or placebo groups mid-cycle followed by a 21-day course of combined hormonal contraception found no difference between UPA and placebo groups in the time for women's ovaries to reach quiescence by ultrasound and serum estradiol (296); this finding suggests that UPA did not have an effect on the combined hormonal contraception. In another pharmacodynamic study with a crossover design, women were randomly assigned to one of three groups: 1) UPA followed by desogestrel for 20 days started 1 day later; 2) UPA plus placebo; or 3) placebo plus desogestrel for 20 days (295). Among women taking UPA followed by desogestrel, a higher incidence of ovulation in the first 5 days was found compared with UPA alone (45% versus 3%, respectively), suggesting desogestrel might decrease the effectiveness of UPA. No concern exists that administering combined estrogen and progestin or levonorgestrel formulations of ECPs concurrently with systemic hormonal contraception decreases the effectiveness of either emergency or regular contraceptive methods because these formulations do not have antiprogestin properties like UPA. If a woman is planning to initiate contraception after the next menstrual bleeding after ECP use, the cycle in which ECPs are used might be shortened, prolonged, or involve unscheduled bleeding.\n\n# Prevention and Management of Nausea and Vomiting with ECP Use\n\n# Nausea and Vomiting\n- Levonorgestrel and UPA ECPs cause less nausea and vomiting than combined estrogen and progestin ECPs. - Routine use of antiemetics before taking ECPs is not recommended. Pretreatment with antiemetics may be considered depending on availability and clinical judgment.\n\n# Vomiting Within 3 Hours of Taking ECPs\n- Another dose of ECP should be taken as soon as possible.\nUse of an antiemetic should be considered. Comments and Evidence Summary. Many women do not experience nausea or vomiting when taking ECPs, and predicting which women will experience nausea or vomiting is difficult. Although routine use of antiemetics before taking ECPs is not recommended, antiemetics are effective in some women and can be offered when appropriate. Health care providers who are deciding whether to offer antiemetics to women taking ECPs should consider the following: 1) women taking combined estrogen and progestin ECPs are more likely to experience nausea and vomiting than those who take levonorgestrel or UPA ECPs; 2) evidence indicates that antiemetics reduce the occurrence of nausea and vomiting in women taking combined estrogen and progestin ECPs; and 3) women who take antiemetics might experience other side effects from the antiemetics.\nA systematic review examined incidence of nausea and vomiting with different ECP regimens and effectiveness of antinausea drugs in reducing nausea and vomiting with ECP use (298). The levonorgestrel regimen was associated with significantly less nausea than a nonstandard dose of UPA (50 mg) and the standard combined estrogen and progestin regimen (299)(300)(301). Use of the split-dose levonorgestrel showed no differences in nausea and vomiting compared with the single-dose levonorgestrel (288,290,292,302) (Level of evidence: I, good-fair, indirect). Two trials of antinausea drugs, meclizine and metoclopramide, taken before combined estrogen and progestin ECPs, reduced the severity of nausea (303,304). Significantly less vomiting occurred with meclizine but not metoclopramide (Level of evidence: I, good-fair, direct). No direct evidence was found regarding the effects of vomiting after taking ECPs.\n\n# Female Sterilization\nLaparoscopic, abdominal, and hysteroscopic methods of female sterilization are available in the United States, and some of these procedures can be performed in an outpatient procedure or office setting. Fewer than 1 out of 100 women become pregnant in the first year after female sterilization (14). Because these methods are intended to be irreversible, all women should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception. Female sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# When Hysteroscopic Sterilization is\nReliable for Contraception\n- Before a woman can rely on hysteroscopic sterilization for contraception, a hysterosalpingogram (HSG) must be performed 3 months after the sterilization procedure to confirm bilateral tubal occlusion. - The woman should be advised that she needs to abstain from sexual intercourse or use additional contraceptive protection until she has confirmed bilateral tubal occlusion.\n\n# When Laparoscopic and Abdominal Approaches are Reliable for Contraception\n- A woman can rely on sterilization for contraception immediately after laparoscopic and abdominal approaches.\nNo additional contraceptive protection is needed. Comments and Evidence Summary. HSG confirmation is necessary to confirm bilateral tubal occlusion after hysteroscopic sterilization. The inserts for the hysteroscopic sterilization system available in the United States are placed bilaterally into the fallopian tubes and require 3 months for adequate fibrosis and scarring leading to bilateral tubal occlusion. After hysteroscopic sterilization, advise the woman to correctly and consistently use an effective method of contraception while awaiting confirmation. If compliance with another method might be a problem, a woman and her health care provider may consider DMPA injection at the time of sterilization to ensure adequate contraception for 3 months. Unlike laparoscopic and abdominal sterilizations, pregnancy risk beyond 7 years of follow-up has not been studied among women who received hysteroscopic sterilization.\nPregnancy risk with at least 10 years of follow-up has been studied among women who received laparoscopic and abdominal sterilizations (305,306). Although these methods are highly effective, pregnancies can occur many years after the procedure, and the risk for pregnancy is higher among younger women (306,307).\nA systematic review was conducted to identify studies that reported whether pregnancies occurred after hysteroscopic sterilization (308). Twenty-four studies were identified that reported whether pregnancies occurred after hysteroscopic sterilization and found that very few pregnancies occurred among women with confirmed bilateral tubal occlusion; however, few studies include long-term follow-up, and none with follow up for >7 years. Among women who had successful bilateral placement, most pregnancies that occurred after hysteroscopic sterilization were in women who did not have confirmed bilateral tubal occlusion at 3 months, either because of lack of follow up or misinterpretation of HSG results (309)(310)(311). Some pregnancies occurred within 3 months of placement, including among women who were already pregnant at the time of the procedure, women who did not use alternative contraception, or women who had failures of alternative contraception (310)(311)(312)(313)(314)(315). Although these studies generally demonstrated high rates of bilateral placement, some pregnancies occurred as a result of lack of bilateral placement identified on later imaging (310,311,(313)(314)(315)(316). Most pregnancies occurred after deviations from FDA directions, which include placement in the early follicular phase of the menstrual cycle, imaging at 3 months to document proper placement, and use of effective alternative contraception until documented occlusion (Level of evidence: II-3, fair, direct).\n\n# Male Sterilization\nMale sterilization, or vasectomy, is one of the few contraceptive methods available to men and can be performed in an outpatient procedure or office setting. Fewer than 1 woman out of 100 becomes pregnant in the first year after her male partner undergoes sterilization (14). Because male sterilization is intended to be irreversible, all men should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception for women. Male sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n\n# When Vasectomy is Reliable for Contraception\n- A semen analysis should be performed 8-16 weeks after a vasectomy to ensure the procedure was successful. - The man should be advised that he should use additional contraceptive protection or abstain from sexual intercourse until he has confirmation of vasectomy success by postvasectomy semen analysis.\n\n# Other Postprocedure Recommendations\n- The man should refrain from ejaculation for approximately 1 week after the vasectomy to allow for healing of surgical sites and, after certain methods of vasectomy, occlusion of the vas. Comments and Evidence Summary. The Vasectomy Guideline Panel of the American Urological Association performed a systematic review of key issues concerning the practice of vasectomy (317). All English-language publications on vasectomy published during 1949-2011 were reviewed. For more information, see the American Urological Association Vasectomy Guidelines (/ education/clinical-guidance/Vasectomy.pdf ).\nMotile sperm disappear within a few weeks after vasectomy (318)(319)(320)(321). The time to azoospermia varies widely in different studies; however, by 12 weeks after the vasectomy, 80% of men have azoospermia, and almost all others have rare nonmotile sperm (defined as ≤100,000 nonmotile sperm per milliliter) (317). The number of ejaculations after vasectomy is not a reliable indicator of when azoospermia or rare nonmotile sperm will be achieved (317). Once azoospermia or rare nonmotile sperm has been achieved, patients can rely on the vasectomy for contraception, although not with 100% certainty. The risk for pregnancy after a man has achieved postvasectomy azoospermia is approximately one in 2,000 (322)(323)(324)(325)(326).\nA median of 78% (range 33%-100%) of men return for a single postvasectomy semen analysis (317). In the largest cohorts that appear typical of North American vasectomy practice, approximately two thirds of men (55%-71%) return for at least one postvasectomy semen analysis (322,(327)(328)(329)(330)(331). Assigning men an appointment after their vasectomy might improve compliance with follow-up (332).\n\n# When Women Can Stop Using Contraceptives\n- Contraceptive protection is still needed for women aged >44 years if the woman wants to avoid pregnancy. Comments and Evidence Summary. The age at which a woman is no longer at risk for pregnancy is not known. Although uncommon, spontaneous pregnancies occur among women aged >44 years. Both the American College of Obstetricians and Gynecologists and the North American Menopause Society recommend that women continue contraceptive use until menopause or age 50-55 years (333,334). The median age of menopause is approximately 51 years in North America (333) but can vary from ages 40-60 years (335). The median age of definitive loss of natural fertility is 41 years but can range up to age 51 years (336,337). No reliable laboratory tests are available to confirm definitive loss of fertility in a woman. The assessment of follicle-stimulating hormone levels to determine when a woman is no longer fertile might not be accurate (333).\nHealth care providers should consider the risks for becoming pregnant in a woman of advanced reproductive age, as well as any risks of continuing contraception until menopause. Pregnancies among women of advanced reproductive age are at higher risk for maternal complications, such as hemorrhage, venous thromboembolism, and death, and fetal complications, such as spontaneous abortion, stillbirth, and congenital anomalies (338)(339)(340). Risks associated with continuing contraception, in particular risks for acute cardiovascular events (venous thromboembolism, myocardial infarction, or stroke) or breast cancer, also are important to consider. U.S. MEC states that on the basis of age alone, women aged >45 years can use POPs, implants, the LNG-IUD, or the Cu-IUD (U.S. MEC 1) (5). Women aged >45 years generally can use combined hormonal contraceptives and DMPA (U.S. MEC 2) (5). However, women in this age group might have chronic conditions or other risk factors that might render use of hormonal contraceptive methods unsafe; U.S. MEC might be helpful in guiding the safe use of contraceptives in these women.\nIn two studies, the incidence of venous thromboembolism was higher among oral contraceptive users aged ≥45 years compared with younger oral contraceptive users (341)(342)(343); however, an interaction between hormonal contraception and increased age compared with baseline risk was not demonstrated (341,342) or was not examined (343). The relative risk for myocardial infarction was higher among all oral contraceptive users than in nonusers, although a trend of increased relative risk with increasing age was not demonstrated (344,345). No studies were found regarding the risk for stroke in COC users aged ≥45 years (Level of evidence: II-2, good to poor, direct).\nA pooled analysis by the Collaborative Group on Hormonal Factors and Breast Cancer in 1996 (346) found small increased relative risks for breast cancer among women aged ≥45 years whose last use of combined hormonal contraceptives was <5 years previously and for those whose last use was 5-9 years previously. Seven more recent studies suggested small but nonsignificant increased relative risks for breast carcinoma in situ or breast cancer among women who had used oral contraceptives or DMPA when they were aged ≥40 years compared with those who had never used either method (347-353) (Level of evidence: II-2, fair, direct).\n\n# Conclusion\nMost women can start most contraceptive methods at any time, and few examinations or tests, if any, are needed before starting a contraceptive method. Routine follow-up for most women includes assessment of her satisfaction with the contraceptive method, concerns about method use, and changes in health status or medications that could affect medical eligibility for continued use of the method. Because changes in bleeding patterns are one of the major reasons for discontinuation of contraception, recommendations are provided for the management of bleeding irregularities with various contraceptive methods. In addition, because women and health care providers can be confused about the procedures for missed pills and dosing errors with the contraceptive patch and ring, the instructions are streamlined for easier use. ECPs and emergency use of the Cu-IUD are important options for women, and recommendations on using these methods, as well as starting regular contraception after use of emergency contraception, are provided. Male and female sterilization are highly effective methods of contraception for men, women, and couples who have completed childbearing; for men undergoing vasectomy and women undergoing a hysteroscopic sterilization procedure, additional contraceptive protection is needed until the success of the procedure can be confirmed.\nCDC is committed to working with partners at the federal, national, and local levels to disseminate, implement, and evaluate U.S. SPR recommendations so that the information reaches health care providers. Strategies for dissemination and implementation include collaborating with other federal agencies and professional and service organizations to widely distribute the recommendations through presentations, electronic distribution, newsletters, and other publications; development of provider tools and job aids to assist providers in implementing the new recommendations; and training activities for students, as well as for continuing education. CDC conducts surveys of family planning health care providers to assess attitudes and practices related to contraceptive use. Results from these surveys will assist CDC in evaluating the impact of these recommendations on the provision of contraceptives in the United States. Finally, CDC will continually monitor new scientific evidence and will update these recommendations as warranted by new evidence. Updates to the recommendations, as well as provider tools and other resources, are available on the CDC U.S. SPR website: http:// www.cdc.gov/reproductivehealth/UnintendedPregnancy/ USSPR.htm.\n\n# Handling Conflict of Interest\nTo promote transparency, all participants were asked to disclose any potential conflicts of interest to CDC prior to the expert meeting and to report any potential conflicts of interest during the introductory portion of the expert meeting. All potential conflicts of interest are listed above. No participants were excluded from discussion based on potential conflicts of interest. One presenter was an employee of a pharmaceutical company and participated by teleconference; after the presentation and questions related to the presentation, the presenter was excused from the discussion. CDC staff who ultimately decided and developed these recommendations have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters relevant to these recommendations. ) for clarifications to the numeric categories, as well as for summaries of the evidence and additional comments. Hormonal contraceptives and intrauterine devices do not protect against sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV), and women using these methods should be counseled that consistent and correct use of the male latex condom reduces the risk for transmission of HIV and other STDs. Use of female condoms can provide protection from transmission of STDs, although data are limited.\nHealth-care providers can use the summary table as a quick reference guide to the classifications for hormonal contraceptive methods and intrauterine contraception to compare classifications across these methods (Box A1) (Table A1). For BOX A1. Categories for classifying hormonal contraceptives and intrauterine devices 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. - In instances in which blood pressure cannot be measured by a provider, blood pressure measured in other settings can be reported by the woman to her provider. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § A bimanual examination (not cervical inspection) is needed for diaphragm fitting. ¶ Most women do not require additional STD screening at the time of IUD insertion. If a woman with risk factors for STDs has not been screened for gonorrhea and chlamydia according to CDC's STD Treatment Guidelines (), screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with current purulent cervicitis or chlamydial infection or gonococcal infection should not undergo IUD insertion (U.S. MEC 4).\nThe examinations or tests noted apply to women who are presumed to be healthy (Table C1). Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. The 2016 U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) might be useful in such circumstances (1). The following classification was considered useful in differentiating the applicability of the various examinations or tests:\n- Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. - Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. - Class C: does not contribute substantially to safe and effective use of the contraceptive method.\nThese classifications focus on the relationship of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. Any additional screening needed for preventive health care can be performed at the time of contraception initiation and initiation should not be delayed for test results.\nNo examinations or tests are needed before initiating condoms or spermicides. A bimanual examination is necessary for diaphragm fitting. A bimanual examination and cervical inspection are needed for cervical cap fitting."},"raw_text":{"kind":"string","value":"Disclosure of Relationship CDC, our planners, and our content experts wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. This document will not include any discussion of the unlabeled use of a product or a product under investigational use, with the exception that some of the recommendations in this document might be inconsistent with package labeling.# Introduction\nUnintended pregnancy rates remain high in the United States; approximately 45% of all pregnancies are unintended, with higher proportions among adolescent and young women, women who are racial/ethnic minorities, and women with lower levels of education and income (1). Unintended pregnancies increase the risk for poor maternal and infant outcomes (2) and in 2010, resulted in U.S. government health care expenditures of $21 billion (3). Approximately half of unintended pregnancies are among women who were not using contraception at the time they became pregnant; the other half are among women who became pregnant despite reported use of contraception (4). Strategies to prevent unintended pregnancy include assisting women at risk for unintended pregnancy and their partners with choosing appropriate contraceptive methods and helping them use methods correctly and consistently to prevent pregnancy.\nIn 2013, CDC published the first U.S. Selected Practice Recommendations for Contraceptive Use (U.S. SPR), adapted from global guidance developed by the World Health Organization (WHO SPR), which provided evidence-based guidance on how to use contraceptive methods safely and effectively once they are deemed to be medically appropriate.\n# U.S. SPR is a companion document to U.S. Medical Eligibility\nCriteria for Contraceptive Use (U.S. MEC) (http://www.cdc. gov/reproductivehealth/unintendedpregnancy/usmec.htm), which provides recommendations on safe use of contraceptive methods for women with various medical conditions and other characteristics (5). WHO intended for the global guidance to be used by local or national policy makers, family planning program managers, and the scientific community as a reference when they develop family planning guidance at the country or program level. During 2012-2013, CDC went through a formal process to adapt the global guidance for best implementation in the United States, which included rigorous identification and critical appraisal of the scientific evidence through systematic reviews, and input from national experts on how to translate that evidence into recommendations for U.S. health care providers (6). At that time, CDC committed to keeping this guidance up to date and based on the best available evidence, with full review every few years (6).\nThis document updates the 2013 U.S. SPR (6) with new evidence and input from experts. Major updates include 1) revised recommendations for starting regular contraception after the use of emergency contraceptive pills and 2) new recommendations for the use of medications to ease insertion of intrauterine devices (IUDs). Recommendations are provided for health care providers on the safe and effective use of contraceptive methods and address provision of contraceptive methods and management of side effects and other problems with contraceptive method use, within the framework of removing unnecessary medical barriers to accessing and using contraception. These recommendations are meant to serve as a source of clinical guidance for health care providers; health care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients, who should seek advice from their health care providers when considering family planning options.\n# Summary of Changes from the 2013 U.S. SPR Updated Recommendations\nRecommendations have been updated regarding when to start regular contraception after ulipristal acetate (UPA) emergency contraceptive pills:\n• Advise the woman to start or resume hormonal contraception no sooner than 5 days after use of UPA, and provide or prescribe the regular contraceptive method as needed. For methods requiring a visit to a health care provider, such as depo-medroxyprogesterone acetate (DMPA), implants, and IUDs, starting the method at the time of UPA use may be considered; the risk that the regular contraceptive method might decrease the effectiveness of UPA must be weighed against the risk of not starting a regular hormonal contraceptive method. • The woman needs to abstain from sexual intercourse or use barrier contraception for the next 7 days after starting or resuming regular contraception or until her next menses, whichever comes first. • Any nonhormonal contraceptive method can be started immediately after the use of UPA. • Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks.\n# New Recommendations\nNew recommendations have been made for medications to ease IUD insertion:\n• Misoprostol is not recommended for routine use before IUD insertion. Misoprostol might be helpful in select circumstances (e.g., in women with a recent failed insertion). • Paracervical block with lidocaine might reduce patient pain during IUD insertion.\n# Methods\nSince publication of the 2013 U.S. SPR, CDC has monitored the literature for new evidence relevant to the recommendations through the WHO/CDC continuous identification of research evidence (CIRE) system (7). This system identifies new evidence as it is published and allows WHO and CDC to update systematic reviews and facilitate updates to recommendations as new evidence warrants. Automated searches are run in PubMed weekly, and the results are reviewed. Abstracts that meet specific criteria are added to the web-based CIRE system, which facilitates coordination and peer review of systematic reviews for both WHO and CDC. In 2014, CDC reviewed all of the existing recommendations in the 2013 U.S. SPR for new evidence identified by CIRE that had the potential to lead to a changed recommendation. During August 27-28, 2014, CDC held a meeting in Atlanta, Georgia, of 11 family planning experts and representatives from partner organizations to solicit their input on the scope of and process for updating both the 2010 U.S. MEC and the 2013 U.S. SPR. The participants were experts in family planning and represented different provider types and organizations that represent health care providers. A list of participants is provided at the end of this report. The meeting related to topics to be addressed in the update of U.S. SPR based on new scientific evidence published since 2013 (identified though the CIRE system), topics addressed at a 2014 WHO meeting to update global guidance, and suggestions CDC received from providers for the addition of recommendations not included in the 2013 U.S. SPR (e.g., from provider feedback through e-mail, public inquiry, and questions received at conferences). CDC identified one topic to consider adding to the guidance: the use of medications to ease IUD insertion (evidence question: \"Among women of reproductive age, does use of medications before IUD insertion improve the safety or effectiveness of the procedure [ease of insertion, need for adjunctive insertion measures, or insertion success] or affect patient outcomes [pain or side effects] compared with nonuse of these medications?\"). CDC also identified one topic for which new evidence warranted a review of an existing recommendation: initiation of regular contraception after emergency contraceptive pills (evidence question: \"Does ulipristal acetate for emergency contraception interact with regular use of hormonal contraception leading to decreased effectiveness of either contraceptive method?\"). CDC determined that all other recommendations in the 2013 U.S. SPR were up to date and consistent with the current body of evidence for that recommendation.\nIn preparation for a subsequent expert meeting August [26][27][28]2015, to review the scientific evidence\n# Maintaining Updated Guidance\nAs with any evidence-based guidance document, a key challenge is keeping the recommendations up to date as new scientific evidence becomes available. Working with WHO, CDC uses the CIRE system to ensure that WHO and CDC guidance is based on the best available evidence and that a mechanism is in place to update guidance when new evidence becomes available (7). CDC will continue to work with WHO to identify and assess all new relevant evidence and determine whether changes in the recommendations are warranted. In most cases, U.S. SPR will follow any updates in the WHO guidance, which typically occurs every 5 years (or sooner if warranted by new data). In addition, CDC will review any interim WHO updates for their application in the United States. CDC also will identify and assess any new literature for the recommendations that are not included in the WHO guidance and will completely review U.S. SPR every 5 years. Updates to the guidance can be found on the U.S. SPR website (http://www.cdc.gov/reproductivehealth/ UnintendedPregnancy/USSPR.htm).\n# How To Use This Document\nThe recommendations in this report are intended to help health care providers address issues related to use of contraceptives, such as how to help a woman initiate use of a contraceptive method, which examinations and tests are needed before initiating use of a contraceptive method, what regular follow-up is needed, and how to address problems that often arise during use, including missed pills and side effects such as unscheduled bleeding. Each recommendation addresses what a woman or health care provider can do in specific situations. For situations in which certain groups of women might be medically ineligible to follow the recommendations, comments and reference to U.S. MEC are provided (5). The full U.S. MEC recommendations and the evidence supporting those recommendations have been updated in 2016 (5) and are summarized (Appendix A).\nThe information in this document is organized by contraceptive method, and the methods generally are presented in order of effectiveness, from highest to lowest. However, the recommendations are not intended to provide guidance on every aspect of provision and management of contraceptive method use. Instead, they incorporate the best available evidence to address specific issues regarding common, yet sometimes complex, clinical issues. Each contraceptive method section generally includes information about initiation of the method, regular follow-up, and management of problems with use (e.g., usage errors and side effects). Each section first provides the recommendation and then includes comments and a brief summary of the scientific evidence on which the recommendation is based. The level of evidence from the systematic reviews for each evidence summary are provided based on the U.S. Preventive Services Task Force system, which includes ratings for study design (I: randomized controlled trials; II-1: controlled trials without randomization; II-2: observational studies; and II-3: multiple time series or descriptive studies), ratings for internal validity (good, fair, or poor), and categorization of the evidence as direct or indirect for the specific review question (10).\nRecommendations in this document are provided for permanent methods of contraception, such as vasectomy and female sterilization, as well as for reversible methods of contraception, including the copper-containing intrauterine device (Cu-IUD); levonorgestrel-releasing IUDs (LNG-IUDs); the etonogestrel implant; progestin-only injectables; progestinonly pills (POPs); combined hormonal contraceptive methods that contain both estrogen and a progestin, including combined oral contraceptives (COCs), a transdermal contraceptive patch, and a vaginal contraceptive ring; and the standard days method (SDM). Recommendations also are provided for emergency use of the Cu-IUD and emergency contraceptive pills (ECPs).\nFor each contraceptive method, recommendations are provided on the timing for initiation of the method and indications for when and for how long additional contraception, or a back-up method, is needed. Many of these recommendations include guidance that a woman can start a contraceptive method at any time during her menstrual cycle if it is reasonably certain that she is not pregnant. Guidance for health care providers on how to be reasonably certain that a woman is not pregnant also is provided.\nFor each contraceptive method, recommendations include the examinations and tests needed before initiation of the method. These recommendations apply to persons who are presumed to be healthy. Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5). Most women need no or very few examinations or tests before initiating a contraceptive method although they might be needed to address other noncontraceptive health needs (12). Any additional screening needed for preventive health care can be performed at the time of contraception initiation, and initiation should not be delayed for test results. The following classification system was developed by WHO and adopted by CDC to categorize the applicability of the various examinations or tests before initiation of contraceptive methods (13): Class A: These tests and examinations are essential and mandatory in all circumstances for safe and effective use of the contraceptive method.\nClass B: These tests and examinations contribute substantially to safe and effective use, although implementation can be considered within the public health context, service context, or both. The risk for not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: These tests and examinations do not contribute substantially to safe and effective use of the contraceptive method.\nThese classifications focus on the relation of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. Systematic reviews were conducted for several different types of examinations and tests to assess whether a screening test was associated with safe use of contraceptive methods. Because no single convention exists for screening panels for certain diseases, including diabetes, lipid disorders, and liver diseases, the search strategies included broad terms for the tests and diseases of interest.\nSummary charts and clinical algorithms that summarize the guidance for the various contraceptive methods have been developed for many of the recommendations, including when to start using specific contraceptive methods (Appendix B), examinations and tests needed before initiating the various contraceptive methods (Appendix C), routine follow-up after initiating contraception (Appendix D), management of bleeding irregularities (Appendix E), and management of IUDs when users are found to have pelvic inflammatory disease (PID) (Appendix F). These summaries might be helpful to health care providers when managing family planning patients. Additional tools are available on the U.S. SPR website (http://www.cdc. gov/reproductivehealth/UnintendedPregnancy/USSPR.htm).\n# Contraceptive Method Choice\nMany elements need to be considered individually by a woman, man, or couple when choosing the most appropriate contraceptive method. Some of these elements include safety, effectiveness, availability (including accessibility and affordability), and acceptability. Although most contraceptive methods are safe for use by most women, U.S. MEC provides recommendations on the safety of specific contraceptive methods for women with certain characteristics and medical conditions (5); a U.S. MEC summary (Appendix A) and the categories of medical eligibility criteria for contraceptive use (Box 1) are provided.\nVoluntary informed choice of contraceptive methods is an essential guiding principle, and contraceptive counseling, where applicable, might be an important contributor to the successful use of contraceptive methods.\nContraceptive method effectiveness is critically important in minimizing the risk for unintended pregnancy, particularly among women for whom an unintended pregnancy would pose additional health risks. The effectiveness of contraceptive methods depends both on the inherent effectiveness of the method itself and on how consistently and correctly it is used (Figure 1). Both consistent and correct use can vary greatly with characteristics such as age, income, desire to prevent or delay pregnancy, and culture. Methods that depend on consistent and correct use by clients have a wide range of effectiveness between typical use (actual use, including incorrect or inconsistent use) and perfect use (correct and consistent use according to directions) (14). IUDs and implants are considered longacting, reversible contraception (LARC); these methods are highly effective because they do not depend on regular compliance from the user. LARC methods are appropriate for most women, including adolescents and nulliparous women. All women should be counseled about the full range and effectiveness of contraceptive options for which they are medically eligible so that they can identify the optimal method.\nIn choosing a method of contraception, dual protection from the simultaneous risk for human immunodeficiency virus (HIV) and other sexually transmitted diseases (STDs) also should be considered. Although hormonal contraceptives and IUDs are highly effective at preventing pregnancy, they do not protect against STDs, including HIV. Consistent and correct use of the male latex condom reduces the risk for HIV infection and other STDs, including chlamydial infection, gonococcal infection, and trichomoniasis (15). Although evidence is limited, use of female condoms can provide protection from acquisition and transmission of STDs (15). All patients, regardless of contraceptive choice, should be counseled about the use of condoms and the risk for STDs, including HIV infection (15). Additional information about prevention and treatment of STDs is available from the CDC Sexually Transmitted Diseases Treatment Guidelines (http://www. cdc.gov/std/treatment) (15).\nWomen, men, and couples have increasing numbers of safe and effective choices for contraceptive methods, including LARC methods such as IUDs and implants, to reduce the risk for unintended pregnancy. However, with these expanded options comes the need for evidence-based guidance to help health care providers offer quality family planning care to their patients, including assistance in choosing the most appropriate contraceptive method for individual circumstances and using that method correctly, consistently, and continuously to maximize effectiveness. Removing unnecessary barriers can help patients access and successfully use contraceptive methods. Several medical barriers to initiating and continuing contraceptive methods might exist, such as unnecessary screening examinations and tests before starting the method (e.g., a pelvic examination before initiation of COCs), inability to receive the contraceptive on the same day as the visit (e.g., waiting for test results that might not be needed or waiting until the woman's next menstrual cycle to start use), and difficulty obtaining continued contraceptive supplies (e.g., restrictions on number of pill packs dispensed at one time). Removing unnecessary steps, such as providing prophylactic antibiotics at the time of IUD insertion or requiring unnecessary follow-up procedures, also can help patients access and successfully use contraception.\n# How To Be Reasonably Certain that a Woman Is Not Pregnant\nIn most cases, a detailed history provides the most accurate assessment of pregnancy risk in a woman who is about to start using a contraceptive method. Several criteria for assessing pregnancy risk are listed in the recommendation that follows. These criteria are highly accurate (i.e., a negative predictive value of 99%-100%) in ruling out pregnancy among women who are not pregnant (16)(17)(18)(19). Therefore, CDC recommends that health care providers use these criteria to assess pregnancy status in a woman who is about to start using contraceptives (Box 2). If a woman meets one of these criteria (and therefore the health care provider can be reasonably certain that she is not pregnant), a urine pregnancy BOX 1. Categories of medical eligibility criteria for contraceptive use • U.S. MEC 1 = A condition for which there is no restriction for the use of the contraceptive method. • U.S. MEC 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. • U.S. MEC 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. • U.S. MEC 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. test might be considered in addition to these criteria (based on clinical judgment), bearing in mind the limitations of the accuracy of pregnancy testing. If a woman does not meet any of these criteria, then the health care provider cannot be reasonably certain that she is not pregnant, even with a negative pregnancy test. Routine pregnancy testing for every woman is not necessary. On the basis of clinical judgment, health care providers might consider the addition of a urine pregnancy test; however, they should be aware of the limitations, including accuracy of the test relative to the time of last sexual intercourse, recent delivery, or spontaneous or induced abortion. Routine pregnancy testing for every woman is not necessary. If a woman has had recent (i.e., within the last 5 days) unprotected sexual intercourse, consider offering emergency contraception (either a Cu-IUD or ECPs) if pregnancy is not desired.\nComments and Evidence Summary. The criteria for determining whether a woman is pregnant depend on the assurance that she has not ovulated within a certain amount of time after her last menses, spontaneous or induced abortion, or delivery. Among menstruating women, the timing of ovulation can vary widely. During an average 28-day cycle, ovulation generally occurs during days 9-20 (20). In addition, the likelihood of ovulation is low from days 1-7 of the menstrual cycle (21). After a spontaneous or an induced abortion, ovulation can occur within 2-3 weeks and has been found to occur as early as 8-13 days after the end of the pregnancy. Therefore, the likelihood of ovulation is low ≤7 days after \n# JANUARY\n\n# S p e r m i c i d e\n\n# Spermicide\n\n# How to make your method most e ective\n\n# Vasectomy and hysteroscopic sterilization:\nAfter procedure, little or nothing to do or remember.\nUse another method for rst 3 months.\nInjectable: Get repeat injections on time.\nPills: Take a pill each day. \n# Least E ective\n\n# Most E ective\nLess than 1 pregnancy 6-12 pregnancies per 100 women in a year per 100 women in a year 18 or more pregnancies per 100 women in a year\n# CONDOMS SHOULD ALWAYS BE USED TO REDUCE THE RISK OF SEXUALLY TRANSMITTED INFECTIONS.\nOther Methods of Contraception Lactational Amenorrhea Method: LAM is a highly e ective, temporary method of contraception. Emergency Contraception: Emergency contraceptive pills or a copper IUD after unprotected intercourse substantially reduces risk of pregnancy. an abortion (22)(23)(24). A systematic review reported that the mean day of first ovulation among postpartum nonlactating women occurred 45-94 days after delivery (25). In one study, the earliest ovulation was reported at 25 days after delivery. Among women who are within 6 months postpartum, are fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority [≥85%] of feeds are breastfeeds), and are amenorrheic, the risk for pregnancy is <2% (26,27).\nAlthough pregnancy tests often are performed before initiating contraception, the accuracy of qualitative urine pregnancy tests varies depending on the timing of the test relative to missed menses, recent sexual intercourse, or recent pregnancy. The sensitivity of a pregnancy test is defined as the concentration of human chorionic gonadotropin (hCG) at which 95% of tests are positive. Most qualitative pregnancy tests approved by the U.S. Food and Drug Administration (FDA) report a sensitivity of 20-25 mIU/mL in urine (28)(29)(30)(31). However, pregnancy detection rates can vary widely because of differences in test sensitivity and the timing of testing relative to missed menses (30,32). Some studies have shown that an additional 11 days past the day of expected menses are needed to detect 100% of pregnancies using qualitative tests (29). In addition, pregnancy tests cannot detect a pregnancy resulting from recent sexual intercourse. Qualitative tests also might have positive results for several weeks after termination of pregnancy because hCG can be present for several weeks after delivery or abortion (spontaneous or induced) (33)(34)(35).\nFor contraceptive methods other than IUDs, the benefits of starting to use a contraceptive method likely exceed any risk, even in situations in which the health care provider is uncertain whether the woman is pregnant. Therefore, the health care provider can consider having patients start using contraceptive methods other than IUDs at any time, with a follow-up pregnancy test in 2-4 weeks. The risks of not starting to use contraception should be weighed against the risks of initiating contraception use in a woman who might be already pregnant. Most studies have shown no increased risk for adverse outcomes, including congenital anomalies or neonatal or infant death, among infants exposed in utero to COCs (36)(37)(38). Studies also have shown no increased risk for neonatal or infant death or developmental abnormalities among infants exposed in utero to DMPA (37,39,40).\nIn contrast, for women who want to begin using an IUD (Cu-IUD or LNG-IUD), in situations in which the health care provider is uncertain whether the woman is pregnant, the woman should be provided with another contraceptive method to use until the health care provider is reasonably certain that she is not pregnant and can insert the IUD. Pregnancies among women with IUDs are at higher risk for complications such as spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis (41).\nA systematic review identified four analyses of data from three diagnostic accuracy studies that evaluated the performance of the listed criteria (Box 2) through use of a pregnancy checklist compared with a urine pregnancy test conducted concurrently (42). The performance of the checklist to diagnose or exclude pregnancy varied, with sensitivity of 55%-100% and specificity of 39%-89%. The negative predictive value was consistent across studies at 99%-100%; the pregnancy checklist correctly ruled out women who were not pregnant. One of the studies assessed the added usefulness of signs and symptoms of pregnancy and found that these criteria did not substantially improve the performance of the pregnancy checklist, although the number of women with signs and symptoms was small (16) (Level of evidence: Diagnostic accuracy studies, fair, direct).\n# Intrauterine Contraception\nFour IUDs are available in the United States, the coppercontaining IUD and three levonorgestrel-releasing IUDs (containing a total of either 13.5 mg or 52 mg levonorgestrel). Fewer than 1 woman out of 100 becomes pregnant in the first year of using IUDs (with typical use) (14). IUDs are long-acting, are reversible, and can be used by women of all ages, including adolescents, and by parous and nulliparous women. IUDs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# BOX 2. How to be reasonably certain that a woman is not pregnant\nA health care provider can be reasonably certain that a woman is not pregnant if she has no symptoms or signs of pregnancy and meets any one of the following criteria: • is ≤7 days after the start of normal menses • has not had sexual intercourse since the start of last normal menses. • has been correctly and consistently using a reliable method of contraception • is ≤7 days after spontaneous or induced abortion • is within 4 weeks postpartum • is fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority [≥85%] of feeds are breastfeeds), amenorrheic, and <6 months postpartum\n# Initiation of Cu-IUDs Timing\n• The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). • The Cu-IUD also can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. If the day of ovulation can be estimated, the Cu-IUD also can be inserted >5 days after sexual intercourse as long as insertion does not occur >5 days after ovulation.\n# Need for Back-Up Contraception\n• No additional contraceptive protection is needed after Cu-IUD insertion.\n# Special Considerations\nAmenorrhea (Not Postpartum)\n• Timing: The Cu-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: No additional contraceptive protection is needed.\n# Postpartum (Including After Cesarean Delivery)\n• Timing: The Cu-IUD can be inserted at any time postpartum, including immediately postpartum (U.S. MEC 1 or 2) (Box 1), if it is reasonably certain that the woman is not pregnant (Box 2). The Cu-IUD should not be inserted in a woman with postpartum sepsis (e.g., chorioamnionitis or endometritis) (U.S. MEC 4). • Need for back-up contraception: No additional contraceptive protection is needed.\n# Postabortion (Spontaneous or Induced)\n• Timing: The Cu-IUD can be inserted within the first 7 days, including immediately postabortion (U.S. MEC 1 for first-trimester abortion and U.S. MEC 2 for secondtrimester abortion). The Cu-IUD should not be inserted immediately after a septic abortion (U.S. MEC 4). • Need for back-up contraception: No additional contraceptive protection is needed.\n# Switching from Another Contraceptive Method\n• Timing: The Cu-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. • Need for back-up contraception: No additional contraceptive protection is needed.\nComments and Evidence Summary. In situations in which the health care provider is not reasonably certain that the woman is not pregnant, the woman should be provided with another contraceptive method to use until the health care provider can be reasonably certain that she is not pregnant and can insert the Cu-IUD.\nA systematic review identified eight studies that suggested that timing of Cu-IUD insertion in relation to the menstrual cycle in non-postpartum women had little effect on longterm outcomes (rates of continuation, removal, expulsion, or pregnancy) or on short-term outcomes (pain at insertion, bleeding at insertion, or immediate expulsion) (43) (Level of evidence: II-2, fair, direct).\n# Initiation of LNG-IUDs\n\n# Timing of LNG-IUD Insertion\n• The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n# Need for Back-Up Contraception\n• If the LNG-IUD is inserted within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. • If the LNG-IUD is inserted >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Special Considerations\nAmenorrhea (Not Postpartum)\n• Timing: The LNG-IUD can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Postpartum (Including After Cesarean Delivery)\n• \n# Switching from Another Contraceptive Method\n• Timing: The LNG-IUD can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. • Need for back-up contraception: If it has been >7 days since menstrual bleeding began, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. • Switching from a Cu-IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider providing any type of ECPs at the time of LNG-IUD insertion. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the woman should be provided with another contraceptive method to use until the health care provider can be reasonably certain that she is not pregnant and can insert the LNG-IUD. If a woman needs to use additional contraceptive protection when switching to an LNG-IUD from another contraceptive method, consider continuing her previous method for 7 days after LNG-IUD insertion. No direct evidence was found regarding the effects of inserting LNG-IUDs on different days of the cycle on short-or longterm outcomes (43).\n# Examinations and Tests Needed Before Initiation of a Cu-IUD or an LNG-IUD\nAmong healthy women, few examinations or tests are needed before initiation of an IUD (Table 1). Bimanual examination and cervical inspection are necessary before IUD insertion. A baseline weight and BMI measurement might be useful for monitoring IUD users over time. If a woman has not been screened for STDs according to STD screening guidelines, screening can be performed at the time of insertion. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use IUDs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of IUDs. However, measuring weight and calculating * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § Most women do not require additional STD screening at the time of IUD insertion.\nIf a woman with risk factors for STDs has not been screened for gonorrhea and chlamydia according to CDC's STD Treatment Guidelines (http://www.cdc.gov/std/ treatment), screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with current purulent cervicitis or chlamydial infection or gonococcal infection should not undergo IUD insertion (U.S. MEC 4).\n# BMI (weight [kg] / height [m 2 ]\n) at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. Bimanual examination and cervical inspection: Bimanual examination and cervical inspection are necessary before IUD insertion to assess uterine size and position and to detect any cervical or uterine abnormalities that might indicate infection or otherwise prevent IUD insertion (44,45).\nSTDs: Women should be routinely screened for chlamydial infection and gonorrhea according to national screening guidelines. The CDC Sexually Transmitted Diseases Treatment Guidelines provide information on screening eligibility, timing, and frequency of screening and on screening for persons with risk factors (15) (http://www.cdc.gov/std/treatment). If STD screening guidelines have been followed, most women do not need additional STD screening at the time of IUD insertion, and insertion should not be delayed. If a woman with risk factors for STDs has not been screened for gonorrhea and chlamydia according to CDC STD treatment guidelines, screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with current purulent cervicitis or chlamydial infection or gonococcal infection should not undergo IUD insertion (U.S. MEC 4). A systematic review identified two studies that demonstrated no differences in PID rates among women who screened positive for gonorrhea or chlamydia and underwent concurrent IUD insertion compared with women who screened positive and initiated other contraceptive methods (46). Indirect evidence demonstrates women who undergo same-day STD screening and IUD insertion have similar PID rates compared with women who have delayed IUD insertion. Women who undergo same-day STD screening and IUD insertion have low incidence rates of PID. Algorithms for predicting PID among women with risk factors for STDs have poor predictive value. Risk for PID among women with risk factors for STDs is low (15,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57). Although women with STDs at the time of IUD insertion have a higher risk for PID, the overall rate of PID among all IUD users is low (51,54).\nHemoglobin: Women with iron-deficiency anemia can use the LNG-IUD (U.S. MEC 1) (5); therefore, screening for anemia is not necessary for safe initiation of the LNG-IUD. Women with iron-deficiency anemia generally can use Cu-IUDs (U.S. MEC 2) (5). Measurement of hemoglobin before initiation of Cu-IUDs is not necessary because of the minimal change in hemoglobin among women with and without anemia using Cu-IUDs. A systematic review identified four studies that provided direct evidence for changes in hemoglobin among women with anemia who received Cu-IUDs (58). Evidence from one randomized trial (59) and one prospective cohort study (60) showed no significant changes in hemoglobin among Cu-IUD users with anemia, whereas two prospective cohort studies (61,62) showed a statistically significant decrease in hemoglobin levels during 12 months of follow-up; however, the magnitude of the decrease was small and most likely not clinically significant. The systematic review also identified 21 studies that provided indirect evidence by examining changes in hemoglobin among healthy women receiving Cu-IUDs (63-83), which generally showed no clinically significant changes in hemoglobin levels with up to 5 years of follow up (Level of evidence: I to II-2, fair, direct).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of Cu-IUD or LNG-IUD because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results about the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Women with liver disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for liver disease is not necessary for the safe initiation of the Cu-IUD. Although women with certain liver diseases generally should not use the LNG-IUD (U.S. MEC 3) (5), screening for liver disease before initiation of the LNG-IUD is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptive use (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited, and no evidence exists for the LNG-IUD.\nClinical breast examination: Women with breast disease can use the Cu-IUD (U.S. MEC 1) (5); therefore, screening for breast disease is not necessary for the safe initiation of the Cu-IUD. Although women with current breast cancer should not use the LNG-IUD (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before inserting an IUD is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nCervical cytology: Although women with cervical cancer should not undergo IUD insertion (U.S. MEC 4) (5), screening asymptomatic women with cervical cytology before IUD insertion is not necessary because of the high rates of cervical screening, low incidence of cervical cancer in the United States, and high likelihood that a woman with cervical cancer already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with cervical cytology before initiation of IUDs (57). Cervical cancer is rare in the United States, with an incidence rate of 9.8 per 100,000 women during 2012 (96). The incidence and mortality rates from cervical cancer have declined dramatically in the United States, largely because of cervical cytology screening (97). Overall screening rates for cervical cancer in the United States are high; in 2013 among women aged 18-44 years, approximately 77% reported having cervical cytology screening within the last 3 years (98).\nHIV screening: Women with HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) IUDs (5). Therefore, HIV screening is not necessary before IUD insertion. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened for HIV infection before IUD insertion (57). Limited evidence suggests that IUDs are not associated with disease progression, increased infection, or other adverse health effects among women with HIV infection (99)(100)(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114).\nOther screening: Women with hypertension, diabetes, or thrombogenic mutations can use (U.S. MEC 1) or generally can use (U.S. MEC 2) IUDs (5). Therefore, screening for these conditions is not necessary for the safe initiation of IUDs.\n# Provision of Medications to Ease\nIUD Insertion\n• Misoprostol is not recommended for routine use before IUD insertion. Misoprostol might be helpful in select circumstances (e.g., in women with a recent failed insertion). • Paracervical block with lidocaine might reduce patient pain during IUD insertion. Comments and Evidence Summary. Potential barriers to IUD use include anticipated pain with insertion and provider concerns about difficult insertion. Identifying effective approaches to ease IUD insertion might increase IUD initiation.\nEvidence for misoprostol from two systematic reviews, including a total of 10 randomized controlled trials, suggests that misoprostol does not improve provider ease of insertion, reduce the need for adjunctive insertion measures, or improve insertion success (Level of evidence: I, good to fair, direct) and might increase patient pain and side effects (Level of evidence: I, high quality) (115,116). However, one randomized controlled trial examined women with a recent failed IUD insertion and found significantly higher insertion success with second insertion attempt among women pretreated with misoprostol versus placebo (Level of evidence: I, good, direct) (117).\nLimited evidence for paracervical block with lidocaine from one systematic review suggests that it might reduce patient pain (115). In this review, two randomized controlled trials found significantly reduced pain at either tenaculum placement or IUD insertion among women receiving paracervical block with 1% lidocaine 3-5 minutes before IUD insertion (118,119). Neither trial found differences in side effects among women receiving paracervical block compared with controls (Level of evidence: I, moderate to low quality) (118,119).\nLimited evidence on nonsteroidal antiinflammatory drugs (NSAIDs) and nitric oxide donors generally suggested no positive effect; evidence on lidocaine with administration other than paracervical block was limited and inconclusive (Level of evidence for provider ease of insertion: I, good to poor, direct; Level of evidence for need for adjunctive insertion measures: I, fair, direct; Level of evidence for patient pain: I, high to low quality; Level of evidence for side effects: I, high to low quality) (115,116).\n# Provision of Prophylactic Antibiotics at the Time of IUD Insertion\n• Prophylactic antibiotics are generally not recommended for Cu-IUD or LNG-IUD insertion. Comments and Evidence Summary. Theoretically, IUD insertion could induce bacterial spread and lead to complications such as PID or infective endocarditis. A metaanalysis was conducted of randomized controlled trials examining antibiotic prophylaxis versus placebo or no treatment for IUD insertion (120). Use of prophylaxis reduced the frequency of unscheduled return visits but did not significantly reduce the incidence of PID or premature IUD discontinuation. Although the risk for PID was higher within the first 20 days after insertion, the incidence of PID was low among all women who had IUDs inserted (51). In addition, the American Heart Association recommends that the use of prophylactic antibiotics solely to prevent infective endocarditis is not needed for genitourinary procedures (121). Studies have not demonstrated a conclusive link between genitourinary procedures and infective endocarditis or a preventive benefit of prophylactic antibiotics during such procedures (121).\n# Routine Follow-Up After IUD Insertion\nThese recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, persons with certain medical conditions or characteristics, and persons with multiple medical conditions.\n• Advise the woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. • At other routine visits, health care providers who see IUD users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the IUD for safe and effective continued use on the basis of U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider performing an examination to check for the presence of the IUD strings. -Consider assessing weight changes and counseling women who are concerned about weight changes perceived to be associated with their contraceptive method. Comments and Evidence Summary. Evidence from a systematic review about the effect of a specific follow-up visit schedule on IUD continuation is very limited and of poor quality. The evidence did not suggest that greater frequency of visits or earlier timing of the first follow-up visit after insertion improves continuation of use ( 122) (Level of evidence: II-2, poor, direct). Evidence from four studies from a systematic review on the incidence of PID among IUD initiators, or IUD removal as a result of PID, suggested that the incidence of PID did not differ between women using Cu-IUDs and those using DMPA, COCs, or LNG-IUDs (123) (Level of evidence: I to II-2, good, indirect). Evidence on the timing of PID after IUD insertion is mixed. Although the rate of PID generally was low, the largest study suggested that the rate of PID was significantly higher in the first 20 days after insertion (51) (Level of evidence: I to II-3, good to poor, indirect).\n# Bleeding Irregularities with Cu-IUD Use\n• Before Cu-IUD insertion, provide counseling about potential changes in bleeding patterns during Cu-IUD use. Unscheduled spotting or light bleeding, as well as heavy or prolonged bleeding, is common during the first 3-6 months of Cu-IUD use, is generally not harmful, and decreases with continued Cu-IUD use. • If clinically indicated, consider an underlying gynecological problem, such as Cu-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids), especially in women who have already been using the Cu-IUD for a few months or longer and who have developed a new onset of heavy or prolonged bleeding. If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecological problem is not found and the woman requests treatment, the following treatment option can be considered during days of bleeding: -NSAIDs for short-term treatment (5-7 days) • If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the Cu-IUD, information about common side effects such as unscheduled spotting or light bleeding or heavy or prolonged menstrual bleeding, especially during the first 3-6 months of use, should be discussed (64). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other contraceptives (i.e., DMPA) (124,125).\nEvidence is limited on specific drugs, doses, and durations of use for effective treatments for bleeding irregularities with Cu-IUD use. Therefore, although this report includes general recommendations for treatments to consider, evidence for specific regimens is lacking.\nA systematic review identified 11 studies that examined various therapeutic treatments for heavy menstrual bleeding, prolonged menstrual bleeding, or both among women using Cu-IUDs (126). Nine studies examined the use of various oral NSAIDs for the treatment of heavy or prolonged menstrual bleeding among Cu-IUD users and compared them with either a placebo or a baseline cycle. Three of these trials examined the use of indomethacin (127)(128)(129), three examined mefenamic acid (130)(131)(132), and three examined flufenamic acid (127,128,133). Other NSAIDs used in the reported trials included alclofenac (127,128), suprofen (134), and diclofenac sodium (135). All but one NSAID study ( 131) demonstrated statistically significant or notable reductions in mean total menstrual blood loss with NSAID use. One study among 19 Cu-IUD users with heavy bleeding suggested that treatment with oral tranexamic acid can significantly reduce mean blood loss during treatment compared with placebo (135). Data regarding the overall safety of tranexamic acid are limited; an FDA warning states that tranexamic acid is contraindicated in women with active thromboembolic disease or with a history or intrinsic risk for thrombosis or thromboembolism (136,137). Treatment with aspirin demonstrated no statistically significant change in mean blood loss among women whose pretreatment menstrual blood loss was >80 ml or 60-80 mL; treatment resulted in a significant increase among women whose pretreatment menstrual blood loss was <60 mL (138). One study examined the use of a synthetic form of vasopressin, intranasal desmopressin (300 µg/day), for the first 5 days of menses for three treatment cycles and found a significant reduction in mean blood loss compared with baseline (130) (Level of evidence: I to II-3, poor to fair, direct). Only one small study examined treatment of spotting with three separate NSAIDs and did not observe improvements in spotting in any of the groups (127) (Level of evidence: I, poor, direct).\n# Bleeding Irregularities (Including Amenorrhea) with LNG-IUD Use\n• Before LNG-IUD insertion, provide counseling about potential changes in bleeding patterns during LNG-IUD use. Unscheduled spotting or light bleeding is expected during the first 3-6 months of LNG-IUD use, is generally not harmful, and decreases with continued LNG-IUD use. Over time, bleeding generally decreases with LNG-IUD use, and many women experience only light menstrual bleeding or amenorrhea. Heavy or prolonged bleeding, either unscheduled or menstrual, is uncommon during LNG-IUD use.\n# Irregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding)\n• If clinically indicated, consider an underlying gynecological problem, such as LNG-IUD displacement, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired.\n# Amenorrhea\n• Amenorrhea does not require any medical treatment. Provide reassurance.\n-If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. • If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired Comments and Evidence Summary. During contraceptive counseling and before insertion of the LNG-IUD, information about common side effects such as unscheduled spotting or light bleeding, especially during the first 3-6 months of use, should be discussed. Approximately half of LNG-IUD users are likely to experience amenorrhea or oligomenorrhea by 2 years of use (139). These bleeding irregularities are generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (124,125). No direct evidence was found regarding therapeutic treatments for bleeding irregularities during LNG-IUD use.\n# Management of the IUD when a Cu-IUD or an LNG-IUD User Is Found To Have PID\n• Treat the PID according to the CDC Sexually Transmitted Diseases Treatment Guidelines (15). • Provide comprehensive management for STDs, including counseling about condom use. • The IUD does not need to be removed immediately if the woman needs ongoing contraception. • Reassess the woman in 48-72 hours. If no clinical improvement occurs, continue antibiotics and consider removal of the IUD. • If the woman wants to discontinue use, remove the IUD sometime after antibiotics have been started to avoid the potential risk for bacterial spread resulting from the removal procedure. • If the IUD is removed, consider ECPs if appropriate.\nCounsel the woman on alternative contraceptive methods, and offer another method if it is desired. • A summary of IUD management in women with PID is provided (Appendix F). Comments and Evidence Summary. Treatment outcomes do not generally differ between women with PID who retain the IUD and those who have the IUD removed; however, appropriate antibiotic treatment and close clinical follow-up are necessary.\nA systematic review identified four studies that included women using copper or nonhormonal IUDs who developed PID and compared outcomes between women who had the IUD removed or did not (140). One randomized trial showed that women with IUDs removed had longer hospitalizations than those who did not, although no differences in PID recurrences or subsequent pregnancies were observed (141). Another randomized trial showed no differences in laboratory findings among women who removed the IUD compared with those who did not (142). One prospective cohort study showed no differences in clinical or laboratory findings during hospitalization; however, the IUD removal group had longer hospitalizations (143). One randomized trial showed that the rate of recovery for most clinical signs and symptoms was higher among women who had the IUD removed than among women who did not (144). No evidence was found regarding women using LNG-IUDs (Level of evidence: I to II-2, fair, direct.)\n# Management of the IUD when a Cu-IUD or an LNG-IUD User is Found To Be Pregnant\n• Evaluate for possible ectopic pregnancy.\n• Advise the woman that she has an increased risk for spontaneous abortion (including septic abortion that might be life threatening) and for preterm delivery if the IUD is left in place. The removal of the IUD reduces these risks but might not decrease the risk to the baseline level of a pregnancy without an IUD.\n-If she does not want to continue the pregnancy, counsel her about options. -If she wants to continue the pregnancy, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever.\n# IUD Strings Are Visible or Can Be Retrieved Safely from the Cervical Canal\n• Advise the woman that the IUD should be removed as soon as possible.\n-If the IUD is to be removed, remove it by pulling on the strings gently. -Advise the woman that she should return promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. • If she chooses to keep the IUD, advise her to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever.\n# IUD Strings Are Not Visible and Cannot Be Safely Retrieved\n• If ultrasonography is available, consider performing or referring for ultrasound examination to determine the location of the IUD. If the IUD cannot be located, it might have been expelled or have perforated the uterine wall. • If ultrasonography is not possible or the IUD is determined by ultrasound to be inside the uterus, advise the woman to seek care promptly if she has heavy bleeding, cramping, pain, abnormal vaginal discharge, or fever. Comments and Evidence Summary. Removing the IUD improves the pregnancy outcome if the IUD strings are visible or the device can be retrieved safely from the cervical canal. Risks for spontaneous abortion, preterm delivery, and infection are substantial if the IUD is left in place.\nTheoretically, the fetus might be affected by hormonal exposure from an LNG-IUD. However, whether this exposure increases the risk for fetal abnormalities is unknown.\nA systematic review identified nine studies suggesting that women who did not remove their IUDs during pregnancy were at greater risk for adverse pregnancy outcomes (including spontaneous abortion, septic abortion, preterm delivery, and chorioamnionitis) compared with women who had their IUDs removed or who did not have an IUD (41). Cu-IUD removal decreased risks but not to the baseline risk for pregnancies without an IUD. One case series examined LNG-IUDs. When they were not removed, 8 out of 10 pregnancies ended in spontaneous abortions (Level of evidence: II-2, fair, direct).\n# Implants\nThe etonogestrel implant, a single rod with 68 mg of etonogestrel, is available in the United States. Fewer than 1 woman out of 100 become pregnant in the first year of use of the etonogestrel implant with typical use (14). The implant is long acting, is reversible, and can be used by women of all ages, including adolescents. The implant does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# Initiation of Implants Timing\n• The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n# Need for Back-Up Contraception\n• If the implant is inserted within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. • If the implant is inserted >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Special Considerations\nAmenorrhea (Not Postpartum)\n• Timing: The implant can be inserted at any time if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Postpartum (Breastfeeding)\n• \n# Postabortion (Spontaneous or Induced)\n• Timing: The implant can be inserted within the first 7 days, including immediately after the abortion (U.S. MEC 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the implant is placed at the time of a surgical abortion.\n# Switching from Another Contraceptive Method\n• Timing: The implant can be inserted immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. • Need for back-up contraception: If it has been >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days after insertion. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options:\n-Advise the woman to retain the IUD for at least 7 days after the implant is inserted and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs (with the exception of UPA) at the time of IUD removal. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting the implant likely exceed any risk; therefore, starting the implant should be considered at any time, with a follow-up pregnancy test in 2-4 weeks.\nIf a woman needs to use additional contraceptive protection when switching to an implant from another contraceptive method, consider continuing her previous method for 7 days after implant insertion. No direct evidence was found regarding the effects of starting the etonogestrel implant at different times of the cycle.\n# Examinations and Tests Needed Before Implant Insertion\nAmong healthy women, no examinations or tests are needed before initiation of an implant, although a baseline weight and BMI measurement might be useful for monitoring implant users over time (Table 2). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use implants (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of implants. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nBimanual examination and cervical inspection: A pelvic examination is not necessary before initiation of implants because it would not facilitate detection of conditions for which implant use would be unsafe. Women with current breast cancer should not use implants (U.S. MEC 4); women with certain liver diseases generally should not (U.S. MEC 3) use implants (5). However, none of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed. No evidence was found regarding implants (Level of evidence: II-2 fair, direct).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of implants because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/ dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results regarding the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases generally should not use implants (U.S. MEC 3) (5), screening for liver disease before initiation of implants is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, the percentage of U.S. women with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for implants.\nClinical breast examination: Although women with current breast cancer should not use implants (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. examination before initiation of implants is not necessary because of the low prevalence of breast cancer among women of reproductive age (15-49 years). A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with hypertension, diabetes, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) implants (5); therefore, screening for these conditions is not necessary for the safe initiation of implants.\n# Routine Follow-Up After Implant Insertion\nThese recommendations address when routine follow-up is needed for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n• Advise the woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time to remove or replace the contraceptive method. No routine follow-up visit is required. • At other routine visits, health care providers seeing implant users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the implant for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. A systematic review did not identify any evidence regarding whether a routine follow-up visit after initiating an implant improves correct or continued use (122).\n# Bleeding Irregularities (Including Amenorrhea) During Implant Use\n• Before implant insertion, provide counseling about potential changes in bleeding patterns during implant use. Unscheduled spotting or light bleeding is common with implant use, and some women experience amenorrhea. These bleeding changes are generally not harmful and might or might not decrease with continued implant use. Heavy or prolonged bleeding, unscheduled or menstrual, is uncommon during implant use.\nIrregular Bleeding (Spotting, Light Bleeding, or Heavy or Prolonged Bleeding)\n• If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) • If irregular bleeding persists and the woman finds it unacceptable, counsel her on alternative methods, and offer another method if it is desired.\n# Amenorrhea\n• Amenorrhea does not require any medical treatment. Provide reassurance.\n-If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. • If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before insertion of the implant, information about common side effects, such as unscheduled spotting or light bleeding and amenorrhea, especially during the first year of use, should be discussed. A pooled analysis of data from 11 clinical trials indicates that a significant proportion of etonogestrel implant users had relatively little bleeding: 22% of women experienced amenorrhea and 34% experienced infrequent spotting, although 7% reported frequent bleeding and 18% reported prolonged bleeding (146). Unscheduled bleeding or amenorrhea is generally not harmful. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce discontinuation in clinical trials with other hormonal contraceptives (i.e., DMPA) (124,125).\nA systematic review and four newly published studies examined several medications for the treatment of bleeding irregularities with primarily levonorgestrel contraceptive implants (147)(148)(149)(150)(151). Two small studies found significant cessation of bleeding within 7 days of start of treatment among women taking oral celecoxib (200 mg) daily for 5 days or oral mefenamic acid (500 mg) 3 times daily for 5 days compared with placebo (149,150). Differences in bleeding cessation were not found among women with etonogestrel implants taking mifepristone but were found when women with the implants combined mifepristone with either ethinyl estradiol or doxycycline (151,152). Doxycycline alone or in combination with ethinyl estradiol did not improve bleeding cessation among etonogestrel implant users (151). Among LNG implant users, mifepristone reduced the number of bleeding or spotting days but only after 6 months of treatment (153). Evidence also suggests that estrogen (154)(155)(156), daily COCs (154), LNG pills (155), tamoxifen (157), or tranexamic acid (158) can reduce the number of bleeding or spotting days during treatment among LNG implant users. In one small study, vitamin E was found to significantly reduce the mean number of bleeding days after the first treatment cycle; however, another larger study reported no significant differences in length of bleeding and spotting episodes with vitamin E treatment (159,160). Use of aspirin did not result in a significant difference in median length of bleeding or bleeding and spotting episodes after treatment (159). One study among implant users reported a reduction in number of bleeding days after initiating ibuprofen; however, another trial did not demonstrate any significant differences in the number of spotting and bleeding episodes with ibuprofen compared with placebo (148,155).\n# Injectables\nProgestin-only injectable contraceptives (DMPA, 150 mg intramuscularly or 104 mg subcutaneously) are available in the United States; the only difference between these two formulations is the route of administration. Approximately 6 out of 100 women will become pregnant in the first year of use of DMPA with typical use (14). DMPA is reversible and can be used by women of all ages, including adolescents. DMPA does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# Initiation of Injectables Timing\n• The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n# Need for Back-Up Contraception\n• If DMPA is started within the first 7 days since menstrual bleeding started, no additional contraceptive protection is needed. • If DMPA is started >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Special Considerations\nAmenorrhea (Not Postpartum)\n• Timing: The first DMPA injection can be given at any time if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Postpartum (Breastfeeding)\n• Postabortion (Spontaneous or Induced)\n• Timing: The first DMPA injection can be given within the first 7 days, including immediately after the abortion (U.S. MEC 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless the injection is given at the time of a surgical abortion.\n# Switching from Another Contraceptive Method\n• Timing: The first DMPA injection can be given immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. • Need for back-up contraception: If it has been >7 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after the injection and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs (with the exception of UPA) at the time of IUD removal. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting DMPA likely exceed any risk; therefore, starting DMPA should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to DMPA from another contraceptive method, consider continuing her previous method for 7 days after DMPA injection.\nA systematic review identified eight articles examining DMPA initiation on different days of the menstrual cycle (161). Evidence from two studies with small sample sizes indicated that DMPA injections given up to day 7 of the menstrual cycle inhibited ovulation; when DMPA was administered after day 7, ovulation occurred in some women. Cervical mucus was of poor quality (i.e., not favorable for sperm penetration) in 90% of women within 24 hours of the injection (Level of evidence: II-2, fair) (162)(163)(164). Studies found that use of another contraceptive method until DMPA could be initiated (bridging option) did not help women initiate DMPA and was associated with more unintended pregnancies than immediate receipt of DMPA (165-169) (Level of evidence: I to II-3, fair to poor, indirect).\n# Examinations and Tests Needed Before Initiation of an Injectable\nAmong healthy women, no examinations or tests are needed before initiation of DMPA, although a baseline weight and BMI measurement might be useful to monitor DMPA users over time (Table 3). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for obesity is not necessary for the safe initiation of DMPA. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. (See guidance on follow-up for DMPA users for evidence on weight gain with DMPA use).\nBimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of DMPA because it does not facilitate detection of conditions for which DMPA would be unsafe. Although women with current breast cancer should not use DMPA (U.S. MEC 4), and women with severe hypertension, heart disease, vascular disease, or certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), none of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two casecontrol studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were observed (Level of evidence: II-2, fair, direct).\nBlood pressure: Women with hypertension generally can use DMPA (U.S. MEC 2), with the exception of women with severe hypertension or vascular disease, who generally should not use DMPA (U.S. MEC 3) (5). Screening for hypertension before initiation of DMPA is not necessary because of the low prevalence of undiagnosed severe hypertension and the high likelihood that women with these conditions already would have had them diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a blood pressure measurement before initiation of progestin-only contraceptives (170). The prevalence of undiagnosed hypertension among women of reproductive age is low. During 2009-2012 among women aged 20-44 years in the United States, the prevalence of hypertension was 8.7% (84). During 1999-2008, the percentage of women aged 20-44 years with undiagnosed hypertension was 1.9% (85).\nGlucose: Although women with complicated diabetes generally should not use DMPA (U.S. MEC 3) (5), screening for diabetes before initiation of DMPA is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes would already have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (57). The prevalence of diabetes among women of reproductive age is low. During 2009-2012 among women aged 20-44 years in the United States, the prevalence of diabetes was 3.3% (84). During 1999-2008, the percentage of women aged 20-44 years with undiagnosed diabetes was 0.5% (85).\nAlthough hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (171)(172)(173)(174)(175)(176)(177).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of injectables because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results about the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases generally should not use DMPA (U.S. MEC 3) (5), screening for liver disease before initiation of DMPA is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited and no evidence exists for DMPA. * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\n# Clinical breast examination:\nAlthough women with current breast cancer should not use DMPA (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating DMPA is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) DMPA (5); therefore, screening for these conditions is not necessary for the safe initiation of DMPA.\n# Routine Follow-Up After Injectable Initiation\nThese recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n• Advise the woman to return at any time to discuss side effects or other problems, if she wants to change the method being used, and when it is time for reinjection.\nNo routine follow-up visit is required. • At other routine visits, health care providers seeing injectable users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of the injectable for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. Although no evidence exists regarding whether a routine follow-up visit after initiating DMPA improves correct or continued use, monitoring weight or BMI change over time is important for DMPA users.\nA systematic review identified a limited body of evidence that examined whether weight gain in the few months after DMPA initiation predicted future weight gain (123). Two studies found significant differences in weight gain or BMI at follow-up periods ranging from 12 to 36 months between early weight gainers (i.e., those who gained >5% of their baseline body weight within 6 months after initiation) and those who were not early weight gainers (178,179). The differences between groups were more pronounced at 18, 24, and 36 months than at 12 months. One study found that most adolescent DMPA users who had gained >5% of their baseline weight by 3 months gained even more weight by 12 months (180) (Level of evidence: II-2, fair, to II-3, fair, direct).\n# Timing of Repeat Injections Reinjection Interval\n• Provide repeat DMPA injections every 3 months (13 weeks).\n# Special Considerations Early Injection\n• The repeat DMPA injection can be given early when necessary.\n# Late Injection\n• The repeat DMPA injection can be given up to 2 weeks late (15 weeks from the last injection) without requiring additional contraceptive protection. • If the woman is >2 weeks late (>15 weeks from the last injection) for a repeat DMPA injection, she can have the injection if it is reasonably certain that she is not pregnant (Box 2). She needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. She might consider the use of emergency contraception (with the exception of UPA) if appropriate. Comments and Evidence Summary. No time limits exist for early injections; injections can be given when necessary (e.g., when a woman cannot return at the routine interval). WHO has extended the time that a woman can have a late reinjection (i.e., grace period) for DMPA use from 2 weeks to 4 weeks on the basis of data from one study showing low pregnancy rates through 4 weeks; however, the CDC expert group did not consider the data to be generalizable to the United States because a large proportion of women in the study were breastfeeding. Therefore, U.S. SPR recommends a grace period of 2 weeks.\nA systematic review identified 12 studies evaluating time to pregnancy or ovulation after the last injection of DMPA (181). Although pregnancy rates were low during the 2-week interval following the reinjection date and for 4 weeks following the reinjection date, data were sparse, and one study included a large proportion of breastfeeding women (182)(183)(184). Studies also indicated a wide variation in time to ovulation after the last DMPA injection, with the majority ranging from 15 to 49 weeks from the last injection (185)(186)(187)(188)(189)(190)(191)(192)(193) \n# Unscheduled Spotting or Light Bleeding\n• If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment option during days of bleeding can be considered: -NSAIDs for short-term treatment (5-7 days) • If unscheduled spotting or light bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired.\n# Heavy or Prolonged Bleeding\n• If clinically indicated, consider an underlying gynecological problem, such as interactions with other medications, an STD, pregnancy, or new pathologic uterine conditions (such as fibroids or polyps). If an underlying gynecologic problem is identified, treat the condition or refer for care. • If an underlying gynecologic problem is not found and the woman wants treatment, the following treatment options during days of bleeding can be considered: -NSAIDS for short-term treatment (5-7 days) -Hormonal treatment (if medically eligible) with lowdose COCs or estrogen for short-term treatment (10-20 days) • If heavy or prolonged bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired.\n# Amenorrhea\n• Amenorrhea does not require any medical treatment. Provide reassurance.\n-If a woman's regular bleeding pattern changes abruptly to amenorrhea, consider ruling out pregnancy if clinically indicated. • If amenorrhea persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiation of DMPA, information about common side effects such as irregular bleeding should be discussed. Unscheduled bleeding or spotting is common with DMPA use (194). In addition, amenorrhea is common after ≥1 years of continuous use (194,195). These bleeding irregularities are generally not harmful. Enhanced counseling among DMPA users detailing expected bleeding patterns and reassurance that these irregularities generally are not harmful has been shown to reduce DMPA discontinuation in clinical trials (124,125).\nA systematic review, as well as two additional studies, examined the treatment of bleeding irregularities during DMPA use (195)(196)(197). Two small studies found significant cessation of bleeding within 7 days of starting treatment among women taking valdecoxib for 5 days or mefenamic acid for 5 days compared with placebo (198,199). Treatment with ethinyl estradiol was found to stop bleeding better than placebo during the treatment period, although rates of discontinuation were high and safety outcomes were not examined (200). In one small study among DMPA users who had been experiencing amenorrhea for 2 months, treatment with COCs was found to alleviate amenorrhea better than placebo (201). No studies examined the effects of aspirin on bleeding irregularities among DMPA users.\n# Combined Hormonal Contraceptives\nCombined hormonal contraceptives contain both estrogen and a progestin and include 1) COCs (various formulations), 2) a transdermal contraceptive patch (which releases 150 µg of norelgestromin and 20 µg ethinyl estradiol daily), and 3) a vaginal contraceptive ring (which releases 120 µg etonogestrel and 15 µg ethinyl estradiol daily). Approximately 9 out of 100 women become pregnant in the first year of use with combined hormonal contraceptives with typical use (14). These methods are reversible and can be used by women of all ages. Combined hormonal contraceptives are generally used for US Department of Health and Human Services/Centers for Disease Control and Prevention 21-24 consecutive days, followed by 4-7 hormone-free days (either no use or placebo pills). These methods are sometimes used for an extended period with infrequent or no hormonefree days. Combined hormonal contraceptives do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# Initiation of Combined Hormonal Contraceptives Timing\n• Combined hormonal contraceptives can be initiated at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n# Need for Back-Up Contraception\n• If combined hormonal contraceptives are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. • If combined hormonal contraceptives are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Special Considerations\nAmenorrhea (Not Postpartum)\n• Timing: Combined hormonal contraceptives can be started at any time if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days.\n# Postpartum (Breastfeeding)\n• Timing: Combined hormonal contraceptives can be started when the woman is medically eligible to use the method (5) and if it is reasonably certain that she is not pregnant. ( \n# Postabortion (Spontaneous or Induced)\n• Timing: Combined hormonal contraceptives can be started within the first 7 days following first-trimester or second-trimester abortion, including immediately postabortion (U.S. MEC 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days unless combined hormonal contraceptives are started at the time of a surgical abortion.\n# Switching from Another Contraceptive Method\n• Timing: Combined hormonal contraceptives can be started immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. • Need for back-up contraception: If it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 7 days. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options: -Advise the women to retain the IUD for at least 7 days after combined hormonal contraceptives are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs at the time of IUD removal. Combined hormonal contraceptives can be started immediately after use of ECPs (with the exception of UPA). Combined hormonal contraceptives can be started no sooner than 5 days after use of UPA. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting combined hormonal contraceptives likely exceed any risk; therefore, starting combined hormonal contraceptives should be considered at any time, with a follow-up pregnancy test in 2-4 weeks. If a woman needs to use additional contraceptive protection when switching to combined hormonal contraceptives from another contraceptive method, consider continuing her previous method for 7 days after starting combined hormonal contraceptives.\nA systematic review of 18 studies examined the effects of starting combined hormonal contraceptives on different days of the menstrual cycle (202). Overall, the evidence suggested that pregnancy rates did not differ by the timing of combined hormonal contraceptive initiation (169,(203)(204)(205) (Level of evidence: I to II-3, fair, indirect). The more follicular activity that occurred before starting COCs, the more likely ovulation was to occur; however, no ovulations occurred when COCs were started at a follicle diameter of 10 mm (mean cycle day 7.6) or when the ring was started at 13 mm (median cycle day 11) (206-215) (Level of evidence: I to II-3, fair, indirect). Bleeding patterns and other side effects did not vary with the timing of combined hormonal contraceptive initiation (204,205,(216)(217)(218)(219)(220) (Level of evidence: I to II-2, good to poor, direct). Although continuation rates of combined hormonal contraceptives were initially improved by the \"quick start\" approach (i.e., starting on the day of the visit), the advantage disappeared over time (203,204,(216)(217)(218)(219)(220)(221) (Level of evidence: I to II-2, good to poor, direct).\n# Examinations and Test Needed Before Initiation of Combined Hormonal Contraceptives\nAmong healthy women, few examinations or tests are needed before initiation of combined hormonal contraceptives (Table 4). Blood pressure should be measured before initiation of combined hormonal contraceptives. Baseline weight and BMI measurements might be useful for monitoring combined hormonal contraceptive users over time. Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Blood pressure: Women who have more severe hypertension (systolic pressure of ≥160 mmHg or diastolic pressure of ≥100 mm Hg) or vascular disease should not use combined hormonal contraceptives (U.S. MEC 4), and women who have less severe hypertension (systolic pressure of 140-159 mm Hg or diastolic pressure of 90-99 mm Hg) or adequately controlled hypertension generally should not use combined hormonal contraceptives (U.S. MEC 3) (5). Therefore, blood pressure should be evaluated before initiating combined hormonal contraceptives. In instances in which blood pressure cannot be measured by a provider, blood pressure measured in other settings can be reported by the woman to her provider. Evidence suggests that cardiovascular outcomes are worse among women who did not have their blood pressure measured before initiating COCs. A systematic review identified six articles from three studies that reported cardiovascular outcomes among women who had blood pressure measurements and women who did not have blood pressure measurements before initiating COCs (170). Three case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for acute myocardial infarction than women who did have blood pressure measurements (222)(223)(224). Two case-control studies showed that women who did not have blood pressure measurements before initiating COCs had a higher risk for ischemic stroke than women who did have blood pressure measurements (225,226). One case-control study showed no difference in the risk for hemorrhagic stroke among women who initiated COCs regardless of whether their blood pressure was measured (227). Studies that examined hormonal contraceptive methods other than COCs were not identified (Level of evidence: II-2, fair, direct).\n# Weight (BMI):\nObese women generally can use combined hormonal contraceptives (U.S. MEC 2) (5); therefore, screening for obesity is not necessary for the safe initiation of combined hormonal contraceptives. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nBimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of combined hormonal contraceptives because it does not facilitate detection of conditions for which hormonal contraceptives would be unsafe. Women with certain conditions such as current breast cancer, severe hypertension or vascular disease, heart disease, migraine headaches with aura, and certain liver diseases, as well as women aged ≥35 years and who smoke ≥15 cigarettes per day, should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5); however, none of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two case-control studies that compared delayed and immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal wet mounts were found (Level of evidence: Level II-2 fair, direct).\nGlucose: Although women with complicated diabetes should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives, depending on the severity of the condition (5), screening for diabetes before initiation of hormonal contraceptives is not necessary because of the low prevalence of undiagnosed diabetes and the high likelihood that women with complicated diabetes already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with glucose measurement before initiation of hormonal contraceptives (57). The prevalence of diabetes among women of reproductive age is low. During 2009-2012 among women aged 20-44 years in the United States, the prevalence of diabetes was 3.3% (84). During 1999-2008, the percentage of women aged 20-44 years with undiagnosed diabetes was 0.5% (85). Although hormonal contraceptives can have some adverse effects on glucose metabolism in healthy and diabetic women, the overall clinical effect is minimal (171)(172)(173)(174)(175)(176)(177).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of combined hormonal contraceptives because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). A systematic review identified few studies, all of poor quality, that suggest that women with known dyslipidemias using combined hormonal contraceptives might be at increased risk for myocardial infarction, cerebrovascular accident, or venous thromboembolism compared with women without dyslipidemias; no studies were identified that examined risk for pancreatitis among women with known dyslipidemias using combined hormonal contraceptives (89). Studies have shown mixed results regarding the effects of hormonal contraceptives on lipid levels among both healthy women and women with * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † In instances in which blood pressure cannot be measured by a provider, blood pressure measured in other settings can be reported by the woman to her provider. § Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nbaseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases should not use (U.S. MEC 4) or generally should not use (U.S. MEC 3) combined hormonal contraceptives (5), screening for liver disease before initiation of combined hormonal contraceptives is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would have had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94), although evidence is limited; no evidence exists for other types of combined hormonal contraceptives.\nThrombogenic mutations: Women with thrombogenic mutations should not use combined hormonal contraceptives (U.S. MEC 4) (5) because of the increased risk for venous thromboembolism (228). However, studies have shown that universal screening for thrombogenic mutations before initiating COCs is not cost-effective because of the rarity of the conditions and the high cost of screening (229)(230)(231).\nClinical breast examination: Although women with current breast cancer should not use combined hormonal contraceptives (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating combined hormonal contraceptives is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with anemia, cervical intraepithelial neoplasia, cervical cancer, HIV infection, or other STDs can use (U.S. MEC 1) or generally can use (U.S. MEC 2) combined hormonal contraceptives (5); therefore, screening for these conditions is not necessary for the safe initiation of combined hormonal contraceptives.\n# Number of Pill Packs that Should Be Provided at Initial and Return Visits\n• At the initial and return visits, provide or prescribe up to a 1-year supply of COCs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. • A woman should be able to obtain COCs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy.\nA systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (232). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (233)(234)(235). However, one study found no difference in continuation when patients were provided one and then three packs versus four packs all at once (236). In addition to continuation, a greater number of pills packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (i.e., 13 packs versus three packs) also was associated with increased pill wastage in one study (234) (Level of evidence: I to II-2, fair, direct).\n# Routine Follow-Up After Combined Hormonal Contraceptive Initiation\nThese recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n• Advise the woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. • At other routine visits, health care providers seeing combined hormonal contraceptive users should do the following:\n-Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of combined hormonal contraceptives for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Assess blood pressure.\n-Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence exists regarding whether a routine follow-up visit after initiating combined hormonal contraceptives improves correct or continued use. Monitoring blood pressure is important for combined hormonal contraceptive users. Health care providers might consider recommending women obtain blood pressure measurements in other settings.\nA systematic review identified five studies that examined the incidence of hypertension among women who began using a COC versus those who started a nonhormonal method of contraception or a placebo (123). Few women developed hypertension after initiating COCs, and studies examining increases in blood pressure after COC initiation found mixed results. No studies were identified that examined changes in blood pressure among patch or vaginal ring users (Level of evidence: I, fair, to II-2, fair, indirect).\n# Late or Missed Doses and Side Effects from Combined Hormonal Contraceptive Use\nFor the following recommendations, a dose is considered late when <24 hours have elapsed since the dose should have been taken. A dose is considered missed if ≥24 hours have elapsed since the dose should have been taken. For example, if a COC pill was supposed to have been taken on Monday at 9:00 a.m. and is taken at 11:00 a.m., the pill is late; however, by Tuesday morning at 11:00 a.m., Monday's 9:00 a.m. pill has been missed and Tuesday's 9:00 a.m. pill is late. For COCs, the recommendations only apply to late or missed hormonally active pills and not to placebo pills. Recommendations are provided for late or missed pills (Figure 2), the patch (Figure 3), and the ring (Figure 4).\nComments and Evidence Summary. Inconsistent or incorrect use of combined hormonal contraceptives is a major cause of combined hormonal contraceptive failure. Extending the hormone-free interval is considered to be a particularly risky time to miss combined hormonal contraceptives. Seven days of continuous combined hormonal contraceptive use is deemed necessary to reliably prevent ovulation. The recommendations reflect a balance between simplicity and precision of science. Women who frequently miss COCs or experience other usage errors with combined hormonal patch or combined vaginal ring should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable).\nA systematic review identified 36 studies that examined measures of contraceptive effectiveness of combined hormonal contraceptives during cycles with extended hormone-free intervals, shortened hormone-free intervals, or deliberate nonadherence on days not adjacent to the hormone-free interval (237). Most of the studies examined COCs (215,, two examined the combined hormonal patch (259,266), and six examined the combined vaginal ring (211,(267)(268)(269)(270)(271). No direct evidence on the effect of missed pills on the risk for pregnancy was found. Studies of women deliberately extending the hormone-free interval up to 14 days found wide variability in the amount of follicular development and occurrence of ovulation (241,244,246,247,249,250,(252)(253)(254)(255); in general, the risk for ovulation was low, and among women who did ovulate, cycles were usually abnormal. In studies of women who deliberately missed pills on various days during the cycle not adjacent to the hormone-free interval, ovulation occurred infrequently (239,(245)(246)(247)255,256,258,259). Studies comparing 7-day hormone-free intervals with shorter hormone-free intervals found lower rates of pregnancy (238,242,251,257) and significantly greater suppression of ovulation (240,250,(261)(262)(263)265) among women with shorter intervals in all but one study (260), which found no difference. Two studies that compared 30-µg ethinyl estradiol pills with 20-µg ethinyl estradiol pills showed more follicular activity when 20-µg ethinyl estradiol pills were missed (241,244). In studies examining the combined vaginal ring, three studies found that nondeliberate extension of the hormone-free interval for 24 to <48 hours from the scheduled period did not increase the risk for pregnancy (267,268,270); one study found that ring insertion after a deliberately extended hormone-free interval that allowed a 13-mm follicle to develop interrupted ovarian function and further follicular growth (211); and one study found that inhibition of ovulation was maintained after deliberately forgetting to remove the ring for up to 2 weeks after normal ring use (271). In studies examining the combined hormonal patch, one study found that missing 1-3 consecutive days before patch replacement (either wearing one patch 3 days longer before replacement or going 3 days without a patch before replacing the next patch) on days not adjacent to the patch-free interval resulted in little follicular activity and low risk for ovulation (259), and one pharmacokinetic study found that serum levels of If one hormonal pill is late: (<24 hours since a pill should have been taken) If one hormonal pill has been missed: (24 to <48 hours since a pill should have been taken) If two or more consecutive hormonal pills have been missed: (≥48 hours since a pill should have been taken)\n• Take the late or missed pill as soon as possible.\n• Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day).\n• No additional contraceptive protection is needed. • Emergency contraception is not usually needed but can be considered (with the exception of UPA) if hormonal pills were missed earlier in the cycle or in the last week of the previous cycle.\n• Take the most recent missed pill as soon as possible. (Any other missed pills should be discarded.) • Continue taking the remaining pills at the usual time (even if it means taking two pills on the same day).\n• Use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills have been taken for 7 consecutive days. • If pills were missed in the last week of hormonal pills (e.g., days 15-21 for 28-day pill packs):\no Omit the hormone-free interval by nishing the hormonal pills in the current pack and starting a new pack the next day. o If unable to start a new pack immediately, use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills from a new pack have been taken for 7 consecutive days. • Emergency contraception should be considered (with the exception of UPA) if hormonal pills were missed during the rst week and unprotected sexual intercourse occurred in the previous 5 days. • Emergency contraception may also be considered (with the exception of UPA) at other times as appropriate. ethinyl estradiol and progestin norelgestromin remained within reference ranges after extending patch wear for 3 days (266).\nNo studies were found on extending the patch-free interval. In studies that provide indirect evidence on the effects of missed combined hormonal contraception on surrogate measures of pregnancy, how differences in surrogate measures correspond to pregnancy risk is unclear (Level of evidence: I, good, indirect to II-3, poor, direct).\n# Vomiting or Severe Diarrhea While Using COCs\nCertain steps should be taken by women who experience vomiting or severe diarrhea while using COCs (Figure 5).\nComments and Evidence Summary. Theoretically, the contraceptive effectiveness of COCs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence that addresses vomiting or severe diarrhea while using COCs, these recommendations are based on the recommendations for missed COCs. No evidence was found on the effects of vomiting or diarrhea on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality.\n# Unscheduled Bleeding with Extended or Continuous Use of Combined Hormonal Contraceptives\n• Before initiation of combined hormonal contraceptives, provide counseling about potential changes in bleeding patterns during extended or continuous combined hormonal contraceptive use. (Extended contraceptive use is defined as a planned hormone-free interval after at least two contiguous cycles. Continuous contraceptive use is defined as uninterrupted use of hormonal contraception without a hormone-free interval) (272). • Unscheduled spotting or bleeding is common during the first 3-6 months of extended or continuous combined hormonal contraceptive use. It is generally not harmful and decreases with continued combined hormonal contraceptive use. • If clinically indicated, consider an underlying gynecological problem, such as inconsistent use, interactions with other medications, cigarette smoking, an STD, pregnancy, or new pathologic uterine conditions (e.g., polyps or fibroids). If an underlying gynecological problem is found, treat the condition or refer for care. • If an underlying gynecological problem is not found and the woman wants treatment, the following treatment option can be considered:\nDelayed insertion of a new ring or delayed reinsertion of a current ring for <48 hours since a ring should have been inserted\nDelayed insertion of a new ring or delayed reinsertion for ≥48 hours since a ring should have been inserted\n• Insert ring as soon as possible.\n• Keep the ring in until the scheduled ring removal day.\n• No additional contraceptive protection is needed.\n• Emergency contraception is not usually needed but can be considered (with the exception of UPA) if delayed insertion or reinsertion occurred earlier in the cycle or in the last week of the previous cycle.\n• Insert ring as soon as possible.\n• Keep the ring in until the scheduled ring removal day.\n• Use back-up contraception (e.g., condoms) or avoid sexual intercourse until a ring has been worn for 7 consecutive days. • Emergency contraception may also be considered (with the exception of UPA) at other times as appropriate.\n# FIGURE 4. Recommended actions after delayed insertion or reinsertion* with combined vaginal ring\nAbbreviation: UPA = ulipristal acetate. * If removal takes place but the woman is unsure of how long the ring has been removed, consider the ring to have been removed for ≥48 hours since a ring should have been inserted or reinserted.\n-Advise the woman to discontinue combined hormonal contraceptive use (i.e., a hormone-free interval) for 3-4 consecutive days; a hormone-free interval is not recommended during the first 21 days of using the continuous or extended combined hormonal contraceptive method. A hormone-free interval also is not recommended more than once per month because contraceptive effectiveness might be reduced. • If unscheduled spotting or bleeding persists and the woman finds it unacceptable, counsel her on alternative contraceptive methods, and offer another method if it is desired. Comments and Evidence Summary. During contraceptive counseling and before initiating extended or continuous combined hormonal contraceptives, information about common side effects such as unscheduled spotting or bleeding, especially during the first 3-6 months of use, should be discussed (273). These bleeding irregularities are generally not harmful and usually improve with persistent use of the hormonal method. To avoid unscheduled spotting or bleeding, counseling should emphasize the importance of correct use and timing; for users of contraceptive pills, emphasize consistent pill use. Enhanced counseling about expected bleeding patterns and reassurance that bleeding irregularities are generally not harmful has been shown to reduce method discontinuation in clinical trials with DMPA (124,125,274).\nA systematic review identified three studies with small study populations that addressed treatments for unscheduled bleeding among women using extended or continuous combined hormonal contraceptives (275). In two separate randomized clinical trials in which women were taking either contraceptive pills or using the contraceptive ring continuously for 168 days, women assigned to a hormone-free interval of 3 or 4 days reported improved bleeding. Although they noted an initial increase in flow, this was followed by an abrupt decrease 7-8 days later with eventual cessation of flow 11-12 days later. These findings were compared with women who continued to use their method without a hormonefree interval, in which a greater proportion reported either treatment failure or fewer days of amenorrhea (276,277). In another randomized trial of 66 women with unscheduled bleeding among women using 84 days of hormonally active contraceptive pills, oral doxycycline (100 mg twice daily) initiated the first day of bleeding and taken for 5 days did not result in any improvement in bleeding compared with placebo (278) (Level of evidence: I, fair, direct).\nVomiting or diarrhea (for any reason, for any duration), that occurs within 24 hours after taking a hormonal pill Vomiting or diarrhea, for any reason, continuing for 24 to <48 hours after taking any hormonal pill Vomiting or diarrhea, for any reason, continuing for ≥48 hours after taking any hormonal pill • Taking another hormonal pill (redose) is unnecessary.\n• Continue taking pills daily at the usual time (if possible, despite discomfort). • No additional contraceptive protection is needed. • Emergency contraception is not usually needed but can be considered (with the exception of UPA) as appropriate.\n• Continue taking pills daily at the usual time (if possible, despite discomfort). • Use back-up contraception (e.g., condoms) or avoid sexual intercourse until hormonal pills have been taken for 7 consecutive days after vomiting or diarrhea has resolved. \n# Progestin-Only Pills\nPOPs contain only a progestin and no estrogen and are available in the United States. Approximately 9 out of 100 women become pregnant in the first year of use with POPs with typical use (14). POPs are reversible and can be used by women of all ages. POPs do not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# Initiation of POPs Timing\n• POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 2).\n# Need for Back-Up Contraception\n• If POPs are started within the first 5 days since menstrual bleeding started, no additional contraceptive protection is needed. • If POPs are started >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n# Special Considerations\nAmenorrhea (Not Postpartum)\n• Timing: POPs can be started at any time if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n# Postpartum (Breastfeeding)\n• Timing: POPs can be started at any time, including immediately postpartum (U.S. MEC 2 if <1 month postpartum; U.S. MEC 1 if ≥1 month postpartum) if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: If the woman is <6 months postpartum, amenorrheic, and fully or nearly fully breastfeeding (exclusively breastfeeding or the vast majority [≥85%] of feeds are breastfeeds) (27), no additional contraceptive protection is needed. Otherwise, a woman who is ≥21 days postpartum and has not experienced return of her menstrual cycles, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. If her menstrual cycles have returned and it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n# Postpartum (Not Breastfeeding)\n• Timing: POPs can be started at any time, including immediately postpartum (U.S. MEC 1), if it is reasonably certain that the woman is not pregnant (Box 2). • Need for back-up contraception: If a woman is <21 days postpartum, no additional contraceptive protection is needed. Women who are ≥21 days postpartum and whose menstrual cycles have not returned need to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. If her menstrual cycles have returned and it has been >5 days since menstrual bleeding started, she needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days.\n# Postabortion (Spontaneous or Induced)\n• Timing: POPs can be started within the first 7 days, including immediately postabortion (U.S. MEC 1). • Need for back-up contraception: The woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days unless POPs are started at the time of a surgical abortion.\n# Switching from Another Contraceptive Method\n• Timing: POPs can be started immediately if it is reasonably certain that the woman is not pregnant (Box 2). Waiting for her next menstrual cycle is unnecessary. • Need for back-up contraception: If it has been >5 days since menstrual bleeding started, the woman needs to abstain from sexual intercourse or use additional contraceptive protection for the next 2 days. • Switching from an IUD: If the woman has had sexual intercourse since the start of her current menstrual cycle and it has been >5 days since menstrual bleeding started, theoretically, residual sperm might be in the genital tract, which could lead to fertilization if ovulation occurs. A health care provider may consider any of the following options: -Advise the women to retain the IUD for at least 2 days after POPs are initiated and return for IUD removal. -Advise the woman to abstain from sexual intercourse or use barrier contraception for 7 days before removing the IUD and switching to the new method. -If the woman cannot return for IUD removal and has not abstained from sexual intercourse or used barrier contraception for 7 days, advise the woman to use ECPs at the time of IUD removal. POPs can be started immediately after use of ECPs (with the exception of UPA). POPs can be started no sooner than 5 days after use of UPA. Comments and Evidence Summary. In situations in which the health care provider is uncertain whether the woman might be pregnant, the benefits of starting POPs likely exceed any risk; therefore, starting POPs should be considered at any time, with a follow-up pregnancy test in 2-4 weeks.\nUnlike COCs, POPs inhibit ovulation in about half of cycles, although the rates vary widely by individual (279). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (279). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use has been deemed necessary to achieve the contraceptive effects on cervical mucus (279). If a woman needs to use additional contraceptive protection when switching to POPs from another contraceptive method, consider continuing her previous method for 2 days after starting POPs. No direct evidence was found regarding the effects of starting POPs at different times of the cycle.\n# Examinations and Tests Needed Before Initiation of POPs\nAmong healthy women, no examinations or tests are needed before initiation of POPs, although a baseline weight and BMI measurement might be useful for monitoring POP users over time (Table 5). Women with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. The U.S. MEC might be useful in such circumstances (5).\nComments and Evidence Summary. Weight (BMI): Obese women can use POPs (U.S. MEC 1) (5); therefore, screening for obesity is not necessary for the safe initiation of POPs. However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nBimanual examination and cervical inspection: Pelvic examination is not necessary before initiation of POPs because it does not facilitate detection of conditions for which POPs would be unsafe. Women with current breast cancer should not use POPs (U.S. MEC 4), and women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5); however, neither of these conditions are likely to be detected by pelvic examination (145). A systematic review identified two casecontrol studies that compared delayed versus immediate pelvic examination before initiation of hormonal contraceptives, specifically oral contraceptives or DMPA (95). No differences in risk factors for cervical neoplasia, incidence of STDs, incidence of abnormal Papanicolaou smears, or incidence of abnormal findings from wet mounts were observed (Level of evidence: II-2 fair, direct).\nLipids: Screening for dyslipidemias is not necessary for the safe initiation of POPs because of the low prevalence of undiagnosed disease in women of reproductive age and the low likelihood of clinically significant changes with use of hormonal contraceptives. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with lipid measurement before initiation of hormonal contraceptives (57). During 2009-2012 among women aged 20-44 years in the United States, 7.6% had high cholesterol, defined as total serum cholesterol ≥240 mg/dL (84). During 1999-2008, the prevalence of undiagnosed hypercholesterolemia among women aged 20-44 years was approximately 2% (85). Studies have shown mixed results about the effects of hormonal methods on lipid levels among both healthy women and women with baseline lipid abnormalities, and the clinical significance of these changes is unclear (86)(87)(88)(89).\nLiver enzymes: Although women with certain liver diseases generally should not use POPs (U.S. MEC 3) (5), screening for liver disease before initiation of POPs is not necessary because of the low prevalence of these conditions and the high likelihood that women with liver disease already would * Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; the risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. Class C: does not contribute substantially to safe and effective use of the contraceptive method. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method.\nhave had the condition diagnosed. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with liver enzyme tests before initiation of hormonal contraceptives (57). In 2012, among U.S. women, the percentage with liver disease (not further specified) was 1.3% (90). In 2013, the incidence of acute hepatitis A, B, or C was ≤1 per 100,000 U.S. population (91). During 2002-2011, the incidence of liver carcinoma among U.S. women was approximately 3.7 per 100,000 population (92). Because estrogen and progestins are metabolized in the liver, the use of hormonal contraceptives among women with liver disease might, theoretically, be a concern. The use of hormonal contraceptives, specifically COCs and POPs, does not affect disease progression or severity in women with hepatitis, cirrhosis, or benign focal nodular hyperplasia (93,94).\nClinical breast examination: Although women with current breast cancer should not use POPs (U.S. MEC 4) (5), screening asymptomatic women with a clinical breast examination before initiating POPs is not necessary because of the low prevalence of breast cancer among women of reproductive age. A systematic review did not identify any evidence regarding outcomes among women who were screened versus not screened with a clinical breast examination before initiation of hormonal contraceptives (95). The incidence of breast cancer among women of reproductive age in the United States is low. In 2012, the incidence of breast cancer among women aged 20-49 years was approximately 70.7 per 100,000 women (96).\nOther screening: Women with hypertension, diabetes, anemia, thrombogenic mutations, cervical intraepithelial neoplasia, cervical cancer, STDs, or HIV infection can use (U.S. MEC 1) or generally can use (U.S. MEC 2) POPs (5); therefore, screening for these conditions is not necessary for the safe initiation of POPs.\n# Number of Pill Packs that Should Be Provided at Initial and Return Visits\n• At the initial and return visit, provide or prescribe up to a 1-year supply of POPs (e.g., 13 28-day pill packs), depending on the woman's preferences and anticipated use. • A woman should be able to obtain POPs easily in the amount and at the time she needs them. Comments and Evidence Summary. The more pill packs given up to 13 cycles, the higher the continuation rates. Restricting the number of pill packs distributed or prescribed can result in unwanted discontinuation of the method and increased risk for pregnancy.\nA systematic review of the evidence suggested that providing a greater number of pill packs was associated with increased continuation (232). Studies that compared provision of one versus 12 packs, one versus 12 or 13 packs, or three versus seven packs found increased continuation of pill use among women provided with more pill packs (233)(234)(235). However, one study found no difference in continuation when patients were provided one and then three packs versus four packs all at once (236). In addition to continuation, a greater number of pill packs provided was associated with fewer pregnancy tests, fewer pregnancies, and lower cost per client. However, a greater number of pill packs (13 packs versus three packs) also was associated with increased pill wastage in one study (234) (Level of evidence: I to II-2, fair, direct).\n# Routine Follow-Up After POP Initiation\nThese recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women. The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from more frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n• Advise the woman to return at any time to discuss side effects or other problems or if she wants to change the method being used. No routine follow-up visit is required. • At other routine visits, health care providers seeing POP users should do the following: -Assess the woman's satisfaction with her contraceptive method and whether she has any concerns about method use. -Assess any changes in health status, including medications, that would change the appropriateness of POPs for safe and effective continued use based on U.S. MEC (e.g., category 3 and 4 conditions and characteristics). -Consider assessing weight changes and counseling women who are concerned about weight change perceived to be associated with their contraceptive method. Comments and Evidence Summary. No evidence was found regarding whether a routine follow-up visit after initiating POPs improves correct and continued use.\n# Missed POPs\nFor the following recommendations, a dose is considered missed if it has been >3 hours since it should have been taken.\n• Take one pill as soon as possible.\n• Continue taking pills daily, one each day, at the same time each day, even if it means taking two pills on the same day. • Use back-up contraception (e.g., condoms) or avoid sexual intercourse until pills have been taken correctly, on time, for 2 consecutive days.\n• Emergency contraception should be considered (with the exception of UPA) if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Inconsistent or incorrect use of oral contraceptive pills is a major reason for oral contraceptive failure. Unlike COCs, POPs inhibit ovulation in about half of cycles, although this rate varies widely by individual (279). Peak serum steroid levels are reached about 2 hours after administration, followed by rapid distribution and elimination, such that by 24 hours after administration, serum steroid levels are near baseline (279). Therefore, taking POPs at approximately the same time each day is important. An estimated 48 hours of POP use was deemed necessary to achieve the contraceptive effects on cervical mucus (279). Women who frequently miss POPs should consider an alternative contraceptive method that is less dependent on the user to be effective (e.g., IUD, implant, or injectable). No evidence was found regarding the effects of missed POPs available in the United States on measures of contraceptive effectiveness including pregnancy, follicular development, hormone levels, or cervical mucus quality.\n# Vomiting or Diarrhea (for any Reason or Duration) that Occurs Within 3 Hours After\nTaking a Pill\n• Take another pill as soon as possible (if possible, despite discomfort). • Continue taking pills daily, one each day, at the same time each day. • Use back-up contraception (e.g., condoms) or avoid sexual intercourse until 2 days after vomiting or diarrhea has resolved. • Emergency contraception should be considered (with the exception of UPA) if the woman has had unprotected sexual intercourse. Comments and Evidence Summary. Theoretically, the contraceptive effectiveness of POPs might be decreased because of vomiting or severe diarrhea. Because of the lack of evidence to address this question, these recommendations are based on the recommendations for missed POPs. No evidence was found regarding the effects of vomiting or diarrhea on measures of contraceptive effectiveness, including pregnancy, follicular development, hormone levels, or cervical mucus quality.\n# Standard Days Method\nSDM is a method based on fertility awareness; users must avoid unprotected sexual intercourse on days 8-19 of the menstrual cycle (280). Approximately 5 out of 100 women become pregnant in the first year of use with perfect (i.e., correct and consistent) use of SDM (280); effectiveness based on typical use is not available for this method but is expected to be lower than that for perfect use. SDM is reversible and can be used by women of all ages. SDM does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# Use of SDM Among Women with Various Durations of the Menstrual Cycle Menstrual Cycles of 26-32 Days\n• The woman may use the method.\n• Provide a barrier method of contraception for protection on days 8-19 if she wants one. • If she has unprotected sexual intercourse during days 8-19, consider the use of emergency contraception if appropriate.\n# Two or More Cycles of <26 or >32 Days Within Any 1 Year of SDM Use\n• Advise the woman that the method might not be appropriate for her because of a higher risk for pregnancy. Help her consider another method. Comments and Evidence Summary. The probability of pregnancy is increased when the menstrual cycle is outside the range of 26-32 days, even if unprotected sexual intercourse is avoided on days 8-19. A study of 7,600 menstrual cycles, including information on cycle length and signs of ovulation, concluded that the theoretical effectiveness of SDM is greatest for women with cycles of 26-32 days, that the method is still effective for women who occasionally have a cycle outside this range, and that it is less effective for women who consistently have cycles outside this range. Information from daily hormonal measurements shows that the timing of the 6-day fertile window varies greatly, even among women with regular cycles (21,281,282).\n# Emergency Contraception\nEmergency contraception consists of methods that can be used by women after sexual intercourse to prevent pregnancy. Emergency contraception methods have varying ranges of effectiveness depending on the method and timing of administration. Four options are available in the United States: the Cu-IUD and three types of ECPs.\n# Types of Emergency Contraception Intrauterine Device\n• Cu-IUD\n# ECPs\n• UPA in a single dose (30 mg) • Levonorgestrel in a single dose (1.5 mg) or as a split dose (1 dose of 0.75 mg of levonorgestrel followed by a second dose of 0.75 mg of levonorgestrel 12 hours later) • Combined estrogen and progestin in 2 doses (Yuzpe regimen: 1 dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel followed by a second dose of 100 µg of ethinyl estradiol plus 0.50 mg of levonorgestrel 12 hours later)\n# Initiation of Emergency Contraception\nTiming Cu-IUD\n• The Cu-IUD can be inserted within 5 days of the first act of unprotected sexual intercourse as an emergency contraceptive. • In addition, when the day of ovulation can be estimated, the Cu-IUD can be inserted beyond 5 days after sexual intercourse, as long as insertion does not occur >5 days after ovulation.\n# ECPs\n• ECPs should be taken as soon as possible within 5 days of unprotected sexual intercourse. Comments and Evidence Summary. Cu-IUDs are highly effective as emergency contraception (283) and can be continued as regular contraception. UPA and levonorgestrel ECPs have similar effectiveness when taken within 3 days after unprotected sexual intercourse; however, UPA has been shown to be more effective than the levonorgestrel formulation 3-5 days after unprotected sexual intercourse (284). The combined estrogen and progestin regimen is less effective than UPA or levonorgestrel and also is associated with more frequent occurrence of side effects (nausea and vomiting) (285). The levonorgestrel formulation might be less effective than UPA among obese women (286).\nTwo studies of UPA use found consistent decreases in pregnancy rates when administered within 120 hours of unprotected sexual intercourse (284,287). Five studies found that the levonorgestrel and combined regimens decreased risk for pregnancy through the fifth day after unprotected sexual intercourse; however, rates of pregnancy were slightly higher when ECPs were taken after 3 days (288)(289)(290)(291)(292). A meta-analysis of levonorgestrel ECPs found that pregnancy rates were low when administered within 4 days after unprotected sexual intercourse but increased at 4-5 days (293) (Level of evidence: I to II-2, good to poor, direct).\n# Advance Provision of ECPs\n• An advance supply of ECPs may be provided so that ECPs will be available when needed and can be taken as soon as possible after unprotected sexual intercourse. Comments and Evidence Summary. A systematic review identified 17 studies that reported on safety or effectiveness of advance ECPs in adult or adolescent women (294). Any use of ECPs was two to seven times greater among women who received an advance supply of ECPs. However, a summary estimate (relative risk = 0.97; 95% confidence interval = 0.77-1.22) of five randomized controlled trials did not indicate a significant reduction in unintended pregnancies at 12 months with advance provision of ECPs. In the majority of studies among adults or adolescents, patterns of regular contraceptive use, pregnancy rates, and incidence of STDs did not vary between those who received advance ECPs and those who did not. Although available evidence supports the safety of advance provision of ECPs, effectiveness of advance provision of ECPs in reducing pregnancy rates at the population level has not been demonstrated (Level of evidence: I to II-3, good to poor, direct).\n# Initiation of Regular Contraception After ECPs\n\n# UPA\n• Advise the woman to start or resume hormonal contraception no sooner than 5 days after use of UPA, and provide or prescribe the regular contraceptive method as needed. For methods requiring a visit to a health care provider, such as DMPA, implants, and IUDs, starting the method at the time of UPA use may be considered; the risk that the regular contraceptive method might decrease the effectiveness of UPA must be weighed against the risk of not starting a regular hormonal contraceptive method. • The woman needs to abstain from sexual intercourse or use barrier contraception for the next 7 days after starting or resuming regular contraception or until her next menses, whichever comes first. • Any nonhormonal contraceptive method can be started immediately after the use of UPA. • Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks.\n# Levonorgestrel and Combined Estrogen and Progestin ECPs\n• Any regular contraceptive method can be started immediately after the use of levonorgestrel or combined estrogen and progestin ECPs. • The woman needs to abstain from sexual intercourse or use barrier contraception for 7 days. • Advise the woman to have a pregnancy test if she does not have a withdrawal bleed within 3 weeks. Comments and Evidence Summary. The resumption or initiation of regular hormonal contraception after ECP use involves consideration of the risk for pregnancy if ECPs fail and the risks for unintended pregnancy if contraception initiation is delayed until the subsequent menstrual cycle. A health care provider may provide or prescribe pills, the patch, or the ring for a woman to start no sooner than 5 days after use of UPA. For methods requiring a visit to a health care provider, such as DMPA, implants, and IUDs, starting the method at the time of UPA use may be considered; the risk that the regular contraceptive method might decrease the effectiveness of UPA must be weighed against the risk of not starting a regular hormonal contraceptive method.\nData on when a woman can start regular contraception after ECPs are limited to pharmacodynamic data and expert opinion (295)(296)(297). In one pharmacodynamic study of women who were randomly assigned to either UPA or placebo groups mid-cycle followed by a 21-day course of combined hormonal contraception found no difference between UPA and placebo groups in the time for women's ovaries to reach quiescence by ultrasound and serum estradiol (296); this finding suggests that UPA did not have an effect on the combined hormonal contraception. In another pharmacodynamic study with a crossover design, women were randomly assigned to one of three groups: 1) UPA followed by desogestrel for 20 days started 1 day later; 2) UPA plus placebo; or 3) placebo plus desogestrel for 20 days (295). Among women taking UPA followed by desogestrel, a higher incidence of ovulation in the first 5 days was found compared with UPA alone (45% versus 3%, respectively), suggesting desogestrel might decrease the effectiveness of UPA. No concern exists that administering combined estrogen and progestin or levonorgestrel formulations of ECPs concurrently with systemic hormonal contraception decreases the effectiveness of either emergency or regular contraceptive methods because these formulations do not have antiprogestin properties like UPA. If a woman is planning to initiate contraception after the next menstrual bleeding after ECP use, the cycle in which ECPs are used might be shortened, prolonged, or involve unscheduled bleeding.\n# Prevention and Management of Nausea and Vomiting with ECP Use\n\n# Nausea and Vomiting\n• Levonorgestrel and UPA ECPs cause less nausea and vomiting than combined estrogen and progestin ECPs. • Routine use of antiemetics before taking ECPs is not recommended. Pretreatment with antiemetics may be considered depending on availability and clinical judgment.\n# Vomiting Within 3 Hours of Taking ECPs\n• Another dose of ECP should be taken as soon as possible.\nUse of an antiemetic should be considered. Comments and Evidence Summary. Many women do not experience nausea or vomiting when taking ECPs, and predicting which women will experience nausea or vomiting is difficult. Although routine use of antiemetics before taking ECPs is not recommended, antiemetics are effective in some women and can be offered when appropriate. Health care providers who are deciding whether to offer antiemetics to women taking ECPs should consider the following: 1) women taking combined estrogen and progestin ECPs are more likely to experience nausea and vomiting than those who take levonorgestrel or UPA ECPs; 2) evidence indicates that antiemetics reduce the occurrence of nausea and vomiting in women taking combined estrogen and progestin ECPs; and 3) women who take antiemetics might experience other side effects from the antiemetics.\nA systematic review examined incidence of nausea and vomiting with different ECP regimens and effectiveness of antinausea drugs in reducing nausea and vomiting with ECP use (298). The levonorgestrel regimen was associated with significantly less nausea than a nonstandard dose of UPA (50 mg) and the standard combined estrogen and progestin regimen (299)(300)(301). Use of the split-dose levonorgestrel showed no differences in nausea and vomiting compared with the single-dose levonorgestrel (288,290,292,302) (Level of evidence: I, good-fair, indirect). Two trials of antinausea drugs, meclizine and metoclopramide, taken before combined estrogen and progestin ECPs, reduced the severity of nausea (303,304). Significantly less vomiting occurred with meclizine but not metoclopramide (Level of evidence: I, good-fair, direct). No direct evidence was found regarding the effects of vomiting after taking ECPs.\n# Female Sterilization\nLaparoscopic, abdominal, and hysteroscopic methods of female sterilization are available in the United States, and some of these procedures can be performed in an outpatient procedure or office setting. Fewer than 1 out of 100 women become pregnant in the first year after female sterilization (14). Because these methods are intended to be irreversible, all women should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception. Female sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# When Hysteroscopic Sterilization is\nReliable for Contraception\n• Before a woman can rely on hysteroscopic sterilization for contraception, a hysterosalpingogram (HSG) must be performed 3 months after the sterilization procedure to confirm bilateral tubal occlusion. • The woman should be advised that she needs to abstain from sexual intercourse or use additional contraceptive protection until she has confirmed bilateral tubal occlusion.\n# When Laparoscopic and Abdominal Approaches are Reliable for Contraception\n• A woman can rely on sterilization for contraception immediately after laparoscopic and abdominal approaches.\nNo additional contraceptive protection is needed. Comments and Evidence Summary. HSG confirmation is necessary to confirm bilateral tubal occlusion after hysteroscopic sterilization. The inserts for the hysteroscopic sterilization system available in the United States are placed bilaterally into the fallopian tubes and require 3 months for adequate fibrosis and scarring leading to bilateral tubal occlusion. After hysteroscopic sterilization, advise the woman to correctly and consistently use an effective method of contraception while awaiting confirmation. If compliance with another method might be a problem, a woman and her health care provider may consider DMPA injection at the time of sterilization to ensure adequate contraception for 3 months. Unlike laparoscopic and abdominal sterilizations, pregnancy risk beyond 7 years of follow-up has not been studied among women who received hysteroscopic sterilization.\nPregnancy risk with at least 10 years of follow-up has been studied among women who received laparoscopic and abdominal sterilizations (305,306). Although these methods are highly effective, pregnancies can occur many years after the procedure, and the risk for pregnancy is higher among younger women (306,307).\nA systematic review was conducted to identify studies that reported whether pregnancies occurred after hysteroscopic sterilization (308). Twenty-four studies were identified that reported whether pregnancies occurred after hysteroscopic sterilization and found that very few pregnancies occurred among women with confirmed bilateral tubal occlusion; however, few studies include long-term follow-up, and none with follow up for >7 years. Among women who had successful bilateral placement, most pregnancies that occurred after hysteroscopic sterilization were in women who did not have confirmed bilateral tubal occlusion at 3 months, either because of lack of follow up or misinterpretation of HSG results (309)(310)(311). Some pregnancies occurred within 3 months of placement, including among women who were already pregnant at the time of the procedure, women who did not use alternative contraception, or women who had failures of alternative contraception (310)(311)(312)(313)(314)(315). Although these studies generally demonstrated high rates of bilateral placement, some pregnancies occurred as a result of lack of bilateral placement identified on later imaging (310,311,(313)(314)(315)(316). Most pregnancies occurred after deviations from FDA directions, which include placement in the early follicular phase of the menstrual cycle, imaging at 3 months to document proper placement, and use of effective alternative contraception until documented occlusion (Level of evidence: II-3, fair, direct).\n# Male Sterilization\nMale sterilization, or vasectomy, is one of the few contraceptive methods available to men and can be performed in an outpatient procedure or office setting. Fewer than 1 woman out of 100 becomes pregnant in the first year after her male partner undergoes sterilization (14). Because male sterilization is intended to be irreversible, all men should be appropriately counseled about the permanency of sterilization and the availability of highly effective, long-acting, reversible methods of contraception for women. Male sterilization does not protect against STDs; consistent and correct use of male latex condoms reduces the risk for STDs, including HIV.\n# When Vasectomy is Reliable for Contraception\n• A semen analysis should be performed 8-16 weeks after a vasectomy to ensure the procedure was successful. • The man should be advised that he should use additional contraceptive protection or abstain from sexual intercourse until he has confirmation of vasectomy success by postvasectomy semen analysis.\n# Other Postprocedure Recommendations\n• The man should refrain from ejaculation for approximately 1 week after the vasectomy to allow for healing of surgical sites and, after certain methods of vasectomy, occlusion of the vas. Comments and Evidence Summary. The Vasectomy Guideline Panel of the American Urological Association performed a systematic review of key issues concerning the practice of vasectomy (317). All English-language publications on vasectomy published during 1949-2011 were reviewed. For more information, see the American Urological Association Vasectomy Guidelines (https://www.auanet.org/common/pdf/ education/clinical-guidance/Vasectomy.pdf ).\nMotile sperm disappear within a few weeks after vasectomy (318)(319)(320)(321). The time to azoospermia varies widely in different studies; however, by 12 weeks after the vasectomy, 80% of men have azoospermia, and almost all others have rare nonmotile sperm (defined as ≤100,000 nonmotile sperm per milliliter) (317). The number of ejaculations after vasectomy is not a reliable indicator of when azoospermia or rare nonmotile sperm will be achieved (317). Once azoospermia or rare nonmotile sperm has been achieved, patients can rely on the vasectomy for contraception, although not with 100% certainty. The risk for pregnancy after a man has achieved postvasectomy azoospermia is approximately one in 2,000 (322)(323)(324)(325)(326).\nA median of 78% (range 33%-100%) of men return for a single postvasectomy semen analysis (317). In the largest cohorts that appear typical of North American vasectomy practice, approximately two thirds of men (55%-71%) return for at least one postvasectomy semen analysis (322,(327)(328)(329)(330)(331). Assigning men an appointment after their vasectomy might improve compliance with follow-up (332).\n# When Women Can Stop Using Contraceptives\n• Contraceptive protection is still needed for women aged >44 years if the woman wants to avoid pregnancy. Comments and Evidence Summary. The age at which a woman is no longer at risk for pregnancy is not known. Although uncommon, spontaneous pregnancies occur among women aged >44 years. Both the American College of Obstetricians and Gynecologists and the North American Menopause Society recommend that women continue contraceptive use until menopause or age 50-55 years (333,334). The median age of menopause is approximately 51 years in North America (333) but can vary from ages 40-60 years (335). The median age of definitive loss of natural fertility is 41 years but can range up to age 51 years (336,337). No reliable laboratory tests are available to confirm definitive loss of fertility in a woman. The assessment of follicle-stimulating hormone levels to determine when a woman is no longer fertile might not be accurate (333).\nHealth care providers should consider the risks for becoming pregnant in a woman of advanced reproductive age, as well as any risks of continuing contraception until menopause. Pregnancies among women of advanced reproductive age are at higher risk for maternal complications, such as hemorrhage, venous thromboembolism, and death, and fetal complications, such as spontaneous abortion, stillbirth, and congenital anomalies (338)(339)(340). Risks associated with continuing contraception, in particular risks for acute cardiovascular events (venous thromboembolism, myocardial infarction, or stroke) or breast cancer, also are important to consider. U.S. MEC states that on the basis of age alone, women aged >45 years can use POPs, implants, the LNG-IUD, or the Cu-IUD (U.S. MEC 1) (5). Women aged >45 years generally can use combined hormonal contraceptives and DMPA (U.S. MEC 2) (5). However, women in this age group might have chronic conditions or other risk factors that might render use of hormonal contraceptive methods unsafe; U.S. MEC might be helpful in guiding the safe use of contraceptives in these women.\nIn two studies, the incidence of venous thromboembolism was higher among oral contraceptive users aged ≥45 years compared with younger oral contraceptive users (341)(342)(343); however, an interaction between hormonal contraception and increased age compared with baseline risk was not demonstrated (341,342) or was not examined (343). The relative risk for myocardial infarction was higher among all oral contraceptive users than in nonusers, although a trend of increased relative risk with increasing age was not demonstrated (344,345). No studies were found regarding the risk for stroke in COC users aged ≥45 years (Level of evidence: II-2, good to poor, direct).\nA pooled analysis by the Collaborative Group on Hormonal Factors and Breast Cancer in 1996 (346) found small increased relative risks for breast cancer among women aged ≥45 years whose last use of combined hormonal contraceptives was <5 years previously and for those whose last use was 5-9 years previously. Seven more recent studies suggested small but nonsignificant increased relative risks for breast carcinoma in situ or breast cancer among women who had used oral contraceptives or DMPA when they were aged ≥40 years compared with those who had never used either method (347-353) (Level of evidence: II-2, fair, direct).\n# Conclusion\nMost women can start most contraceptive methods at any time, and few examinations or tests, if any, are needed before starting a contraceptive method. Routine follow-up for most women includes assessment of her satisfaction with the contraceptive method, concerns about method use, and changes in health status or medications that could affect medical eligibility for continued use of the method. Because changes in bleeding patterns are one of the major reasons for discontinuation of contraception, recommendations are provided for the management of bleeding irregularities with various contraceptive methods. In addition, because women and health care providers can be confused about the procedures for missed pills and dosing errors with the contraceptive patch and ring, the instructions are streamlined for easier use. ECPs and emergency use of the Cu-IUD are important options for women, and recommendations on using these methods, as well as starting regular contraception after use of emergency contraception, are provided. Male and female sterilization are highly effective methods of contraception for men, women, and couples who have completed childbearing; for men undergoing vasectomy and women undergoing a hysteroscopic sterilization procedure, additional contraceptive protection is needed until the success of the procedure can be confirmed.\nCDC is committed to working with partners at the federal, national, and local levels to disseminate, implement, and evaluate U.S. SPR recommendations so that the information reaches health care providers. Strategies for dissemination and implementation include collaborating with other federal agencies and professional and service organizations to widely distribute the recommendations through presentations, electronic distribution, newsletters, and other publications; development of provider tools and job aids to assist providers in implementing the new recommendations; and training activities for students, as well as for continuing education. CDC conducts surveys of family planning health care providers to assess attitudes and practices related to contraceptive use. Results from these surveys will assist CDC in evaluating the impact of these recommendations on the provision of contraceptives in the United States. Finally, CDC will continually monitor new scientific evidence and will update these recommendations as warranted by new evidence. Updates to the recommendations, as well as provider tools and other resources, are available on the CDC U.S. SPR website: http:// www.cdc.gov/reproductivehealth/UnintendedPregnancy/ USSPR.htm.\n# Handling Conflict of Interest\nTo promote transparency, all participants were asked to disclose any potential conflicts of interest to CDC prior to the expert meeting and to report any potential conflicts of interest during the introductory portion of the expert meeting. All potential conflicts of interest are listed above. No participants were excluded from discussion based on potential conflicts of interest. One presenter was an employee of a pharmaceutical company and participated by teleconference; after the presentation and questions related to the presentation, the presenter was excused from the discussion. CDC staff who ultimately decided and developed these recommendations have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters relevant to these recommendations. ) for clarifications to the numeric categories, as well as for summaries of the evidence and additional comments. Hormonal contraceptives and intrauterine devices do not protect against sexually transmitted diseases (STDs), including human immunodeficiency virus (HIV), and women using these methods should be counseled that consistent and correct use of the male latex condom reduces the risk for transmission of HIV and other STDs. Use of female condoms can provide protection from transmission of STDs, although data are limited.\nHealth-care providers can use the summary table as a quick reference guide to the classifications for hormonal contraceptive methods and intrauterine contraception to compare classifications across these methods (Box A1) (Table A1). For BOX A1. Categories for classifying hormonal contraceptives and intrauterine devices 1 = A condition for which there is no restriction for the use of the contraceptive method. 2 = A condition for which the advantages of using the method generally outweigh the theoretical or proven risks. 3 = A condition for which the theoretical or proven risks usually outweigh the advantages of using the method. 4 = A condition that represents an unacceptable health risk if the contraceptive method is used. * In instances in which blood pressure cannot be measured by a provider, blood pressure measured in other settings can be reported by the woman to her provider. † Weight (BMI) measurement is not needed to determine medical eligibility for any methods of contraception because all methods can be used (U.S. MEC 1) or generally can be used (U.S. MEC 2) among obese women (Box 1). However, measuring weight and calculating BMI at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. § A bimanual examination (not cervical inspection) is needed for diaphragm fitting. ¶ Most women do not require additional STD screening at the time of IUD insertion. If a woman with risk factors for STDs has not been screened for gonorrhea and chlamydia according to CDC's STD Treatment Guidelines (http://www.cdc.gov/std/treatment), screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with current purulent cervicitis or chlamydial infection or gonococcal infection should not undergo IUD insertion (U.S. MEC 4).\nThe examinations or tests noted apply to women who are presumed to be healthy (Table C1). Those with known medical problems or other special conditions might need additional examinations or tests before being determined to be appropriate candidates for a particular method of contraception. The 2016 U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) might be useful in such circumstances (1). The following classification was considered useful in differentiating the applicability of the various examinations or tests:\n• Class A: essential and mandatory in all circumstances for safe and effective use of the contraceptive method. • Class B: contributes substantially to safe and effective use, but implementation may be considered within the public health and/or service context; risk of not performing an examination or test should be balanced against the benefits of making the contraceptive method available. • Class C: does not contribute substantially to safe and effective use of the contraceptive method.\nThese classifications focus on the relationship of the examinations or tests to safe initiation of a contraceptive method. They are not intended to address the appropriateness of these examinations or tests in other circumstances. For example, some of the examinations or tests that are not deemed necessary for safe and effective contraceptive use might be appropriate for good preventive health care or for diagnosing or assessing suspected medical conditions. Any additional screening needed for preventive health care can be performed at the time of contraception initiation and initiation should not be delayed for test results.\nNo examinations or tests are needed before initiating condoms or spermicides. A bimanual examination is necessary for diaphragm fitting. A bimanual examination and cervical inspection are needed for cervical cap fitting.\n# Acknowledgments\n\n# U.S. Selected Practice Recommendations for\n\n# Ovarian cancer\nThis condition is associated with increased risk for adverse health events as a result of pregnancy. \n# Respiratory Conditions\n\n# Cystic fibrosis\nThis condition is associated with increased risk for adverse health events as a result of pregnancy.\n# Sickle cell disease\nThis condition is associated with increased risk for adverse health events as a result of pregnancy. \nSee ) at baseline might be helpful for monitoring any changes and counseling women who might be concerned about weight change perceived to be associated with their contraceptive method. † Most women do not require additional STD screening at the time of IUD insertion. If a woman with risk factors for STDs has not been screened for gonorrhea and chlamydia according to CDC's STD Treatment Guidelines (http://www.cdc.gov/std/treatment), screening can be performed at the time of IUD insertion, and insertion should not be delayed. Women with current purulent cervicitis or chlamydial infection or gonococcal infection should not undergo IUD insertion (U.S. MEC 4). \n# Appendix D Routine Follow-Up After Contraceptive Initiation\n\n# General follow-up\nAdvise women to return at any time to discuss side effects or other problems or if they want to change the method. Advise women using IUDs, implants, or injectables when the IUD or implant needs to be removed or when a reinjection is needed.\nNo routine follow-up visit is required. X X X X X\n# Other routine visits\nAssess the woman's satisfaction with her current method and whether she has any concerns about method use. These recommendations address when routine follow-up is recommended for safe and effective continued use of contraception for healthy women (Table D1). The recommendations refer to general situations and might vary for different users and different situations. Specific populations who might benefit from frequent follow-up visits include adolescents, those with certain medical conditions or characteristics, and those with multiple medical conditions.\n# Appendix E Management of Women with Bleeding Irregularities While Using Contraception*\nIf bleeding persists, or if the woman requests it, medical treatment can be considered.\n# Cu-IUD users\nFor unscheduled spotting or light bleeding or for heavy or prolonged bleeding: Continue IUD.\n•\nReassess in 24-48 hours.\nRemove IUD after beginning antibiotics.\n• Continue antibiotics.\n• Consider removal of IUD.\n• O er another contraceptive method.\n• O er emergency contraception."},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":296,"cells":{"id":{"kind":"string","value":"120c453465d9356f67b499584cff8f4189422c8f"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"# Footnotes (Figures 1 and 2)\nThe influenza vaccination footnote (#1) is revised and shortened to reflect a recommendation for vaccination of all persons aged 6 months and older, including all adults. The high-dose influenza vaccine (Fluzone), licensed in 2010 for adults aged 65 years and older, is mentioned as an option for this age group.\nThe Td/Tdap vaccination footnote (#2) has language added to indicate that persons aged 65 years and older who have close contact with an infant aged less than 12 months should get vaccinated with Tdap; the additional language notes that all persons aged 65 years and older may get vaccinated with Tdap. Also added is the recommendation to administer Tdap regardless of interval since the most recent Td-containing vaccine.\nThe HPV vaccination footnote (#4) has language added to the introductory sentences to indicate that either quadrivalent vaccine or bivalent vaccine is recommended for females.\nThe MMR vaccination footnote (#6) has been revised mainly by consolidating common language that previously had been part of each of the three vaccine component sections into one introductory statement.\nThe revaccination with PPSV footnote (#8) clarifies that one-time revaccination after 5 years only applies to persons with indicated chronic conditions who are aged 19 through 64 years.\nThe meningococcal vaccination footnote (#9) has language added to indicate that a 2-dose series of meningococcal conjugate vaccine is recommended for adults with anatomic or functional asplenia, or persistent complement component deficiencies, as well adults with human immunodeficiency (HIV) virus infection who are vaccinated. Language has been added that a single dose of meningococcal vaccine is still recommended for those with other indications. Also, language has been added to clarify that quadrivalent meningococcal conjugate vaccine (MCV4) is a quadrivalent vaccine.\nThe language for the selected conditions for the Hib footnote (#12) has been shortened to clarify which persons at high risk may receive 1 dose of Hib vaccine.\nThe recommended adult immunization schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians.\n\n# Suggested citation:\nCenters for Disease Control and Prevention. Recommended adult immunization schedule---United States, 2011. MMWR 201160(4).\n\n# NOTE:\nThe above recommendations must be read along with the footnotes on pages 3--4 of this schedule.\n\n# Influenza vaccination\nAnnual vaccination against influenza is recommended for all persons aged 6 months and older, including all adults. Healthy, nonpregnant adults aged less than 50 years without high-risk medical conditions can receive either intranasally administered live, attenuated influenza vaccine (FluMist), or inactivated vaccine. Other persons should receive the inactivated vaccine. Adults aged 65 years and older can receive the standard influenza vaccine or the high-dose (Fluzone) influenza vaccine. Additional information about influenza vaccination is available at .\n\n# Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination\nAdminister a one-time dose of Tdap to adults aged less than 65 years who have not received Tdap previously or for whom vaccine status is unknown to replace one of the 10-year Td boosters, and as soon as feasible to all 1) postpartum women, 2) close contacts of infants younger than age 12 months (e.g., grandparents and child-care providers), and 3) health-care personnel with direct patient contact. Adults aged 65 years and older who have not previously received Tdap and who have close contact with an infant aged less than 12 months also should be vaccinated. Other adults aged 65 years and older may receive Tdap. Tdap can be administered regardless of interval since the most recent tetanus or diphtheria-containing vaccine.\nAdults with uncertain or incomplete history of completing a 3-dose primary vaccination series with Tdcontaining vaccines should begin or complete a primary vaccination series. For unvaccinated adults, administer the first 2 doses at least 4 weeks apart and the third dose 6--12 months after the second. If incompletely vaccinated (i.e., less than 3 doses), administer remaining doses. Substitute a one-time dose of Tdap for one of the doses of Td, either in the primary series or for the routine booster, whichever comes first.\nIf a woman is pregnant and received the most recent Td vaccination 10 or more years previously, administer Td during the second or third trimester. If the woman received the most recent Td vaccination less than 10 years previously, administer Tdap during the immediate postpartum period. At the clinician's discretion, Td may be deferred during pregnancy and Tdap substituted in the immediate postpartum period, or Tdap may be administered instead of Td to a pregnant woman after an informed discussion with the woman.\nThe ACIP statement for recommendations for administering Td as prophylaxis in wound management is available at .\n\n# Varicella vaccination\nAll adults without evidence of immunity to varicella should receive 2 doses of single-antigen varicella vaccine if not previously vaccinated or a second dose if they have received only 1 dose, unless they have a medical contraindication. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care personnel and family contacts of persons with immunocompromising conditions) or 2) are at high risk for exposure or transmission (e.g., teachers; child-care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; nonpregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care personnel and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or having an atypical case, a mild case, or both, health-care providers should seek either an epidemiologic link with a typical varicella case or to a laboratory-confirmed case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on diagnosis or verification of herpes zoster by a health-care provider; or 5) laboratory evidence of immunity or laboratory confirmation of disease.\nPregnant women should be assessed for evidence of varicella immunity. Women who do not have evidence of immunity should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. The second dose should be administered 4--8 weeks after the first dose.\n\n# Human papillomavirus (HPV) vaccination\nHPV vaccination with either quadrivalent (HPV4) vaccine or bivalent vaccine (HPV2) is recommended for females at age 11 or 12 years and catch-up vaccination for females aged 13 through 26 years.\nIdeally, vaccine should be administered before potential exposure to HPV through sexual activity; however, females who are sexually active should still be vaccinated consistent with age-based recommendations. Sexually active females who have not been infected with any of the four HPV vaccine types (types 6, 11, 16, and 18, all of which HPV4 prevents) or any of the two HPV vaccine types (types 16 and 18, both of which HPV2 prevents) receive the full benefit of the vaccination. Vaccination is less beneficial for females who have already been infected with one or more of the HPV vaccine types. HPV4 or HPV2 can be administered to persons with a history of genital warts, abnormal Papanicolaou test, or positive HPV DNA test, because these conditions are not evidence of previous infection with all vaccine HPV types.\nHPV4 may be administered to males aged 9 through 26 years to reduce their likelihood of genital warts. HPV4 would be most effective when administered before exposure to HPV through sexual contact.\nA complete series for either HPV4 or HPV2 consists of 3 doses. The second dose should be administered 1--2 months after the first dose; the third dose should be administered 6 months after the first dose.\nAlthough HPV vaccination is not specifically recommended for persons with the medical indications described in Figure 2, \"Vaccines that might be indicated for adults based on medical and other indications,\" it may be administered to these persons because the HPV vaccine is not a live-virus vaccine. However, the immune response and vaccine efficacy might be less for persons with the medical indications described in Figure 2 than in persons who do not have the medical indications described or who are immunocompetent.\n\n# Herpes zoster vaccination\nA single dose of zoster vaccine is recommended for adults aged 60 years and older regardless of whether they report a previous episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless their condition constitutes a contraindication.\n\n# Measles, mumps, rubella (MMR) vaccination\nAdults born before 1957 generally are considered immune to measles and mumps. All adults born in 1957 or later should have documentation of 1 or more doses of MMR vaccine unless they have a medical contraindication to the vaccine, laboratory evidence of immunity to each of the three diseases, or documentation of provider-diagnosed measles or mumps disease. For rubella, documentation of provider-diagnosed disease is not considered acceptable evidence of immunity.\nMeasles component: A second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is recommended for adults who 1) have been recently exposed to measles or are in an outbreak setting; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. Persons who received inactivated (killed) measles vaccine or measles vaccine of unknown type during 1963--1967 should be revaccinated with 2 doses of MMR vaccine.\nMumps component: A second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is recommended for adults who 1) live in a community experiencing a mumps outbreak and are in an affected age group; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. Persons vaccinated before 1979 with either killed mumps vaccine or mumps vaccine of unknown type who are at high risk for mumps infection (e.g. persons who are working in a health-care facility) should be revaccinated with 2 doses of MMR vaccine.\nRubella component: For women of childbearing age, regardless of birth year, rubella immunity should be determined. If there is no evidence of immunity, women who are not pregnant should be vaccinated. Pregnant women who do not have evidence of immunity should receive MMR vaccine upon completion or termination of pregnancy and before discharge from the health-care facility.\nHealth-care personnel born before 1957: For unvaccinated health-care personnel born before 1957 who lack laboratory evidence of measles, mumps, and/or rubella immunity or laboratory confirmation of disease, health-care facilities should 1) consider routinely vaccinating personnel with 2 doses of MMR vaccine at the appropriate interval (for measles and mumps) and 1 dose of MMR vaccine (for rubella), and 2) recommend 2 doses of MMR vaccine at the appropriate interval during an outbreak of measles or mumps, and 1 dose during an outbreak of rubella. Complete information about evidence of immunity is available at .\n\n# Pneumococcal polysaccharide (PPSV) vaccination\nVaccinate all persons with the following indications:\nMedical: Chronic lung disease (including asthma); chronic cardiovascular diseases; diabetes mellitus; chronic liver diseases; cirrhosis; chronic alcoholism; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy ); immunocompromising conditions (including chronic renal failure or nephrotic syndrome); and cochlear implants and cerebrospinal fluid leaks. Vaccinate as close to HIV diagnosis as possible.\nOther: Residents of nursing homes or long-term care facilities and persons who smoke cigarettes. Routine use of PPSV is not recommended for American Indians/Alaska Natives or persons aged less than 65 years unless they have underlying medical conditions that are PPSV indications. However, public health authorities may consider recommending PPSV for American Indians/Alaska Natives and persons aged 50 through 64 years who are living in areas where the risk for invasive pneumococcal disease is increased.\n\n# Revaccination with PPSV\nOne-time revaccination after 5 years is recommended for persons aged 19 through 64 years with chronic renal failure or nephrotic syndrome; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy); and for persons with immunocompromising conditions. For persons aged 65 years and older, one-time revaccination is recommended if they were vaccinated 5 or more years previously and were aged less than 65 years at the time of primary vaccination.\n\n# Meningococcal vaccination\n\n# Meningococcal vaccine should be administered to persons with the following indications:\nMedical: A 2-dose series of meningococcal conjugate vaccine is recommended for adults with anatomic or functional asplenia, or persistent complement component deficiencies. Adults with HIV infection who are vaccinated should also receive a routine 2-dose series. The 2 doses should be administered at 0 and 2 months.\nOther: A single dose of meningococcal vaccine is recommended for unvaccinated first-year college students living in dormitories; microbiologists routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the \"meningitis belt\" of sub-Saharan Africa during the dry season ), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj.\nMeningococcal conjugate vaccine, quadrivalent (MCV4) is preferred for adults with any of the preceding indications who are aged 55 years and younger; meningococcal polysaccharide vaccine (MPSV4) is preferred for adults aged 56 years and older. Revaccination with MCV4 every 5 years is recommended for adults previously vaccinated with MCV4 or MPSV4 who remain at increased risk for infection (e.g., adults with anatomic or functional asplenia, or persistent complement component deficiencies).\n\n# Hepatitis A vaccination\nVaccinate persons with any of the following indications and any person seeking protection from hepatitis A virus (HAV) infection:\nBehavioral: Men who have sex with men and persons who use injection drugs.\nOccupational: Persons working with HAV-infected primates or with HAV in a research laboratory setting.\nMedical: Persons with chronic liver disease and persons who receive clotting factor concentrates.\nOther: Persons traveling to or working in countries that have high or intermediate endemicity of hepatitis A (a list of countries is available at ).\nUnvaccinated persons who anticipate close personal contact (e.g., household or regular babysitting) with an international adoptee during the first 60 days after arrival in the United States from a country with high or intermediate endemicity should be vaccinated. The first dose of the 2-dose hepatitis A vaccine series should be administered as soon as adoption is planned, ideally 2 or more weeks before the arrival of the adoptee.\nSingle-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6--12 months (Havrix), or 0 and 6--18 months (Vaqta). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule may be used, administered on days 0, 7, and 21--30, followed by a booster dose at month 12.\n\n# Hepatitis B vaccination\nVaccinate persons with any of the following indications and any person seeking protection from hepatitis B virus (HBV) infection:\nBehavioral: Sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months); persons seeking evaluation or treatment for a sexually transmitted disease (STD); current or recent injection-drug users; and men who have sex with men.\nOccupational: Health-care personnel and public-safety workers who are exposed to blood or other potentially infectious body fluids.\nMedical: Persons with end-stage renal disease, including patients receiving hemodialysis; persons with HIV infection; and persons with chronic liver disease.\nOther: Household contacts and sex partners of persons with chronic HBV infection; clients and staff members of institutions for persons with developmental disabilities; and international travelers to countries with high or intermediate prevalence of chronic HBV infection (a list of countries is available at ). Hepatitis B vaccination is recommended for all adults in the following settings: STD treatment facilities; HIV testing and treatment facilities; facilities providing drug-abuse treatment and prevention services; health-care settings targeting services to injection-drug users or men who have sex with men; correctional facilities; end-stage renal disease programs and facilities for chronic hemodialysis patients; and institutions and nonresidential day-care facilities for persons with developmental disabilities.\nAdminister missing doses to complete a 3-dose series of hepatitis B vaccine to those persons not vaccinated or not completely vaccinated. The second dose should be administered 1 month after the first dose; the third dose should be given at least 2 months after the second dose (and at least 4 months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose Twinrix schedule, administered on days 0, 7, and 21 to 30, followed by a booster dose at month 12 may be used.\nAdult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose of 40 µg/mL (Recombivax HB) administered on a 3-dose schedule or 2 doses of 20 µg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months.\n\n# Selected conditions for which Haemophilus influenzae type b (Hib) vaccine may be used\n1 dose of Hib vaccine should be considered for persons who have sickle cell disease, leukemia, or HIV infection, or who have had a splenectomy, if they have not previously received Hib vaccine.\n\n# Immunocompromising conditions\nInactivated vaccines generally are acceptable (e.g., pneumococcal, meningococcal, influenza ) and live vaccines generally are avoided in persons with immune deficiencies or immunocompromising conditions. Information on specific conditions is available at .\nThese schedules indicate the recommended age groups and medical indications for which administration of currently licensed vaccines is commonly indicated for adults ages 19 years and older, as of January 1, 2011. For all vaccines being recommended on the adult immunization schedule: a vaccine series does not need to be restarted, regardless of the time that has elapsed between doses. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those used primarily for travelers or that are issued during the year, consult the manufacturers' package inserts and the complete statements from the Advisory Committee on Immunization Practices (http:// www.cdc.gov/vaccines/pubs/acip-list.htm).\nReport all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at or by telephone, 800-822-7967.\nInformation on how to file a Vaccine Injury Compensation Program claim is available at or by telephone, 800-338-2382. Information about filing a claim for vaccine injury is available through the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005;telephone, 202-357-6400.\nAdditional information about the vaccines in this schedule, extent of available data, and contraindications for vaccination also is available at or from the CDC-INFO Contact Center at 800-CDC- in English and Spanish, 24 hours a day, 7 days a week."},"raw_text":{"kind":"string","value":"# Footnotes (Figures 1 and 2)\nThe influenza vaccination footnote (#1) is revised and shortened to reflect a recommendation for vaccination of all persons aged 6 months and older, including all adults. The high-dose influenza vaccine (Fluzone), licensed in 2010 for adults aged 65 years and older, is mentioned as an option for this age group.\nThe Td/Tdap vaccination footnote (#2) has language added to indicate that persons aged 65 years and older who have close contact with an infant aged less than 12 months should get vaccinated with Tdap; the additional language notes that all persons aged 65 years and older may get vaccinated with Tdap. Also added is the recommendation to administer Tdap regardless of interval since the most recent Td-containing vaccine.\nThe HPV vaccination footnote (#4) has language added to the introductory sentences to indicate that either quadrivalent vaccine or bivalent vaccine is recommended for females.\nThe MMR vaccination footnote (#6) has been revised mainly by consolidating common language that previously had been part of each of the three vaccine component sections into one introductory statement.\nThe revaccination with PPSV footnote (#8) clarifies that one-time revaccination after 5 years only applies to persons with indicated chronic conditions who are aged 19 through 64 years.\nThe meningococcal vaccination footnote (#9) has language added to indicate that a 2-dose series of meningococcal conjugate vaccine is recommended for adults with anatomic or functional asplenia, or persistent complement component deficiencies, as well adults with human immunodeficiency (HIV) virus infection who are vaccinated. Language has been added that a single dose of meningococcal vaccine is still recommended for those with other indications. Also, language has been added to clarify that quadrivalent meningococcal conjugate vaccine (MCV4) is a quadrivalent vaccine.\nThe language for the selected conditions for the Hib footnote (#12) has been shortened to clarify which persons at high risk may receive 1 dose of Hib vaccine.\nThe recommended adult immunization schedule has been approved by the Advisory Committee on Immunization Practices, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the American College of Physicians.\n# Suggested citation:\nCenters for Disease Control and Prevention. Recommended adult immunization schedule---United States, 2011. MMWR 201160(4). \n# NOTE:\nThe above recommendations must be read along with the footnotes on pages 3--4 of this schedule.\n# Influenza vaccination\nAnnual vaccination against influenza is recommended for all persons aged 6 months and older, including all adults. Healthy, nonpregnant adults aged less than 50 years without high-risk medical conditions can receive either intranasally administered live, attenuated influenza vaccine (FluMist), or inactivated vaccine. Other persons should receive the inactivated vaccine. Adults aged 65 years and older can receive the standard influenza vaccine or the high-dose (Fluzone) influenza vaccine. Additional information about influenza vaccination is available at http://www.cdc.gov/vaccines/vpd-vac/flu/default.htm.\n# Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination\nAdminister a one-time dose of Tdap to adults aged less than 65 years who have not received Tdap previously or for whom vaccine status is unknown to replace one of the 10-year Td boosters, and as soon as feasible to all 1) postpartum women, 2) close contacts of infants younger than age 12 months (e.g., grandparents and child-care providers), and 3) health-care personnel with direct patient contact. Adults aged 65 years and older who have not previously received Tdap and who have close contact with an infant aged less than 12 months also should be vaccinated. Other adults aged 65 years and older may receive Tdap. Tdap can be administered regardless of interval since the most recent tetanus or diphtheria-containing vaccine.\nAdults with uncertain or incomplete history of completing a 3-dose primary vaccination series with Tdcontaining vaccines should begin or complete a primary vaccination series. For unvaccinated adults, administer the first 2 doses at least 4 weeks apart and the third dose 6--12 months after the second. If incompletely vaccinated (i.e., less than 3 doses), administer remaining doses. Substitute a one-time dose of Tdap for one of the doses of Td, either in the primary series or for the routine booster, whichever comes first.\nIf a woman is pregnant and received the most recent Td vaccination 10 or more years previously, administer Td during the second or third trimester. If the woman received the most recent Td vaccination less than 10 years previously, administer Tdap during the immediate postpartum period. At the clinician's discretion, Td may be deferred during pregnancy and Tdap substituted in the immediate postpartum period, or Tdap may be administered instead of Td to a pregnant woman after an informed discussion with the woman.\nThe ACIP statement for recommendations for administering Td as prophylaxis in wound management is available at http://www.cdc.gov/vaccines/pubs/acip-list.htm.\n# Varicella vaccination\nAll adults without evidence of immunity to varicella should receive 2 doses of single-antigen varicella vaccine if not previously vaccinated or a second dose if they have received only 1 dose, unless they have a medical contraindication. Special consideration should be given to those who 1) have close contact with persons at high risk for severe disease (e.g., health-care personnel and family contacts of persons with immunocompromising conditions) or 2) are at high risk for exposure or transmission (e.g., teachers; child-care employees; residents and staff members of institutional settings, including correctional institutions; college students; military personnel; adolescents and adults living in households with children; nonpregnant women of childbearing age; and international travelers). Evidence of immunity to varicella in adults includes any of the following: 1) documentation of 2 doses of varicella vaccine at least 4 weeks apart; 2) U.S.-born before 1980 (although for health-care personnel and pregnant women, birth before 1980 should not be considered evidence of immunity); 3) history of varicella based on diagnosis or verification of varicella by a health-care provider (for a patient reporting a history of or having an atypical case, a mild case, or both, health-care providers should seek either an epidemiologic link with a typical varicella case or to a laboratory-confirmed case or evidence of laboratory confirmation, if it was performed at the time of acute disease); 4) history of herpes zoster based on diagnosis or verification of herpes zoster by a health-care provider; or 5) laboratory evidence of immunity or laboratory confirmation of disease.\nPregnant women should be assessed for evidence of varicella immunity. Women who do not have evidence of immunity should receive the first dose of varicella vaccine upon completion or termination of pregnancy and before discharge from the health-care facility. The second dose should be administered 4--8 weeks after the first dose.\n# Human papillomavirus (HPV) vaccination\nHPV vaccination with either quadrivalent (HPV4) vaccine or bivalent vaccine (HPV2) is recommended for females at age 11 or 12 years and catch-up vaccination for females aged 13 through 26 years.\nIdeally, vaccine should be administered before potential exposure to HPV through sexual activity; however, females who are sexually active should still be vaccinated consistent with age-based recommendations. Sexually active females who have not been infected with any of the four HPV vaccine types (types 6, 11, 16, and 18, all of which HPV4 prevents) or any of the two HPV vaccine types (types 16 and 18, both of which HPV2 prevents) receive the full benefit of the vaccination. Vaccination is less beneficial for females who have already been infected with one or more of the HPV vaccine types. HPV4 or HPV2 can be administered to persons with a history of genital warts, abnormal Papanicolaou test, or positive HPV DNA test, because these conditions are not evidence of previous infection with all vaccine HPV types.\nHPV4 may be administered to males aged 9 through 26 years to reduce their likelihood of genital warts. HPV4 would be most effective when administered before exposure to HPV through sexual contact.\nA complete series for either HPV4 or HPV2 consists of 3 doses. The second dose should be administered 1--2 months after the first dose; the third dose should be administered 6 months after the first dose.\nAlthough HPV vaccination is not specifically recommended for persons with the medical indications described in Figure 2, \"Vaccines that might be indicated for adults based on medical and other indications,\" it may be administered to these persons because the HPV vaccine is not a live-virus vaccine. However, the immune response and vaccine efficacy might be less for persons with the medical indications described in Figure 2 than in persons who do not have the medical indications described or who are immunocompetent.\n# Herpes zoster vaccination\nA single dose of zoster vaccine is recommended for adults aged 60 years and older regardless of whether they report a previous episode of herpes zoster. Persons with chronic medical conditions may be vaccinated unless their condition constitutes a contraindication.\n# Measles, mumps, rubella (MMR) vaccination\nAdults born before 1957 generally are considered immune to measles and mumps. All adults born in 1957 or later should have documentation of 1 or more doses of MMR vaccine unless they have a medical contraindication to the vaccine, laboratory evidence of immunity to each of the three diseases, or documentation of provider-diagnosed measles or mumps disease. For rubella, documentation of provider-diagnosed disease is not considered acceptable evidence of immunity.\nMeasles component: A second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is recommended for adults who 1) have been recently exposed to measles or are in an outbreak setting; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. Persons who received inactivated (killed) measles vaccine or measles vaccine of unknown type during 1963--1967 should be revaccinated with 2 doses of MMR vaccine.\nMumps component: A second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is recommended for adults who 1) live in a community experiencing a mumps outbreak and are in an affected age group; 2) are students in postsecondary educational institutions; 3) work in a health-care facility; or 4) plan to travel internationally. Persons vaccinated before 1979 with either killed mumps vaccine or mumps vaccine of unknown type who are at high risk for mumps infection (e.g. persons who are working in a health-care facility) should be revaccinated with 2 doses of MMR vaccine.\nRubella component: For women of childbearing age, regardless of birth year, rubella immunity should be determined. If there is no evidence of immunity, women who are not pregnant should be vaccinated. Pregnant women who do not have evidence of immunity should receive MMR vaccine upon completion or termination of pregnancy and before discharge from the health-care facility.\nHealth-care personnel born before 1957: For unvaccinated health-care personnel born before 1957 who lack laboratory evidence of measles, mumps, and/or rubella immunity or laboratory confirmation of disease, health-care facilities should 1) consider routinely vaccinating personnel with 2 doses of MMR vaccine at the appropriate interval (for measles and mumps) and 1 dose of MMR vaccine (for rubella), and 2) recommend 2 doses of MMR vaccine at the appropriate interval during an outbreak of measles or mumps, and 1 dose during an outbreak of rubella. Complete information about evidence of immunity is available at http://www.cdc.gov/vaccines/recs/provisional/default.htm.\n# Pneumococcal polysaccharide (PPSV) vaccination\nVaccinate all persons with the following indications:\nMedical: Chronic lung disease (including asthma); chronic cardiovascular diseases; diabetes mellitus; chronic liver diseases; cirrhosis; chronic alcoholism; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy [if elective splenectomy is planned, vaccinate at least 2 weeks before surgery]); immunocompromising conditions (including chronic renal failure or nephrotic syndrome); and cochlear implants and cerebrospinal fluid leaks. Vaccinate as close to HIV diagnosis as possible.\nOther: Residents of nursing homes or long-term care facilities and persons who smoke cigarettes. Routine use of PPSV is not recommended for American Indians/Alaska Natives or persons aged less than 65 years unless they have underlying medical conditions that are PPSV indications. However, public health authorities may consider recommending PPSV for American Indians/Alaska Natives and persons aged 50 through 64 years who are living in areas where the risk for invasive pneumococcal disease is increased.\n# Revaccination with PPSV\nOne-time revaccination after 5 years is recommended for persons aged 19 through 64 years with chronic renal failure or nephrotic syndrome; functional or anatomic asplenia (e.g., sickle cell disease or splenectomy); and for persons with immunocompromising conditions. For persons aged 65 years and older, one-time revaccination is recommended if they were vaccinated 5 or more years previously and were aged less than 65 years at the time of primary vaccination.\n# Meningococcal vaccination\n\n# Meningococcal vaccine should be administered to persons with the following indications:\nMedical: A 2-dose series of meningococcal conjugate vaccine is recommended for adults with anatomic or functional asplenia, or persistent complement component deficiencies. Adults with HIV infection who are vaccinated should also receive a routine 2-dose series. The 2 doses should be administered at 0 and 2 months.\nOther: A single dose of meningococcal vaccine is recommended for unvaccinated first-year college students living in dormitories; microbiologists routinely exposed to isolates of Neisseria meningitidis; military recruits; and persons who travel to or live in countries in which meningococcal disease is hyperendemic or epidemic (e.g., the \"meningitis belt\" of sub-Saharan Africa during the dry season [December through June]), particularly if their contact with local populations will be prolonged. Vaccination is required by the government of Saudi Arabia for all travelers to Mecca during the annual Hajj.\nMeningococcal conjugate vaccine, quadrivalent (MCV4) is preferred for adults with any of the preceding indications who are aged 55 years and younger; meningococcal polysaccharide vaccine (MPSV4) is preferred for adults aged 56 years and older. Revaccination with MCV4 every 5 years is recommended for adults previously vaccinated with MCV4 or MPSV4 who remain at increased risk for infection (e.g., adults with anatomic or functional asplenia, or persistent complement component deficiencies).\n# Hepatitis A vaccination\nVaccinate persons with any of the following indications and any person seeking protection from hepatitis A virus (HAV) infection:\nBehavioral: Men who have sex with men and persons who use injection drugs.\nOccupational: Persons working with HAV-infected primates or with HAV in a research laboratory setting.\nMedical: Persons with chronic liver disease and persons who receive clotting factor concentrates.\nOther: Persons traveling to or working in countries that have high or intermediate endemicity of hepatitis A (a list of countries is available at http://wwwn.cdc.gov/travel/contentdiseases.aspx).\nUnvaccinated persons who anticipate close personal contact (e.g., household or regular babysitting) with an international adoptee during the first 60 days after arrival in the United States from a country with high or intermediate endemicity should be vaccinated. The first dose of the 2-dose hepatitis A vaccine series should be administered as soon as adoption is planned, ideally 2 or more weeks before the arrival of the adoptee.\nSingle-antigen vaccine formulations should be administered in a 2-dose schedule at either 0 and 6--12 months (Havrix), or 0 and 6--18 months (Vaqta). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose schedule may be used, administered on days 0, 7, and 21--30, followed by a booster dose at month 12.\n# Hepatitis B vaccination\nVaccinate persons with any of the following indications and any person seeking protection from hepatitis B virus (HBV) infection:\nBehavioral: Sexually active persons who are not in a long-term, mutually monogamous relationship (e.g., persons with more than one sex partner during the previous 6 months); persons seeking evaluation or treatment for a sexually transmitted disease (STD); current or recent injection-drug users; and men who have sex with men.\nOccupational: Health-care personnel and public-safety workers who are exposed to blood or other potentially infectious body fluids.\nMedical: Persons with end-stage renal disease, including patients receiving hemodialysis; persons with HIV infection; and persons with chronic liver disease.\nOther: Household contacts and sex partners of persons with chronic HBV infection; clients and staff members of institutions for persons with developmental disabilities; and international travelers to countries with high or intermediate prevalence of chronic HBV infection (a list of countries is available at http://wwwn.cdc.gov/travel/contentdiseases.aspx). Hepatitis B vaccination is recommended for all adults in the following settings: STD treatment facilities; HIV testing and treatment facilities; facilities providing drug-abuse treatment and prevention services; health-care settings targeting services to injection-drug users or men who have sex with men; correctional facilities; end-stage renal disease programs and facilities for chronic hemodialysis patients; and institutions and nonresidential day-care facilities for persons with developmental disabilities.\nAdminister missing doses to complete a 3-dose series of hepatitis B vaccine to those persons not vaccinated or not completely vaccinated. The second dose should be administered 1 month after the first dose; the third dose should be given at least 2 months after the second dose (and at least 4 months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is used, administer 3 doses at 0, 1, and 6 months; alternatively, a 4-dose Twinrix schedule, administered on days 0, 7, and 21 to 30, followed by a booster dose at month 12 may be used.\nAdult patients receiving hemodialysis or with other immunocompromising conditions should receive 1 dose of 40 µg/mL (Recombivax HB) administered on a 3-dose schedule or 2 doses of 20 µg/mL (Engerix-B) administered simultaneously on a 4-dose schedule at 0, 1, 2, and 6 months.\n# Selected conditions for which Haemophilus influenzae type b (Hib) vaccine may be used\n1 dose of Hib vaccine should be considered for persons who have sickle cell disease, leukemia, or HIV infection, or who have had a splenectomy, if they have not previously received Hib vaccine.\n# Immunocompromising conditions\nInactivated vaccines generally are acceptable (e.g., pneumococcal, meningococcal, influenza [inactivated influenza vaccine]) and live vaccines generally are avoided in persons with immune deficiencies or immunocompromising conditions. Information on specific conditions is available at http://www.cdc.gov/vaccines/pubs/acip-list.htm.\nThese schedules indicate the recommended age groups and medical indications for which administration of currently licensed vaccines is commonly indicated for adults ages 19 years and older, as of January 1, 2011. For all vaccines being recommended on the adult immunization schedule: a vaccine series does not need to be restarted, regardless of the time that has elapsed between doses. Licensed combination vaccines may be used whenever any components of the combination are indicated and when the vaccine's other components are not contraindicated. For detailed recommendations on all vaccines, including those used primarily for travelers or that are issued during the year, consult the manufacturers' package inserts and the complete statements from the Advisory Committee on Immunization Practices (http:// www.cdc.gov/vaccines/pubs/acip-list.htm).\nReport all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting System (VAERS). Reporting forms and instructions on filing a VAERS report are available at http://www.vaers.hhs.gov or by telephone, 800-822-7967.\nInformation on how to file a Vaccine Injury Compensation Program claim is available at http://www.hrsa.gov/vaccinecompensation or by telephone, 800-338-2382. Information about filing a claim for vaccine injury is available through the U.S. Court of Federal Claims, 717 Madison Place, N.W., Washington, D.C. 20005;telephone, 202-357-6400.\nAdditional information about the vaccines in this schedule, extent of available data, and contraindications for vaccination also is available at http://www.cdc.gov/vaccines or from the CDC-INFO Contact Center at 800-CDC- in English and Spanish, 24 hours a day, 7 days a week. "},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":297,"cells":{"id":{"kind":"string","value":"1d09e7ac7b1d01505aa5b76dc8e4910ca8d8c4e5"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards. The Division of Criteria Documentation and Standards Development, National Institute for Occupational Safety and Health (NIOSH), had primary responsibility for the development of the criteria and recommended standard for nitriles. Sonia Berg of this Division served as criteria manager. Equitable Environmental Health, Inc. (EEH) developed the basic information for consideration by NIOSH staff and consultants under contract CDC 210-77-0148. The Division review of this document was provided by Jon R. May, Ph.D. (Chairman), and J.# Ceiling (b) Sampling and Analysis\nWorkplace air samples shall be collected and analyzed for nitriles as described in Appendix I or by any method shown to be at least equivalent in accuracy, precision, and sensitivity.\n\n# Section 2 -Medical\nMedical surveillance shall be made available as specified below to all employees subject to exposure to the compounds covered by this standard. ------>\n- U.S. GOVERNMENT PRINTING OFFICE: 1918-6 5 7 -0 6 1 / 1 8 5 3\n\n# D E P A R T M E N T O F H E A L T H , E D U C A T IO N , A N D W E L F A R E P U B L IC H E A L T H S E R V IC E\nCENTER\n114. difference in area is to be expected.\n\n# Documentation of\n\n# (e) Measurement of Area\nThe area of the sample peak is measured by an electronic integrator or some other suitable form of area measurement, and preliminary results are read from a standard curve prepared as discussed in the following sections.\n\n# Determination of Desorption Efficiency (a) Importance\nThe\n\n# (c) Gas Chromatographic Conditions\nThe typical operating conditions for the gas chromatograph are:\n(1) 50 ml/minute (60 psig) nitrogen carrier gas flow.\n(2) 65 ml/minute (24 psig) hydrogen gas flow to detector.\n(3) 500 ml/minute(50 psig) airflow to detector. (3) Keep the patient comfortably warm but not hot.\n\n# MATERIAL SAFETY DATA SHEET PRODUCT IDENTIFICATION\n\n# _________________ V HEALTH HAZARD INFORMATION H E A L T H H A Z A R D D A T A R O U T E S OF EXPO SUR E IN H A L A T IO N S K IN C O N T A C T S K IN A B S O R P T IO N EYE C O N T A C T IN G E S T IO N E FFEC TS OF O V E R E X P O S U R E\nXII.\n\n# TABLES AND FIGURE"},"raw_text":{"kind":"string","value":"The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards. The Division of Criteria Documentation and Standards Development, National Institute for Occupational Safety and Health (NIOSH), had primary responsibility for the development of the criteria and recommended standard for nitriles. Sonia Berg of this Division served as criteria manager. Equitable Environmental Health, Inc. (EEH) developed the basic information for consideration by NIOSH staff and consultants under contract CDC 210-77-0148. The Division review of this document was provided by Jon R. May, Ph.D. (Chairman), and J.# Ceiling (b) Sampling and Analysis\nWorkplace air samples shall be collected and analyzed for nitriles as described in Appendix I or by any method shown to be at least equivalent in accuracy, precision, and sensitivity.\n# Section 2 -Medical\nMedical surveillance shall be made available as specified below to all employees subject to exposure to the compounds covered by this standard. ------> \n# 155\n* U.S. GOVERNMENT PRINTING OFFICE: 1918-6 5 7 -0 6 1 / 1 8 5 3 \n# D E P A R T M E N T O F H E A L T H , E D U C A T IO N , A N D W E L F A R E P U B L IC H E A L T H S E R V IC E\nCENTER\n# 110.\n111.\n# 112.\n\n# 113.\n114. difference in area is to be expected.\n# 120.\n\n# 121.\n\n# 122.\n\n# 123.\n\n# 124.\n\n# 125.\n\n# Documentation of\n\n# (e) Measurement of Area\nThe area of the sample peak is measured by an electronic integrator or some other suitable form of area measurement, and preliminary results are read from a standard curve prepared as discussed in the following sections.\n# Determination of Desorption Efficiency (a) Importance\nThe \n# (c) Gas Chromatographic Conditions\nThe typical operating conditions for the gas chromatograph are:\n(1) 50 ml/minute (60 psig) nitrogen carrier gas flow.\n(2) 65 ml/minute (24 psig) hydrogen gas flow to detector.\n(3) 500 ml/minute(50 psig) airflow to detector. (3) Keep the patient comfortably warm but not hot.\n# 134\n\n# MATERIAL SAFETY DATA SHEET PRODUCT IDENTIFICATION\n\n# _________________ V HEALTH HAZARD INFORMATION H E A L T H H A Z A R D D A T A R O U T E S OF EXPO SUR E IN H A L A T IO N S K IN C O N T A C T S K IN A B S O R P T IO N EYE C O N T A C T IN G E S T IO N E FFEC TS OF O V E R E X P O S U R E\n\n# 149\nXII. \n# TABLES AND FIGURE\n"},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":298,"cells":{"id":{"kind":"string","value":"883a90399fa8c4919f46496c3187b11292afeac4"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Synopsis.................................... prevalence among patients seeking medical care at acute-care hospitals. The guidelines enable hospital staff members to perform a simple, rapid, and inexpensive survey to determine seroprevalence among the patient population, protecting the anonymity of those who are tested. The guidelines are based on national experience with large-scale anonymous, unlinked HIV serosurveys.\nThe data from a rapid assessment survey are particularly useful for evaluating the need to provide routine, voluntary HIV counseling and testing and treatment for HIV infection. Beyond that, such data can be used in targeting education efforts, in reinforcing the use of appropriate universal precautions, in resource allocation, and in determining the need for further studies of HIV infection among the population in the hospital catchment area. The Centers for Disease Control and Prevention has developed guidelines for determining HIV sero-PATIENTS WITH AIDS have been admitted to more than 90 percent of the metropolitan area hospitals in the United States and to about 40 percent of the rural area hospitals (1). In addition, a large number of persons with undiagnosed HIV infection have been hospitalized (2). The number and proportion of their patients infected with HIV is unknown in most hospitals, however.\nHospital seroprevalence data have many uses *evaluating the need to provide routine, voluntary HIV counseling and testing services as recommended by the Centers for Disease Control and Prevention (CDC) (3), - evaluating the need for treatment services for HIV infection and associated conditions, - targeting education efforts, - reinforcing the use of appropriate universal precautions by health care workers, - assisting in making decisions regarding resource allocation, and - determining the need for further epidemiologic studies about demographic and behavioral characteristics in the hospital's catchment population.\nBased on the experience of the 39 U.S. acutecare hospitals participating in the Sentinel Hospital Surveillance System for HIV Infection (2,4,5), CDC has developed and field-tested generic guidelines (6,7), approved by a CDC institutional review board for protection of human subjects. Under the guidelines, hospital personnel can perform a simple, rapid, and inexpensive survey to determine the HIV seroprevalence among the patient population and protect the anonymity of those who are tested. The guidelines provide for anonymous and unlinked testing of residual blood specimens collected for routine diagnostic purposes. Tested patients cannot be identified. This approach prevents bias from self-deferral, such as when persons at high risk for HIV infection refuse to participate in a voluntary study (8). The guidelines are flexible, so they can easily be adapted to the special needs or interests of a particular hospital. This is not to imply that hospitals must or should conduct such surveys. Our purpose is to assist those hospitals that wish to determine their HIV seroprevalence. The guidelines provide help in addressing important issues involved in performing such a survey, including anonymity of patients, scientific validity, and generalizability of results. The results from a hospital survey can apply to its treated population but not necessarily to the general population of its catchment area.\nIt is unclear how frequently these surveys should be performed. Staffs at some hospitals may want to conduct a single survey, others might want to repeat the survey annually or less frequently.\n\n# Survey Design\nFor reasons of ethics and simplicity, exhaustive efforts must be made to destroy any possible link between patients and their blood specimens prior to HIV serologic testing to avoid inadvertent identification of patients whose blood is tested.\nData obtained by CDC's Sentinel Hospital Surveillance System for HIV infection (2,5) show an age distribution similar to that of AIDS patients overall, with the highest seroprevalence rates in the 25-44-year-old age group. To obtain maximal precision of seroprevalence estimates with a minimal sample size, we suggest sampling patients ages 15-54. Since the seroprevalence in patients younger or older than this age category is likely to be very low, sampling in children and the elderly would add little information and could increase the chance of inadvertent identification of a patient who was tested, particularly in hospitals where the overall seroprevalence is low (less than 1 percent).\nThese seroprevalence surveys can be conducted and coordinated by many different persons in a hospital but require knowledge of routine procedures in the hospital's chemistry and hematology laboratories. Possible principal investigators include laboratory directors or infectious disease physicians collaborating with laboratory personnel. Alternatively, infection control personnel can be principal investigators and should collaborate with both laboratory and infectious disease personnel in conducting these surveys. Principal investigators should have knowledge of research study design, issues about confidentiality, and data analysis. In addition, personnel will need to be knowledgeable about laboratory practices, specimen handling, data collection, data management, and HIV-antibody testing.\nDemographic data. The distribution of AIDS cases and HIV infection varies widely by geographic area, sex, age, and race (9,10). In this protocol, for simplicity, \"race\" is used to include ethnicity (for example, Hispanic) as a mutually exclusive race category, even though members of the ethnic group may be of various races. The rates are generally higher among men compared with women and among blacks and Hispanics compared with whites. They are highest among people ages 25 to 44. Therefore, we suggest that data about age group, sex, and race be included. (Specific year of age in combination with the other variables might compromise anonymity; precise year of age is not very useful for the analysis and should not be collected.) Some hospitals may have the ability to collect additional data such as information regarding patient's known HIV status or HIV-related disease. This information could be used to help estimate the number of unrecognized or unsuspected HIV infections in the overall patient population. Collected data considered together, must not, however, allow linkage of HIV test results to specific people. Sample size. For this survey, the recommended sample size is 1,000 patients. With this sample size, if there is only 1 seropositive out of the 1,000 tested, the approximate 95 percent confidence interval for the true seroprevalence can be construed to be between 0.002 percent and 0.56 percent. In a sample with a 1 percent seroprevalence rate (10 seropositive specimens), the equivalent interval would be 0.48 percent to 1.84 percent. If more precise results are needed, larger sample sizes would be required.\nStratification of the sample. To generalize the results of the sample to a defined, hospital-patient subgroup (hospital inpatients or a particular patient service, for example), the sample must be representative of the patient population. Blood specimens collected sequentially in a given period, such as 1-2 days, may not constitute a representative sample, however. To correct for possible biases, the best sample includes stratification by age and sex to ensure that the sample consists of the typical age and sex distribution of patients ages 15-54 at the hospital. The stratification also simplifies the avoidance of duplicate specimens, data management, and analysis of data by age and sex.\nTo obtain the distribution by age and sex of an average patient population ages 15-54 in a specific hospital, discharge data from a representative period, obtained from the hospital medical records or billing department, can be separated by age and sex of all patients in that age category into eight strata: ages 15-24, 25-34, 35-44, and 45-54 for each sex. In general, the discharge data of the last calendar year should yield representative data of an average patient population. Changes like the opening of a new trauma care unit in the middle of the year, however, may have a major impact on the patient distribution. In such a case, one has to be sure that the population from which the age and sex distribution is taken is representative of the actual patient population (for example, discharge data of the last 3 months.)\nThe proportion of each group is calculated by dividing the number of discharges in that group by the total number of discharges of patients ages 15-54. An example of this procedure for an average hospital is given in table 1. To obtain the number of specimens per age-and sex-stratum that should be included in the survey sample, it is necessary to multiply the total sample size (1,000) by the proportion of the appropriate group (table 2). Although this procedure is not a randomized sampling procedure, it should provide a good approximation of the patient population because the numbers per stratum are calculated in advance. If different populations, such as outpatients and inpatients, are included in the survey, collection of separate samples of 1,000 specimens for each population is recommended.\nSampling problems. Laboratory or hospital procedures can also lead to a sampling bias. For example, if some specimens of a particular patient group such as obstetric patients are sequestered for other purposes like special studies, those specimens may not be available for this survey. When designing the survey and interpreting results, investigators should determine if such procedures are practiced in their laboratories.\nIn some hospitals, the total sample could be selected in less than 1 week. For example, if a large group of patients is admitted to the hospital on a certain day of the week for a specific procedure like elective surgery, these patients could be either over-or underrepresented in the sample, depending on whether specimens drawn on that particular day were included or excluded from the sample. One way to compensate for such a bias is to select only every second or third available specimen to ensure that sampling occurs over a sufficiently long period.\n\n# Sampling Procedure\nTo perform this survey, investigators need access to residual blood specimens and corresponding demographic data. The most efficient way to perform the survey is to collect blood specimens and the corresponding demographic data at one central laboratory. The chemistry laboratory, for example, might be the most likely place to obtain leftover serum or plasma without additional procedures like centrifugation of heparinized blood and have specimens from patients that meet the survey population requirements. In addition, personnel at the collection laboratory will need access to patient data on age group, sex, race, and clinical service. If hospitals have different laboratories for different units, investigators could either perform separate surveys of the patients of the different units or stratify the The sequence of serodiagnosis procedures for human immunodeficiency virus using enzyme immunoassay (EIA) tos md bhe use of th Westen blot sway fore o HIV1 el h ben p\"MMlshed (7).\nsample according to the overall patient distribution in the different units. Specimens could then be collected consecutively for each age group and sex stratum in each laboratory. Data collection form. The form used to collect sample data is designed to enable personnel to collect the data, conduct the stratified sampling while avoiding duplicate testing of the same person, and protect the anonymity of patients being selected. Sampling with this form does not require the use of a computer; however, a computerized data base can be easily developed from it.\nBefore the beginning of the survey, investigators must clearly define the information they want to collect. The recommended variables are sex, age group, race, and clinical service. Specific categories are given for sex and age group. The race variable has two generally useful fixed categories of white and black patients. Another race-ethnicity (Hispanic, for example) may be specified if the proportion of this group is at least 10 percent of the patient population. No particular race or ethnic group should be used if it represents less than 10 percent of the patient population; all such groups should be combined and classified as \"other.\" For the service unit, there are four proposed categories, surgery, internal medicine, obstetrics, and psychiatry. Other units, if essential to note, should be categorized in advance. In addition, it could be indicated whether a patient is treated as an inpa-tient, outpatient, or in the emergency room. If additional information is of special importance to a particular hospital, it may be collected and specified. It is especially important to specify such categories in advance to be sure that the meaning is unequivocal and that the data collection is systematic. Any additional data should be essential to interpreting and using the results of the survey and should not allow for the identification of a person tested in the survey. Additional information, such as specific diagnosis, might allow for inadvertent identification, if the diagnosis is rare. Therefore, investigators must be cautious in collecting any additional information.\nAvoiding duplicate sampling. Besides the survey number, which may be preprinted on the data collection forms, the last 4 digits of the patient's hospital identification number (usually 7 digits) can be recorded temporarily on a data collection form to avoid duplicate sampling. These segments of the patient numbers must be removed and destroyed before the specimens are serologically tested. Each specimen should be labelled with the corresponding survey number and prepared labels attached to the data collection forms.\nCollection of specimens and corresponding data.\nWhen the patients and the laboratory site where specimens will be collected are identified and the total number of patients in each of the eight age and sex strata is determined, data collection forms should be prepared. For example, if all specimens can be collected in one laboratory site and the total number of specimens for men ages 25-34 is 82, four data collection forms (for 25 specimens each) could be labeled for this age-sex stratum and stapled together. The last number for this stratum should be highlighted to make it easy to recognize when the total number of this particular stratum is achieved.\nThe specimen selectors in the laboratory can then take the following steps:\n1. Check each specimen after routine testing to determine whether there is enough serum (or plasma) left over. A volume of 0.5 milliliter (ml) or more would be ideal and would allow for extra tests for indeterminate specimens. A minimum of 0.2 ml is enough for the routine HIV serology, however. If there is less than 0.2 ml available, the specimen should be excluded.\n2. If there is at least 0.2 ml available, check whether the specimen fits into one of the eight sex-age strata (ages 15-54 years). If not, exclude it and check the next specimen. If yes, check whether there is already a specimen included in the corresponding age-sex stratum with the same patient number (last four digits). If yes, exclude it and check the next specimen.\n3. If not already sampled (as indicated by the last 4 digits of patient number), the specimen should be selected and the last four digits of the patient number and demographic data recorded on the form. Such data may need to be located through the laboratory's computer system or at another place in the hospital with access to patient demographics. A sample of 0.5 ml (at least 0.2 ml, see step 1) should be taken and the corresponding label, which is attached to the data collection form, should be placed on the tube. No other labels should be attached to the tube holding the sample. Persons aliquoting specimens should wear gloves and a laboratory coat. Some laboratory workers may also prefer to work in a hood, behind a plastic shield, or wear safety glasses (11).\n4. When all forms for a particular stratum are filled (and, thus, the total number of specimens in this stratum is achieved), continue to collect specimens only in the incomplete strata. 5. When the forms of all eight strata are full and before submitting the specimens for HIV testing, cut off and destroy the columns with the last four digits of the patient number.\n\n# Specimen Storage\nAfter the aliquots are collected and the tubes are labeled with their survey numbers, the specimens should be stored in a freezer (at least -20°C) until the total sample size is achieved and the serums (or plasma specimens) are tested for HIV antibodies. If the specimens cannot be frozen the day they are collected, they may be temporarily stored in a refrigerator (4°-80 C) for a maximum of 5 days.\n\n# Guidelines for HIV Antibody Testing\nThe specimens should be tested (see chart) using an FDA-licensed HIV-1 enzyme immunoassay (EIA) kit. If the specimen is nonreactive in the initial test, the specimen is classified as negative. If the specimen is reactive in the initial test, the EIA should be repeated in duplicate, using fresh aliquots of the same specimen. If at least one of the repeated EIAs is reactive, the specimen is classified as \"EIA repeatedly reactive\" and should be tested with a supplemental test. The recommended supple-mental test is an FDA-licensed Western blot kit. Guidelines for the interpretation and use of the Western blot assay have been published by the Association of State and Territorial Public Health Laboratory Directors and Centers for Disease Control and Prevention (12).\nHIV antibody results can be recorded on the data collection form or entered into a computer file. The laboratory technician who performed the HIV antibody testing, but who did not select the specimens to be tested, may enter the HIV antibody results into the appropriate data base. The person(s) who selected the specimens should not see individual test results or the completed data collection forms, as a further protection of the anonymity of the survey.\n\n# Data Management\nA sequence of preprinted survey numbers on data collection forms and preassigned sticker labels facilitate recording of the laboratory results directly on data collection forms. If desired, data can be transferred to a computer (with a data management package such as EPI-Info). The survey can be conducted without the use of a computer, however.\nIf a computer is used to avoid duplicate sampling of the same patient, a separate temporary file, contalning only the age-sex strata and the last 4 digits of the patients' numbers (and not the survey numbers), should be used during sampling to ensure that no link between patient number and HIV test result is possible. After the sampling is completed and before the HIV tests are performed, the data file with the last 4 digits of the patient number must be deleted.\nIf a computer is used for data analysis, a permanent fie with survey number (but without the last 4 digits of the patient number), and demographic information should be used for entering HIV antibody test results. The permanent data file should not contain any information that links percent confidence interval Is 7.60, 24.43, using the formula in table 3. The overall seroprevaence of this population would be 5.2 percent (52 X 100 percent, divided by 1,000). An approximate 95 percent confidence interval for the values of the seroprevalence estimate using the formula on page 000 for samples with more than 20 positive specimern wouid be 3.97, 6.82. personal identifiers, such as patient numbers, with\nHIV test results.\nThe principal investigator can use the data base for analysis of aggregated data but should not report line-by-line results. The principal investigator must be responsible for ensuring that inadvertent linkage of HIV antibody test results to a specific patient does not occur. For further protec-tion of the anonymity of the patients, the person(s) collecting the specimens and checking patient records should not see line-by-line HIV test result data. The specimen collector(s) may, however, see grouped summary data.\n\n# Interpretation of the Results\nThe estimate of seroprevalence in the patient population is\nx n where x is the total number of seropositive patients observed (summed over all strata) and n is the total sample size (number tested). (Multiplying by 100 will express this seroprevalence in percent positive.) Estimates of seroprevalence in a subgroup may also be obtained by dividing the number of seropositives from that subgroup by the number tested in that subgroup. For example, separate estimates of seroprevalence for men and women may be calculated.\nApproximate confidence limits for the seroprevalence can be obtained with the Poisson distribution. Thus, confidence limits for seroprevalence in the individual strata or groups of strata may be calculated by using the procedures described in table 3 if 20 or fewer HIV-seropositive specimens are observed.\nIf more than 20 HIV-seropositive specimens are observed, regardless of the size of the sample, the 95 percent confidence interval is calculated by using the following equation:\nx + 1.92 ± 1.96 lIx + 0.96 X 100 percent n where x = observed number of positive specimens and n = sample size.\nAs an example, suppose that 21 people are found to be seropositive out of a sample of 275 (seroprevalence = 7.6 percent). Then the 95 percent confidence interval for the seroprevalence is 21 + 1.92 ± 1.96 121 + 0.96 X 100 percent 275\nIn this case, the 95 percent confidence interval is 4.99 percent, 11.67 percent.\nAn example of the interpretation of results obtained by a survey following this protocol is given in table 4.\n\n# Personnel Time\nThe time required to conduct a rapid assessment of HIV seroprevalence survey depends on familiarity with laboratory-based studies, the size of the hospital, and the number of laboratory specimens available. In addition to the principal investigator's time, the equivalent of one person working full time for 1 to 2 months is needed to complete the specimen collection and handling and data management. In addition, time is needed for a technician to perform HIV-antibody testing."},"raw_text":{"kind":"string","value":"# \nSynopsis.................................... prevalence among patients seeking medical care at acute-care hospitals. The guidelines enable hospital staff members to perform a simple, rapid, and inexpensive survey to determine seroprevalence among the patient population, protecting the anonymity of those who are tested. The guidelines are based on national experience with large-scale anonymous, unlinked HIV serosurveys.\nThe data from a rapid assessment survey are particularly useful for evaluating the need to provide routine, voluntary HIV counseling and testing and treatment for HIV infection. Beyond that, such data can be used in targeting education efforts, in reinforcing the use of appropriate universal precautions, in resource allocation, and in determining the need for further studies of HIV infection among the population in the hospital catchment area. The Centers for Disease Control and Prevention has developed guidelines for determining HIV sero-PATIENTS WITH AIDS have been admitted to more than 90 percent of the metropolitan area hospitals in the United States and to about 40 percent of the rural area hospitals (1). In addition, a large number of persons with undiagnosed HIV infection have been hospitalized (2). The number and proportion of their patients infected with HIV is unknown in most hospitals, however.\nHospital seroprevalence data have many uses *evaluating the need to provide routine, voluntary HIV counseling and testing services as recommended by the Centers for Disease Control and Prevention (CDC) (3), * evaluating the need for treatment services for HIV infection and associated conditions, * targeting education efforts, * reinforcing the use of appropriate universal precautions by health care workers, * assisting in making decisions regarding resource allocation, and * determining the need for further epidemiologic studies about demographic and behavioral characteristics in the hospital's catchment population.\nBased on the experience of the 39 U.S. acutecare hospitals participating in the Sentinel Hospital Surveillance System for HIV Infection (2,4,5), CDC has developed and field-tested generic guidelines (6,7), approved by a CDC institutional review board for protection of human subjects. Under the guidelines, hospital personnel can perform a simple, rapid, and inexpensive survey to determine the HIV seroprevalence among the patient population and protect the anonymity of those who are tested. The guidelines provide for anonymous and unlinked testing of residual blood specimens collected for routine diagnostic purposes. Tested patients cannot be identified. This approach prevents bias from self-deferral, such as when persons at high risk for HIV infection refuse to participate in a voluntary study (8). The guidelines are flexible, so they can easily be adapted to the special needs or interests of a particular hospital. This is not to imply that hospitals must or should conduct such surveys. Our purpose is to assist those hospitals that wish to determine their HIV seroprevalence. The guidelines provide help in addressing important issues involved in performing such a survey, including anonymity of patients, scientific validity, and generalizability of results. The results from a hospital survey can apply to its treated population but not necessarily to the general population of its catchment area.\nIt is unclear how frequently these surveys should be performed. Staffs at some hospitals may want to conduct a single survey, others might want to repeat the survey annually or less frequently.\n# Survey Design\nFor reasons of ethics and simplicity, exhaustive efforts must be made to destroy any possible link between patients and their blood specimens prior to HIV serologic testing to avoid inadvertent identification of patients whose blood is tested.\nData obtained by CDC's Sentinel Hospital Surveillance System for HIV infection (2,5) show an age distribution similar to that of AIDS patients overall, with the highest seroprevalence rates in the 25-44-year-old age group. To obtain maximal precision of seroprevalence estimates with a minimal sample size, we suggest sampling patients ages 15-54. Since the seroprevalence in patients younger or older than this age category is likely to be very low, sampling in children and the elderly would add little information and could increase the chance of inadvertent identification of a patient who was tested, particularly in hospitals where the overall seroprevalence is low (less than 1 percent).\nThese seroprevalence surveys can be conducted and coordinated by many different persons in a hospital but require knowledge of routine procedures in the hospital's chemistry and hematology laboratories. Possible principal investigators include laboratory directors or infectious disease physicians collaborating with laboratory personnel. Alternatively, infection control personnel can be principal investigators and should collaborate with both laboratory and infectious disease personnel in conducting these surveys. Principal investigators should have knowledge of research study design, issues about confidentiality, and data analysis. In addition, personnel will need to be knowledgeable about laboratory practices, specimen handling, data collection, data management, and HIV-antibody testing.\nDemographic data. The distribution of AIDS cases and HIV infection varies widely by geographic area, sex, age, and race (9,10). In this protocol, for simplicity, \"race\" is used to include ethnicity (for example, Hispanic) as a mutually exclusive race category, even though members of the ethnic group may be of various races. The rates are generally higher among men compared with women and among blacks and Hispanics compared with whites. They are highest among people ages 25 to 44. Therefore, we suggest that data about age group, sex, and race be included. (Specific year of age in combination with the other variables might compromise anonymity; precise year of age is not very useful for the analysis and should not be collected.) Some hospitals may have the ability to collect additional data such as information regarding patient's known HIV status or HIV-related disease. This information could be used to help estimate the number of unrecognized or unsuspected HIV infections in the overall patient population. Collected data considered together, must not, however, allow linkage of HIV test results to specific people. Sample size. For this survey, the recommended sample size is 1,000 patients. With this sample size, if there is only 1 seropositive out of the 1,000 tested, the approximate 95 percent confidence interval for the true seroprevalence can be construed to be between 0.002 percent and 0.56 percent. In a sample with a 1 percent seroprevalence rate (10 seropositive specimens), the equivalent interval would be 0.48 percent to 1.84 percent. If more precise results are needed, larger sample sizes would be required.\nStratification of the sample. To generalize the results of the sample to a defined, hospital-patient subgroup (hospital inpatients or a particular patient service, for example), the sample must be representative of the patient population. Blood specimens collected sequentially in a given period, such as 1-2 days, may not constitute a representative sample, however. To correct for possible biases, the best sample includes stratification by age and sex to ensure that the sample consists of the typical age and sex distribution of patients ages 15-54 at the hospital. The stratification also simplifies the avoidance of duplicate specimens, data management, and analysis of data by age and sex.\nTo obtain the distribution by age and sex of an average patient population ages 15-54 in a specific hospital, discharge data from a representative period, obtained from the hospital medical records or billing department, can be separated by age and sex of all patients in that age category into eight strata: ages 15-24, 25-34, 35-44, and 45-54 for each sex. In general, the discharge data of the last calendar year should yield representative data of an average patient population. Changes like the opening of a new trauma care unit in the middle of the year, however, may have a major impact on the patient distribution. In such a case, one has to be sure that the population from which the age and sex distribution is taken is representative of the actual patient population (for example, discharge data of the last 3 months.)\nThe proportion of each group is calculated by dividing the number of discharges in that group by the total number of discharges of patients ages 15-54. An example of this procedure for an average hospital is given in table 1. To obtain the number of specimens per age-and sex-stratum that should be included in the survey sample, it is necessary to multiply the total sample size (1,000) by the proportion of the appropriate group (table 2). Although this procedure is not a randomized sampling procedure, it should provide a good approximation of the patient population because the numbers per stratum are calculated in advance. If different populations, such as outpatients and inpatients, are included in the survey, collection of separate samples of 1,000 specimens for each population is recommended.\nSampling problems. Laboratory or hospital procedures can also lead to a sampling bias. For example, if some specimens of a particular patient group such as obstetric patients are sequestered for other purposes like special studies, those specimens may not be available for this survey. When designing the survey and interpreting results, investigators should determine if such procedures are practiced in their laboratories.\nIn some hospitals, the total sample could be selected in less than 1 week. For example, if a large group of patients is admitted to the hospital on a certain day of the week for a specific procedure like elective surgery, these patients could be either over-or underrepresented in the sample, depending on whether specimens drawn on that particular day were included or excluded from the sample. One way to compensate for such a bias is to select only every second or third available specimen to ensure that sampling occurs over a sufficiently long period.\n# Sampling Procedure\nTo perform this survey, investigators need access to residual blood specimens and corresponding demographic data. The most efficient way to perform the survey is to collect blood specimens and the corresponding demographic data at one central laboratory. The chemistry laboratory, for example, might be the most likely place to obtain leftover serum or plasma without additional procedures like centrifugation of heparinized blood and have specimens from patients that meet the survey population requirements. In addition, personnel at the collection laboratory will need access to patient data on age group, sex, race, and clinical service. If hospitals have different laboratories for different units, investigators could either perform separate surveys of the patients of the different units or stratify the The sequence of serodiagnosis procedures for human immunodeficiency virus using enzyme immunoassay (EIA) tos md bhe use of th Westen blot sway fore o HIV1 el h ben p\"MMlshed (7).\nsample according to the overall patient distribution in the different units. Specimens could then be collected consecutively for each age group and sex stratum in each laboratory. Data collection form. The form used to collect sample data is designed to enable personnel to collect the data, conduct the stratified sampling while avoiding duplicate testing of the same person, and protect the anonymity of patients being selected. Sampling with this form does not require the use of a computer; however, a computerized data base can be easily developed from it.\nBefore the beginning of the survey, investigators must clearly define the information they want to collect. The recommended variables are sex, age group, race, and clinical service. Specific categories are given for sex and age group. The race variable has two generally useful fixed categories of white and black patients. Another race-ethnicity (Hispanic, for example) may be specified if the proportion of this group is at least 10 percent of the patient population. No particular race or ethnic group should be used if it represents less than 10 percent of the patient population; all such groups should be combined and classified as \"other.\" For the service unit, there are four proposed categories, surgery, internal medicine, obstetrics, and psychiatry. Other units, if essential to note, should be categorized in advance. In addition, it could be indicated whether a patient is treated as an inpa-tient, outpatient, or in the emergency room. If additional information is of special importance to a particular hospital, it may be collected and specified. It is especially important to specify such categories in advance to be sure that the meaning is unequivocal and that the data collection is systematic. Any additional data should be essential to interpreting and using the results of the survey and should not allow for the identification of a person tested in the survey. Additional information, such as specific diagnosis, might allow for inadvertent identification, if the diagnosis is rare. Therefore, investigators must be cautious in collecting any additional information.\nAvoiding duplicate sampling. Besides the survey number, which may be preprinted on the data collection forms, the last 4 digits of the patient's hospital identification number (usually 7 digits) can be recorded temporarily on a data collection form to avoid duplicate sampling. These segments of the patient numbers must be removed and destroyed before the specimens are serologically tested. Each specimen should be labelled with the corresponding survey number and prepared labels attached to the data collection forms.\nCollection of specimens and corresponding data.\nWhen the patients and the laboratory site where specimens will be collected are identified and the total number of patients in each of the eight age and sex strata is determined, data collection forms should be prepared. For example, if all specimens can be collected in one laboratory site and the total number of specimens for men ages 25-34 is 82, four data collection forms (for 25 specimens each) could be labeled for this age-sex stratum and stapled together. The last number for this stratum should be highlighted to make it easy to recognize when the total number of this particular stratum is achieved.\nThe specimen selectors in the laboratory can then take the following steps:\n1. Check each specimen after routine testing to determine whether there is enough serum (or plasma) left over. A volume of 0.5 milliliter (ml) or more would be ideal and would allow for extra tests for indeterminate specimens. A minimum of 0.2 ml is enough for the routine HIV serology, however. If there is less than 0.2 ml available, the specimen should be excluded.\n2. If there is at least 0.2 ml available, check whether the specimen fits into one of the eight sex-age strata (ages 15-54 years). If not, exclude it and check the next specimen. If yes, check whether there is already a specimen included in the corresponding age-sex stratum with the same patient number (last four digits). If yes, exclude it and check the next specimen.\n3. If not already sampled (as indicated by the last 4 digits of patient number), the specimen should be selected and the last four digits of the patient number and demographic data recorded on the form. Such data may need to be located through the laboratory's computer system or at another place in the hospital with access to patient demographics. A sample of 0.5 ml (at least 0.2 ml, see step 1) should be taken and the corresponding label, which is attached to the data collection form, should be placed on the tube. No other labels should be attached to the tube holding the sample. Persons aliquoting specimens should wear gloves and a laboratory coat. Some laboratory workers may also prefer to work in a hood, behind a plastic shield, or wear safety glasses (11).\n4. When all forms for a particular stratum are filled (and, thus, the total number of specimens in this stratum is achieved), continue to collect specimens only in the incomplete strata. 5. When the forms of all eight strata are full and before submitting the specimens for HIV testing, cut off and destroy the columns with the last four digits of the patient number.\n# Specimen Storage\nAfter the aliquots are collected and the tubes are labeled with their survey numbers, the specimens should be stored in a freezer (at least -20°C) until the total sample size is achieved and the serums (or plasma specimens) are tested for HIV antibodies. If the specimens cannot be frozen the day they are collected, they may be temporarily stored in a refrigerator (4°-80 C) for a maximum of 5 days.\n# Guidelines for HIV Antibody Testing\nThe specimens should be tested (see chart) using an FDA-licensed HIV-1 enzyme immunoassay (EIA) kit. If the specimen is nonreactive in the initial test, the specimen is classified as negative. If the specimen is reactive in the initial test, the EIA should be repeated in duplicate, using fresh aliquots of the same specimen. If at least one of the repeated EIAs is reactive, the specimen is classified as \"EIA repeatedly reactive\" and should be tested with a supplemental test. The recommended supple-mental test is an FDA-licensed Western blot kit. Guidelines for the interpretation and use of the Western blot assay have been published by the Association of State and Territorial Public Health Laboratory Directors and Centers for Disease Control and Prevention (12).\nHIV antibody results can be recorded on the data collection form or entered into a computer file. The laboratory technician who performed the HIV antibody testing, but who did not select the specimens to be tested, may enter the HIV antibody results into the appropriate data base. The person(s) who selected the specimens should not see individual test results or the completed data collection forms, as a further protection of the anonymity of the survey.\n# Data Management\nA sequence of preprinted survey numbers on data collection forms and preassigned sticker labels facilitate recording of the laboratory results directly on data collection forms. If desired, data can be transferred to a computer (with a data management package such as EPI-Info). The survey can be conducted without the use of a computer, however.\nIf a computer is used to avoid duplicate sampling of the same patient, a separate temporary file, contalning only the age-sex strata and the last 4 digits of the patients' numbers (and not the survey numbers), should be used during sampling to ensure that no link between patient number and HIV test result is possible. After the sampling is completed and before the HIV tests are performed, the data file with the last 4 digits of the patient number must be deleted.\nIf a computer is used for data analysis, a permanent fie with survey number (but without the last 4 digits of the patient number), and demographic information should be used for entering HIV antibody test results. The permanent data file should not contain any information that links percent confidence interval Is 7.60, 24.43, using the formula in table 3. The overall seroprevaence of this population would be 5.2 percent (52 X 100 percent, divided by 1,000). An approximate 95 percent confidence interval for the values of the seroprevalence estimate using the formula on page 000 for samples with more than 20 positive specimern wouid be 3.97, 6.82. personal identifiers, such as patient numbers, with\nHIV test results.\nThe principal investigator can use the data base for analysis of aggregated data but should not report line-by-line results. The principal investigator must be responsible for ensuring that inadvertent linkage of HIV antibody test results to a specific patient does not occur. For further protec-tion of the anonymity of the patients, the person(s) collecting the specimens and checking patient records should not see line-by-line HIV test result data. The specimen collector(s) may, however, see grouped summary data.\n# Interpretation of the Results\nThe estimate of seroprevalence in the patient population is\nx n where x is the total number of seropositive patients observed (summed over all strata) and n is the total sample size (number tested). (Multiplying by 100 will express this seroprevalence in percent positive.) Estimates of seroprevalence in a subgroup may also be obtained by dividing the number of seropositives from that subgroup by the number tested in that subgroup. For example, separate estimates of seroprevalence for men and women may be calculated.\nApproximate confidence limits for the seroprevalence can be obtained with the Poisson distribution. Thus, confidence limits for seroprevalence in the individual strata or groups of strata may be calculated by using the procedures described in table 3 if 20 or fewer HIV-seropositive specimens are observed.\nIf more than 20 HIV-seropositive specimens are observed, regardless of the size of the sample, the 95 percent confidence interval is calculated by using the following equation:\nx + 1.92 ± 1.96 lIx + 0.96 X 100 percent n where x = observed number of positive specimens and n = sample size.\nAs an example, suppose that 21 people are found to be seropositive out of a sample of 275 (seroprevalence = 7.6 percent). Then the 95 percent confidence interval for the seroprevalence is 21 + 1.92 ± 1.96 121 + 0.96 X 100 percent 275\nIn this case, the 95 percent confidence interval is 4.99 percent, 11.67 percent.\nAn example of the interpretation of results obtained by a survey following this protocol is given in table 4.\n# Personnel Time\nThe time required to conduct a rapid assessment of HIV seroprevalence survey depends on familiarity with laboratory-based studies, the size of the hospital, and the number of laboratory specimens available. In addition to the principal investigator's time, the equivalent of one person working full time for 1 to 2 months is needed to complete the specimen collection and handling and data management. In addition, time is needed for a technician to perform HIV-antibody testing."},"url":{"kind":"string","value":"None"},"overview":{"kind":"string","value":"None"}}},{"rowIdx":299,"cells":{"id":{"kind":"string","value":"25af3fc78ea6c5e2ee5d21aa0aa6311fe12485e2"},"source":{"kind":"string","value":"cdc"},"title":{"kind":"string","value":"None"},"clean_text":{"kind":"string","value":"Although the environment serves as a reservoir for a variety of microorganisms, it is rarely implicated in disease transmission except in the immunocompromised population. Inadvertent exposures to environmental opportunistic pathogens (e.g., Aspergillus spp. and Legionella spp.) or airborne pathogens (e.g., Mycobacterium tuberculosis and varicella-zoster virus) may result in infections with significant morbidity and/or mortality. Lack of adherence to established standards and guidance (e.g., water quality in dialysis, proper ventilation for specialized care areas such as operating rooms, and proper use of disinfectants) can result in adverse patient outcomes in health-care facilities.The objective is to develop an environmental infection-control guideline that reviews and reaffirms strategies for the prevention of environmentally-mediated infections, particularly among health-care workers and immunocompromised patients. The recommendations are evidence-based whenever possible.The contributors to this guideline reviewed predominantly English-language articles identified from MEDLINE literature searches, bibliographies from published articles, and infection-control textbooks.Articles dealing with outbreaks of infection due to environmental opportunistic microorganisms and epidemiological-or laboratory experimental studies were reviewed. Current editions of guidelines and standards from organizations (i.e.# Outcome Measures:\nInfections caused by the microorganisms described in this guideline are rare events, and the effect of these recommendations on infection rates in a facility may not be readily measurable. Therefore, the following steps to measure performance are suggested to evaluate these recommendations:\n1. Document whether infection-control personnel are actively involved in all phases of a healthcare facility's demolition, construction, and renovation. Activities should include performing a risk assessment of the necessary types of construction barriers, and daily monitoring and documenting of the presence of negative airflow within the construction zone or renovation area.\n2. Monitor and document daily the negative airflow in airborne infection isolation rooms (AII) and positive airflow in protective environment rooms (PE), especially when patients are in these rooms.\n3. Perform assays at least once a month by using standard quantitative methods for endotoxin in water used to reprocess hemodialyzers, and for heterotrophic, mesophilic bacteria in water used to prepare dialysate and for hemodialyzer reprocessing.\n\n# Executive Summary\nThe Guidelines for Environmental Infection Control in Health-Care Facilities is a compilation of recommendations for the prevention and control of infectious diseases that are associated with healthcare environments. This document a. revises multiple sections from previous editions of the Centers for Disease Control and Prevention document titled Guideline for Handwashing and Hospital Environmental Control; 1, 2 b. incorporates discussions of air and water environmental concerns from CDC's Guideline for the Prevention of Nosocomial Pneumonia; 3 c. consolidates relevant environmental infection-control measures from other CDC guidelines; and d. includes two topics not addressed in previous CDC guidelines -infection-control concerns related to animals in health-care facilities and water quality in hemodialysis settings.\nPart I of this report, Background Information: Environmental Infection Control in Health-Care Facilities, provides a comprehensive review of the scientific literature. Attention is given to engineering and infectioncontrol concerns during construction, demolition, renovation, and repairs of health-care facilities. Use of an infection-control risk assessment is strongly supported before the start of these or any other activities expected to generate dust or water aerosols. Also reviewed in Part I are infection-control measures used to recover from catastrophic events (e.g., flooding, sewage spills, loss of electricity and ventilation, and disruption of the water supply) and the limited effects of environmental surfaces, laundry, plants, animals, medical wastes, cloth furnishings, and carpeting on disease transmission in healthcare facilities.\nPart II of this guideline, Recommendations for Environmental Infection Control in Health-Care Facilities, outlines environmental infection control in health-care facilities, describing measures for preventing infections associated with air, water, and other elements of the environment. These recommendations represent the views of different divisions within CDC's National Center for Infectious Diseases (NCID) (e.g., the Division of Healthcare Quality Promotion and the Division of Bacterial and Mycotic Diseases ) and the consensus of the Healthcare Infection Control Practices Advisory Committee (HICPAC), a 12-member group that advises CDC on concerns related to the surveillance, prevention, and control of health-care associated infections, primarily in U.S. healthcare facilities.10 In 1999, HICPAC's infection-control focus was expanded from acute-care hospitals to all venues where health care is provided (e.g., outpatient surgical centers, urgent care centers, clinics, outpatient dialysis centers, physicians' offices, and skilled nursing facilities). The topics addressed in this guideline are applicable to the majority of health-care venues in the United States. This document is intended for use primarily by infection-control professionals (ICPs), epidemiologists, employee health and safety personnel, information system specialists, administrators, engineers, facility managers, environmental service professionals, and architects for health-care facilities.\nKey recommendations include a. infection-control impact of ventilation system and water system performance; b. establishment of a multidisciplinary team to conduct infection-control risk assessment; c. use of dust-control procedures and barriers during construction, repair, renovation, or demolition; d. environmental infection-control measures for special care areas with patients at high risk; e. use of airborne particle sampling to monitor the effectiveness of air filtration and dust-control measures; f. procedures to prevent airborne contamination in operating rooms when infectious tuberculosis patients require surgery g. guidance regarding appropriate indications for routine culturing of water as part of a comprehensive control program for legionellae; h. guidance for recovering from water system disruptions, water leaks, and natural disasters ; i. infection-control concepts for equipment that uses water from main lines ); j. environmental surface cleaning and disinfection strategies with respect to antibiotic-resistant microorganisms; k. infection-control procedures for health-care laundry; l. use of animals in health care for activities and therapy; m. managing the presence of service animals in health-care facilities; n. infection-control strategies for when animals receive treatment in human health-care facilities; and o. a call to reinstate the practice of inactivating amplified cultures and stocks of microorganisms on-site during medical waste treatment.\nWhenever possible, the recommendations in Part II are based on data from well-designed scientific studies. However, certain of these studies were conducted by using narrowly defined patient populations or for specific health-care settings (e.g., hospitals versus long-term care facilities), making generalization of findings potentially problematic. Construction standards for hospitals or other healthcare facilities may not apply to residential home-care units. Similarly, infection-control measures indicated for immunosuppressed patient care are usually not necessary in those facilities where such patients are not present. Other recommendations were derived from knowledge gained during infectious disease investigations in health-care facilities, where successful termination of the outbreak was often the result of multiple interventions, the majority of which cannot be independently and rigorously evaluated. This is especially true for construction situations involving air or water.\nOther recommendations are derived from empiric engineering concepts and may reflect an industry standard rather than an evidence-based conclusion. Where recommendations refer to guidance from the American Institute of Architects (AIA), (AIA guidance has been superseded by the Facilities Guidelines Institute ) the statements reflect standards intended for new construction or renovation. Existing structures and engineered systems are expected to be in continued compliance with the standards in effect at the time of construction or renovation. Also, in the absence of scientific confirmation, certain infectioncontrol recommendations that cannot be rigorously evaluated are based on a strong theoretical rationale and suggestive evidence. Finally, certain recommendations are derived from existing federal regulations.\nThe references and the appendices comprise Parts III and IV of this document, respectively.\nInfections caused by the microorganisms described in these guidelines are rare events, and the effect of these recommendations on infection rates in a facility may not be readily measurable. Therefore, the following steps to measure performance are suggested to evaluate these recommendations (Box 1):\nBox 1. Environmental infection control: performance measures 1. Document whether infection-control personnel are actively involved in all phases of a health-care facility's demolition, construction, and renovation. Activities should include performing a risk assessment of the necessary types of construction barriers, and daily monitoring and documenting of the presence of negative airflow within the construction zone or renovation area.\n2. Monitor and document daily the negative airflow in airborne infection isolation (AII) rooms and positive airflow in protective environment (PE) rooms, especially when patients are in these rooms.\n3. Perform assays at least once a month by using standard quantitative methods for endotoxin in water used to reprocess hemodialyzers, and for heterotrophic and mesophilic bacteria in water used to prepare dialysate and for hemodialyzer reprocessing.\n4. Evaluate possible environmental sources (e.g., water, laboratory solutions, or reagents) of specimen contamination when nontuberculous mycobacteria (NTM) of unlikely clinical importance are isolated from clinical cultures. If environmental contamination is found, eliminate the probable mechanisms.\n5. Document policies to identify and respond to water damage. Such policies should result in either repair and drying of wet structural or porous materials within 72 hours, or removal of the wet material if drying is unlikely with 72 hours.\nTopics outside the scope of this document include a. noninfectious adverse events (e.g., sick building syndrome); b. environmental concerns in the home; c. home health care; d. bioterrorism; and e. healthcare-associated foodborne illness.\nThis document includes only limited discussion of handwashing/hand hygiene; standard precautions; and infection-control measures used to prevent instrument or equipment contamination during patient care (e.g., preventing waterborne contamination of nebulizers or ventilator humidifiers).\nThese topics are mentioned only if they are important in minimizing the transfer of pathogens to and from persons or equipment and the environment. Although the document discusses principles of cleaning and disinfection as they are applied to maintenance of environmental surfaces, the full discussion of sterilization and disinfection of medical instruments and direct patient-care devices is deferred for inclusion in the\n\n# Part I. Background Information: Environmental Infection Control in Health-Care Facilities\n\n# A. Introduction\nThe health-care environment contains a diverse population of microorganisms, but only a few are significant pathogens for susceptible humans. Microorganisms are present in great numbers in moist, organic environments, but some also can persist under dry conditions. Although pathogenic microorganisms can be detected in air and water and on fomites, assessing their role in causing infection and disease is difficult. 11 Only a few reports clearly delineate a \"cause and effect\" with respect to the environment and in particular, housekeeping surfaces.\nEight criteria are used to evaluate the strength of evidence for an environmental source or means of transmission of infectious agents (Box 2). 11,12 Applying these criteria to disease investigations allows scientists to assess the contribution of the environment to disease transmission. An example of this application is the identification of a pathogen (e.g., vancomycin-resistant enterococci ) on an environmental surface during an outbreak. The presence of the pathogen does not establish its causal role; its transmission from source to host could be through indirect means (e.g., via hand transferral). 11 The surface, therefore, would be considered one of a number of potential reservoirs for the pathogen, but not the \"de facto\" source of exposure. An understanding of how infection occurs after exposure, based on the principles of the \"chain of infection,\" is also important in evaluating the contribution of the environment to health-care associated disease. 13 All of the components of the \"chain\" must be operational for infection to occur (Box 3).\nBox 2. Eight criteria for evaluating the strength of evidence for environmental sources of infection*+\n1. The organism can survive after inoculation onto the fomite.\n2. The organism can be cultured from in-use fomites.\n3. The organism can proliferate in or on the fomite.\n4. Some measure of acquisition of infection cannot be explained by other recognized modes of transmission.\n5. Retrospective case-control studies show an association between exposure to the fomite and infection.\nProspective case-control studies may be possible when more than one similar type of fomite is in use. 7. Prospective studies allocating exposure to the fomite to a subset of patients show an association between exposure and infection. The presence of the susceptible host is one of these components that underscores the importance of the health-care environment and opportunistic pathogens on fomites and in air and water. As a result of advances in medical technology and therapies (e.g., cytotoxic chemotherapy and transplantation medicine), more patients are becoming immunocompromised in the course of treatment and are therefore at increased risk for acquiring health-care associated opportunistic infections. Trends in health-care delivery (e.g., early discharge of patients from acute care facilities) also are changing the distribution of patient populations and increasing the number of immunocompromised persons in nonacute-care hospitals. According to the American Hospital Association (AHA), in 1998, the number of hospitals in the United States totaled 6,021; these hospitals had a total of 1,013,000 beds, 14 representing a 5.5% decrease in the number of acute-care facilities and a 10.2% decrease in the number of beds over the 5year period 1994-1998. 14 In addition, the total average daily number of patients receiving care in U.S. acute-care hospitals in 1998 was 662,000 (65.4%) -36.5% less than the 1978 average of 1,042,000. 14 As the number of acute-care hospitals declines, the length of stay in these facilities is concurrently decreasing, particularly for immunocompetent patients. Those patients remaining in acute-care facilities are likely to be those requiring extensive medical interventions who therefore at high risk for opportunistic infection. The growing population of severely immunocompromised patients is at odds with demands on the health-care industry to remain viable in the marketplace; to incorporate modern equipment, new diagnostic procedures, and new treatments; and to construct new facilities. Increasing numbers of health-care facilities are likely to be faced with construction in the near future as hospitals consolidate to reduce costs, defer care to ambulatory centers and satellite clinics, and try to create more \"home-like\" acute-care settings. In 1998, approximately 75% of health-care associated construction projects focused on renovation of existing outpatient facilities or the building of such facilities; 15 the number of projects associated with outpatient health care rose by 17% from 1998 through 1999. 16 An aging population is also creating increasing demand for assisted-living facilities and skilled nursing centers. Construction of assisted-living facilities in 1998 increased 49% from the previous year, with 138 projects completed at a cost of $703 million. 16 Overall, from 1998 to 1999, health-care associated construction costs increased by 28.5%, from $11.56 billion to $14.86 billion. 16 Environmental disturbances associated with construction activities near health-care facilities pose airborne and waterborne disease threats risks for the substantial number of patients who are at risk for health-care associated opportunistic infections. The increasing age of hospitals and other health-care facilities is also generating ongoing need for repair and remediation work (e.g., installing wiring for new information systems, removing old sinks, and repairing elevator shafts) that can introduce or increase contamination of the air and water in patient-care environments. Aging equipment, deferred maintenance, and natural disasters provide additional mechanisms for the entry of environmental pathogens into highrisk patient-care areas.\nArchitects, engineers, construction contractors, environmental health scientists, and industrial hygienists historically have directed the design and function of hospitals' physical plants. Increasingly, however, because of the growth in the number of susceptible patients and the increase in construction projects, the involvement of hospital epidemiologists and infection-control professionals is required. These experts help make plans for building, maintaining, and renovating health-care facilities to ensure that the adverse impact of the environment on the incidence of health-care associated infections is minimal. The following are examples of adverse outcomes that could have been prevented had such experts been involved in the planning process: transmission of infections caused by Mycobacterium tuberculosis, varicella-zoster virus (VZV), and measles (i.e., rubeola) facilitated by inappropriate air-handling systems in health-care facilities; 6 disease outbreaks caused by Aspergillus spp., Mucoraceae, 20 and Penicillium spp. associated with the absence of environmental controls during periods of health-care facility-associated construction; 21 infections and/or colonizations of patients and staff with vancomycin-resistant Enterococcus faecium and Clostridium difficile acquired indirectly from contact with organisms present on environmental surfaces in health-care facilities; and outbreaks and pseudoepidemics of legionellae, 26,27 Pseudomonas aeruginosa, 28-30 and the nontuberculous mycobacteria (NTM) 31,32 linked to water and aqueous solutions used in health-care facilities.\nThe purpose of this guideline is to provide useful information for both health-care professionals and engineers in efforts to provide a safe environment in which quality health care may be provided to patients. The recommendations herein provide guidance to minimize the risk for and prevent transmission of pathogens in the indoor environment.\n\n# B. Key Terms Used in this Guideline\nAlthough Appendix A provides definitions for terms discussed in Part I, several terms that pertain to specific patient-care areas and patients who are at risk for health-care associated opportunistic infections are presented here. Specific engineering parameters for these care areas are discussed more fully in the text. Airborne Infection Isolation (AII) refers to the isolation of patients infected with organisms spread via airborne droplet nuclei <5 μm in diameter. This isolation area receives numerous air changes per hour (ACH) (≥12 ACH for new construction as of 2001; ≥6 ACH for construction before 2001), and is under negative pressure, such that the direction of the airflow is from the outside adjacent space (e.g., corridor) into the room. The air in an AII room is preferably exhausted to the outside, but may be recirculated provided that the return air is filtered through a high efficiency particulate air (HEPA) filter. The use of personal respiratory protection is also indicated for persons entering these rooms.\nProtective Environment (PE) is a specialized patient-care area, usually in a hospital, with a positive airflow relative to the corridor (i.e., air flows from the room to the outside adjacent space). The combination of HEPA filtration, high numbers of air changes per hour (≥12 ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients who have undergone allogeneic hematopoietic stem cell transplant (HSCT).\nImmunocompromised patients are those patients whose immune mechanisms are deficient because of immunologic disorders (e.g., human immunodeficiency virus infection, congenital immune deficiency syndrome, chronic diseases ) or immunosuppressive therapy (e.g., radiation, cytotoxic chemotherapy, anti-rejection medication, and steroids). Immunocompromised patients who are identified as high-risk patients have the greatest risk of infection caused by airborne or waterborne microorganisms. Patients in this subset include those who are severely neutropenic for prolonged periods of time (i.e., an absolute neutrophil count of ≤500 cells/mL), allogeneic HSCT patients, and those who have received intensive chemotherapy (e.g., childhood acute myelogenous leukemia patients).\n\n# C. Air 1. Modes of Transmission of Airborne Diseases\nA variety of airborne infections in susceptible hosts can result from exposures to clinically significant microorganisms released into the air when environmental reservoirs (i.e., soil, water, dust, and decaying organic matter) are disturbed. Once these materials are brought indoors into a health-care facility by any of a number of vehicles (e.g., people, air currents, water, construction materials, and equipment), the attendant microorganisms can proliferate in various indoor ecological niches and, if subsequently disbursed into the air, serve as a source for airborne health-care associated infections.\nRespiratory infections can be acquired from exposure to pathogens contained either in droplets or droplet nuclei. Exposure to microorganisms in droplets (e.g., through aerosolized oral and nasal secretions from infected patients 33 ) constitutes a form of direct contact transmission. When droplets are produced during a sneeze or cough, a cloud of infectious particles >5 μm in size is expelled, resulting in the potential exposure of susceptible persons within 3 feet of the source person. 6 Examples of pathogens spread in this manner are influenza virus, rhinoviruses, adenoviruses, and respiratory syncytial virus (RSV). Because these agents primarily are transmitted directly and because the droplets tend to fall out of the air quickly, measures to control air flow in a health-care facility (e.g., use of negative pressure rooms) generally are not indicated for preventing the spread of diseases caused by these agents. Strategies to control the spread of these diseases are outlined in another guideline. 3 The spread of airborne infectious diseases via droplet nuclei is a form of indirect transmission. 34 Droplet nuclei are the residuals of droplets that, when suspended in air, subsequently dry and produce particles ranging in size from 1-5 μm. These particles can a. contain potentially viable microorganisms, b. be protected by a coat of dry secretions, c. remain suspended indefinitely in air, and d. be transported over long distances.\nThe microorganisms in droplet nuclei persist in favorable conditions (e.g., a dry, cool atmosphere with little or no direct exposure to sunlight or other sources of radiation). Pathogenic microorganisms that can be spread via droplet nuclei include Mycobacterium tuberculosis, VZV, measles virus (i.e., rubeola), and smallpox virus (i.e., variola major). 6 Several environmental pathogens have life-cycle forms that are similar in size to droplet nuclei and may exhibit similar behavior in the air. The spores of Aspergillus fumigatus have a diameter of 2-3.5 μm, with a settling velocity estimated at 0.03 cm/second (or about 1 meter/hour) in still air. With this enhanced buoyancy, the spores, which resist desiccation, can remain airborne indefinitely in air currents and travel far from their source. 35\n\n# Airborne Infectious Diseases in Health-Care Facilities a. Aspergillosis and Other Fungal Diseases\nAspergillosis is caused by molds belonging to the genus Aspergillus. Aspergillus spp. are prototype health-care acquired pathogens associated with dusty or moist environmental conditions. Clinical and epidemiologic aspects of aspergillosis (Table 1) are discussed extensively in another guideline. 3 Format Change : The format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Table 1. Clinical and epidemiologic characteristics of aspergillosis\n\n# Modes of transmission\nAirborne transmission of fungal spores; direct inhalation; direct inoculation from environmental sources (rare)\nand equipment can become contaminated with Aspergillus spp. spores and serve as sources of infection if stored in such areas. 57 Most cases of aspergillosis are caused by Aspergillus fumigatus, a thermotolerant/thermophilic fungus capable of growing over a temperature range from 53.6°F-127.4°F (12°C-53°C); optimal growth occurs at approximately 104°F (40°C), a temperature inhibitory to most other saprophytic fungi. 99 It can use cellulose or sugars as carbon sources; because its respiratory process requires an ample supply of carbon, decomposing organic matter is an ideal substrate. (For AIA guidance on Aspergillus spp. see Table 2.)\nOther opportunistic fungi that have been occasionally linked with health-care associated infections are members of the order Mucorales (e.g., Rhizopus spp.) and miscellaneous moniliaceous molds (e.g., Fusarium spp. and Penicillium spp.) (Table 2). Many of these fungi can proliferate in moist environments (e.g., water-damaged wood and building materials). Some fungi (e.g., Fusarium spp. and Pseudoallescheria spp.) also can be airborne pathogens. 100 As with aspergillosis, a major risk factor for disease caused by any of these pathogens is the host's severe immunosuppression from either underlying disease or immunosuppressive therapy. 101,102 Format Change : The format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Table 2. Environmental fungal pathogens: entry into and contamination of the healthcare facility\nFungal pathogen Implicated environmental vehicle Aspergillus spp.\n- Improperly functioning ventilation systems 20,46,47,97,98,103,104 - Air filters+ 17,18, Pigeons, their droppings and roosts are associated with spread of Aspergillus, Cryptococcus, and Histoplasma spp. There have been at least three outbreaks linked to contamination of the filtering systems from bird droppings 98,103,104 Pigeon mites may gain access into a health-care facility through the ventilation system. 119 - Air filter frames 17,18 - Window air conditioners 96 - Backflow of contaminated air 107\n- Air exhaust contamination+ 104 - False ceilings 48,57,97,108 - Fibrous insulation and perforated metal ceilings 66 - Acoustic ceiling tiles, plasterboard 18,109 - Fireproofing material 48,49 - Damp wood building materials 49 - Opening doors to construction site 110\n\n# Construction 69\n- Open windows 20,108,111 105 - Topical anesthetic 117 Acremonium spp.\n- Air filters 105 Cladosporium spp.\n- Air filters 105\n\n# Sporothrix\n- Construction (pseudoepidemic) 118 + The American Institute of Architects (AIA) standards stipulate that for new or renovated construction o exhaust outlets are to be placed >25 feet from air intake systems, o the bottom of outdoor air intakes for HVAC systems should be 6 feet above ground or 3 feet above roof level, and o exhaust outlets from contaminated areas are situated above the roof level and arranged to minimize the recirculation of exhausted air back into the building. 120 Infections due Cryptococcus neoformans, Histoplasma capsulatum, or Coccidioides immitis can occur in health-care settings if nearby ground is disturbed and a malfunction of the facility's air-intake components allows these pathogens to enter the ventilation system. C. neoformans is a yeast usually 4-8 μm in size. However, viable particles of <2 μm diameter (and thus permissive to alveolar deposition) have been found in soil contaminated with bird droppings, particularly from pigeons. 98,103,104,121 H. capsulatum, with the infectious microconidia ranging in size from 2-5 μm, is endemic in the soil of the central river valleys of the United States. Substantial numbers of these infectious particles have been associated with chicken coops and the roosts of blackbirds. 98,103,104,122 Several outbreaks of histoplasmosis have been associated with disruption of the environment; construction activities in an endemic area may be a potential risk factor for health-care acquired airborne infection. 123,124 C. immitis, with arthrospores of 3-5 μm diameter, has similar potential, especially in the endemic southwestern United States and during seasons of drought followed by heavy rainfall. After the 1994 earthquake centered near Northridge, California, the incidence of coccidioidomycosis in the surrounding area exceeded the historical norm. 125 Emerging evidence suggests that Pneumocystis carinii, now classified as a fungus, may be spread via airborne, person-to-person transmission. 126 Controlled studies in animals first demonstrated that P. carinii could be spread through the air. 127 More recent studies in health-care settings have detected nucleic acids of P. carinii in air samples from areas frequented or occupied by P. carinii-infected patients but not in control areas that are not occupied by these patients. 128,129 Clusters of cases have been identified among immunocompromised patients who had contact with a source patient and with each other. Recent studies have examined the presence of P. carinii DNA in oropharyngeal washings and the nares of infected patients, their direct contacts, and persons with no direct contact. 130,131 Molecular analysis of the DNA by polymerase chain reaction (PCR) provides evidence for airborne transmission of P. carinii from infected patients to direct contacts, but immunocompetent contacts tend to become transiently colonized rather than infected. 131 The role of colonized persons in the spread of P. carinii pneumonia (PCP) remains to be determined. At present, specific modifications to ventilation systems to control spread of PCP in a health-care facility are not indicated. Current recommendations outline isolation procedures to minimize or eliminate contact of immunocompromised patients not on PCP prophylaxis with PCP-infected patients. 6,132\n\n# b. Tuberculosis and Other Bacterial Diseases\nThe bacterium most commonly associated with airborne transmission is Mycobacterium tuberculosis. A comprehensive review of the microbiology and epidemiology of M. tuberculosis and guidelines for tuberculosis (TB) infection control have been published. 4,133,134 A summary of the clinical and epidemiologic information from these materials is provided in this guideline (Table 3).\nFormat Change : The format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Factors affecting severity and outcomes\n- Concentration of droplet nuclei in air, duration of exposure - Age at infection - Immunosuppression due to therapy or disease, underlying chronic medical conditions, history of malignancies or lesions or the lungs Occurrence - Worldwide; incidence in the United States is 56 cases/100,000 population (2001) 136 Mortality rate - 930 deaths in the United States (1999) 136 Chemoprophylaxis / treatment - Treatment of latent infection includes isoniazid (INH) or rifampin (RIF) 4,134, - Directly observed therapy (DOT) for active cases as indicated: INH, RIF, pyrazinamide (PZA), ethambutol (EMB), streptomycin (SM) in various combinations determined by prevalent levels of specific resistance 4,134, - Consult therapy guidelines for specific treatment indications 139 - Material in this table is compiled from references 4, 133-141.\nM. tuberculosis is carried by droplet nuclei generated when persons (primarily adults and adolescents) who have pulmonary or laryngeal TB sneeze, cough, speak, or sing; 139 normal air currents can keep these particles airborne for prolonged periods and spread them throughout a room or building. 142 However, transmission of TB has occurred from mycobacteria aerosolized during provision of care (e.g., wound/lesion care or during handling of infectious peritoneal dialysis fluid) for extrapulmonary TB patients. 135,140 Gram-positive cocci (i.e., Staphylococcus aureus, group A beta-hemolytic streptococci), also important health-care associated pathogens, are resistant to inactivation by drying and can persist in the environment and on environmental surfaces for extended periods. These organisms can be shed from heavily colonized persons and discharged into the air. Airborne dispersal of S. aureus is directly associated with the concentration of the bacterium in the anterior nares. 143 Approximately 10% of healthy carriers will disseminate S. aureus into the air, and some persons become more effective disseminators of S. aureus than others. The dispersal of S. aureus into air can be exacerbated by concurrent viral upper respiratory infection, thereby turning a carrier into a \"cloud shedder.\" 149 Outbreaks of surgical site infections (SSIs) caused by group A beta-hemolytic streptococci have been traced to airborne transmission from colonized operating-room personnel to patients. In these situations, the strain causing the outbreak was recovered from the air in the operating room 150,151,154 or on settle plates in a room in which the carrier exercised. S. aureus and group A streptococci have not been linked to airborne transmission outside of operating rooms, burn units, and neonatal nurseries. 155,156 Transmission of these agents occurs primarily via contact and droplets.\nOther gram-positive bacteria linked to airborne transmission include Bacillus spp. which are capable of sporulation as environmental conditions become less favorable to support their growth. Outbreaks and pseudo-outbreaks have been attributed to Bacillus cereus in maternity, pediatric, intensive care, and bronchoscopy units; many of these episodes were secondary to environmental contamination. Gram-negative bacteria rarely are associated with episodes of airborne transmission because they generally require moist environments for persistence and growth. The main exception is Acinetobacter spp., which can withstand the inactivating effects of drying. In one epidemiologic investigation of bloodstream infections among pediatric patients, identical Acinetobacter spp. were cultured from the patients, air, and room air conditioners in a nursery. 161 Aerosols generated from showers and faucets may potentially contain legionellae and other gram-negative waterborne bacteria (e.g., Pseudomonas aeruginosa). Exposure to these organisms is through direct inhalation. However, because water is the source of the organisms and exposure occurs in the vicinity of the aerosol, the discussion of the diseases associated with such aerosols and the prevention measures used to curtail their spread is discussed in another section of the Guideline (see Part I: Water).\n\n# c. Airborne Viral Diseases\nSome human viruses are transmitted from person to person via droplet aerosols, but very few viruses are consistently airborne in transmission (i.e., are routinely suspended in an infective state in air and capable of spreading great distances), and health-care associated outbreaks of airborne viral disease are limited to a few agents. Consequently, infection-control measures used to prevent spread of these viral diseases in health-care facilities primarily involve patient isolation, vaccination of susceptible persons, and antiviral therapy as appropriate rather than measures to control air flow or quality. 6 Infections caused by VZV frequently are described in health-care facilities. Health-care associated airborne outbreaks of VZV infections from patients with primary infection and disseminated zoster have been documented; patients with localized zoster have, on rare occasions, also served as source patients for outbreaks in health-care facilities. VZV infection can be prevented by vaccination, although patients who develop a rash within 6 weeks of receiving varicella vaccine or who develop breakthrough varicella following exposure should be considered contagious. 167 Viruses whose major mode of transmission is via droplet contact rarely have caused clusters of infections in group settings through airborne routes. The factors facilitating airborne distribution of these viruses in an infective state are unknown, but a presumed requirement is a source patient in the early stage of infection who is shedding large numbers of viral particles into the air. Airborne transmission of measles has been documented in health-care facilities. In addition, institutional outbreaks of influenza virus infections have occurred predominantly in nursing homes, and less frequently in medical and neonatal intensive care units, chronic-care areas, HSCT units, and pediatric wards. Some evidence supports airborne transmission of influenza viruses by droplet nuclei, 181,182 and case clusters in pediatric wards suggest that droplet nuclei may play a role in transmitting certain respiratory pathogens (e.g., adenoviruses and respiratory syncytial virus ). 177,183,184 Some evidence also supports airborne transmission of enteric viruses. An outbreak of a Norwalk-like virus infection involving more than 600 staff personnel over a 3-week period was investigated in a Toronto, Ontario hospital in 1985; common sources (e.g., food and water) were ruled out during the investigation, leaving airborne spread as the most likely mode of transmission. 185 Smallpox virus, a potential agent of bioterrorism, is spread predominantly via direct contact with infectious droplets, but it also can be associated with airborne transmission. 186,187 A German hospital study from 1970 documented the ability of this virus to spread over considerable distances and cause infection at low doses in a well-vaccinated population; factors potentially facilitating transmission in this situation included a patient with cough and an extensive rash, indoor air with low relative humidity, and faulty ventilation patterns resulting from hospital design (e.g., open windows). 188 Smallpox patients with extensive rash are more likely to have lesions present on mucous membranes and therefore have greater potential to disseminate virus into the air. 188 In addition to the smallpox transmission in Germany, two cases of laboratory-acquired smallpox virus infection in the United Kingdom in 1978 also were thought to be caused by airborne transmission. 189 Ebola Virus Disease Update : The recommendations in this guideline for Ebola has been superseded by these CDC documents:\n- Infection Prevention and Control Recommendations for Hospitalized Patients with Known or Suspected Ebola Virus Disease in U.S. Hospitals () - Interim Guidance for Environmental Infection Control in Hospitals for Ebola Virus () See CDC's Ebola Virus Disease website () for current information on how Ebola virus is transmitted.\nAirborne transmission may play a role in the natural spread of hantaviruses and certain hemorrhagic fever viruses (e.g., Ebola, Marburg, and Lassa), but evidence for airborne spread of these agents in health-care facilities is inconclusive. 190 Although hantaviruses can be transmitted when aerosolized from rodent excreta, 191,192 person-to-person spread of hantavirus infection from source patients has not occurred in healthcare facilities. Nevertheless, health-care workers are advised to contain potentially infectious aerosols and wear National Institute of Occupational Safety and Health (NIOSH) approved respiratory protection when working with this agent in laboratories or autopsy suites. 196 Lassa virus transmission via aerosols has been demonstrated in the laboratory and incriminated in health-care associated infections in Africa, but airborne spread of this agent in hospitals in developed nations likely is inefficient. 200,201 Yellow fever is considered to be a viral hemorrhagic fever agent with high aerosol infectivity potential, but health-care associated transmission of this virus has not been described. 202 Viral hemorrhagic fever diseases primarily occur after direct exposure to infected blood and body fluids, and the use of standard and droplet precautions prevents transmission early in the course of these illnesses. 203,204 However, whether these viruses can persist in droplet nuclei that might remain after droplet production from coughs or vomiting in the latter stages of illness is unknown. 205 Although the use of a negative-pressure room is not required during the early stages of illness, its use might be prudent at the time of hospitalization to avoid the need for subsequent patient transfer. Current CDC guidelines recommend negative-pressure rooms with anterooms for patients with hemorrhagic fever and use of HEPA respirators by persons entering these rooms when the patient has prominent cough, vomiting, diarrhea, or hemorrhage. 6,203 Face shields or goggles will help to prevent mucous-membrane exposure to potentially-aerosolized infectious material in these situations. If an anteroom is not available, portable, industrial-grade high efficiency particulate air (HEPA) filter units can be used to provide the equivalent of additional air changes per hour (ACH).\n\n# Mycobacterium tuberculosis+\nMeasles (rubeola) virus Varicella-zoster virus Occasional reports in health-care facilities (atypical) Acremonium spp. 105,206 Fusarium spp. 102 Pseudoallescheria boydii 100 Scedosporium spp. 116 Sporothrix cyanescens ¶ 118 Acinetobacter spp. 161 Bacillus spp. ¶ 160,207 Brucella spp. Staphylococcus aureus 148,156 Group A Streptococcus 151 Smallpox virus (variola) § 188,189 Influenza viruses 181,182 Respiratory syncytial virus 183 Adenoviruses 184 Norwalk-like virus 185 No reports in health-care facilities; known to be airborne outside.\nCoccidioides immitis 125 Cryptococcus spp. 121 Histoplasma capsulatum 124 Coxiella burnetii (Q fever) 212 Hantaviruses 193,195 Lassa virus 205 Marburg virus 205 Ebola virus † 205 Crimean-Congo virus 205 Under investigation Pneumocystis carinii 131 n/a n/a - This list excludes microorganisms transmitted from aerosols derived from water.\n\n# Heating, Ventilation, and Air Conditioning Systems in Health-Care Facilities\n\n# a. Basic Components and Operations\nHeating, ventilation, and air conditioning (HVAC) systems in health-care facilities are designed to maintain the indoor air temperature and humidity at comfortable levels for staff, patients, and visitors control odors; remove contaminated air; facilitate air-handling requirements to protect susceptible staff and patients from airborne health-care associated pathogens; and minimize the risk for transmission of airborne pathogens from infected patients. 35,120 An HVAC system includes an outside air inlet or intake; filters; humidity modification mechanisms (i.e., humidity control in summer, humidification in winter); heating and cooling equipment; fans; ductwork; air exhaust or out-takes; and registers, diffusers, or grilles for proper distribution of the air (Figure 1). 213,214 Decreased performance of healthcare facility HVAC systems, filter inefficiencies, improper installation, and poor maintenance can contribute to the spread of health-care associated airborne infections.\nThe American Institute of Architects (AIA) has published guidelines for the design and construction of new health-care facilities and for renovation of existing facilities. These AIA guidelines address indoor air-quality standards (e.g., ventilation rates, temperature levels, humidity levels, pressure relationships, and minimum air changes per hour ) specific to each zone or area in health-care facilities (e.g., operating rooms, laboratories, diagnostic areas, patient-care areas, and support departments). 120 ). More than 40 state agencies that license health-care facilities have either incorporated or adopted by reference these guidelines into their state standards. JCAHO, through its surveys, ensures that facilities are in compliance with the ventilation guidelines of this standard for new construction and renovation.\n\n# Figure 1. Diagram of a ventilation system*\nOutdoor air and recirculated air pass through air cleaners (e.g., filter banks) designed to reduce the concentration of airborne contaminants. Air is conditioned for temperature and humidity before it enters the occupied space as supply air. Infiltration is air leakage inward through cracks and interstitial spaces of walls, floors, and ceilings. Exfiltration is air leakage outward through these same cracks and spaces. Return air is largely exhausted from the system, but a portion is recirculated with fresh, incoming air.\n- Used with permission of the publisher of reference 214 (ASHRAE)\nEngineering controls to contain or prevent the spread of airborne contaminants center on local exhaust ventilation , general ventilation, and air cleaning. 4 General ventilation encompasses dilution and removal of contaminants via well-mixed air distribution of filtered air, directing contaminants toward exhaust registers and grilles via uniform, non-mixed airflow patterns, pressurization of individual spaces relative to all other spaces, and pressurization of buildings relative to the outdoors and other attached buildings.\nA centralized HVAC system operates as follows. Outdoor air enters the system, where low-efficiency or \"roughing\" filters remove large particulate matter and many microorganisms. The air enters the distribution system for conditioning to appropriate temperature and humidity levels, passes through an additional bank of filters for further cleaning, and is delivered to each zone of the building. After the conditioned air is distributed to the designated space, it is withdrawn through a return duct system and delivered back to the HVAC unit. A portion of this \"return air\" is exhausted to the outside while the remainder is mixed with outdoor air for dilution and filtered for removal of contaminants. 215 Air from toilet rooms or other soiled areas is usually exhausted directly to the atmosphere through a separate duct exhaust system. Air from rooms housing tuberculosis patients is exhausted to the outside if possible, or passed through a HEPA filter before recirculation. Ultraviolet germicidal irradiation (UVGI) can be used as an adjunct air-cleaning measure, but it cannot replace HEPA filtration. 15 b. Filtration i. Filter Types and Methods of Filtration Filtration, the physical removal of particulates from air, is the first step in achieving acceptable indoor air quality. Filtration is the primary means of cleaning the air. Five methods of filtration can be used (Table 5). During filtration, outdoor air passes through two filter beds or banks (with efficiencies of 20%-40% and ≥90%, respectively) for effective removal of particles 1-5 μm in diameter. 35,120 The low-to-medium efficiency filters in the first bank have low resistance to airflow, but this feature allows some small particulates to pass onto heating and air conditioning coils and into the indoor environment. 35 Incoming air is mixed with recirculated air and reconditioned for temperature and humidity before being filtered by the second bank of filters. The performance of filters with ≤90% efficiency is measured using either the dust-spot test or the weight-arrestance test. 35,216 The second filter bank usually consists of high-efficiency filters. This filtration system is adequate for most patient-care areas in ambulatory-care facilities and hospitals, including the operating room environment and areas providing central services. 120 Nursing facilities use 90% dust-spot efficient filters as the second bank of filters, 120 whereas a HEPA filter bank may be indicated for special-care areas of hospitals. HEPA filters are at least 99.97% efficient for removing particles ≥0.3 μm in diameter. (As a reference, Aspergillus spores are 2.5-3.0 μm in diameter.) Examples of care areas where HEPA filters are used include PE rooms and those operating rooms designated for orthopedic implant procedures. 35 Maintenance costs associated with HEPA filters are high compared with other types of filters, but use of in-line disposable prefilters can increase the life of a HEPA filter by approximately 25%. Alternatively, if a disposable prefilter is followed by a filter that is 90% efficient, the life of the HEPA filter can be extended ninefold. This concept, called progressive filtration, allows HEPA filters in special care areas to be used for 10 years. 213 Although progressive filtering will extend the mechanical ability of the HEPA filter, these filters may absorb chemicals in the environment and later desorb those chemicals, thereby necessitating a more frequent replacement program. HEPA filter efficiency is monitored with the dioctylphthalate (DOP) particle test using particles that are 0.3 μm in diameter. 218 HEPA filters are usually framed with metal, although some older versions have wood frames. A metal frame has no advantage over a properly fitted wood frame with respect to performance, but wood can compromise the air quality if it becomes and remains wet, allowing the growth of fungi and bacteria. Hospitals are therefore advised to phase out water-damaged or spent wood-framed filter units and replace them with metal-framed HEPA filters.\nHEPA filters are usually fixed into the HVAC system; however, portable, industrial grade HEPA units are available that can filter air at the rate of 300-800 ft 3 /min. Portable HEPA filters are used to a. temporarily recirculate air in rooms with no general ventilation, b. augment systems that cannot provide adequate airflow, and c. provide increased effectiveness in airflow. 4 Portable HEPA units are useful engineering controls that help clean the air when the central HVAC system is undergoing repairs 219 but these units do not satisfy fresh-air requirements. 214 The effectiveness of the portable unit for particle removal is dependent on a. the configuration of the room, b. the furniture and persons in the room, c. the placement of the units relative to the contents and layout of the room, and d. the location of the supply and exhaust registers or grilles.\nIf portable, industrial-grade units are used, they should be capable of recirculating all or nearly all of the room air through the HEPA filter, and the unit should be designed to achieve the equivalent of ≥12 ACH. 4 (An average room has approximately 1,600 ft 3 of airspace.) The hospital engineering department should be contacted to provide ACH information in the event that a portable HEPA filter unit is necessary to augment the existing fixed HVAC system for air cleaning.\nii. Filter Maintenance Efficiency of the filtration system is dependent on the density of the filters, which can create a drop in pressure unless compensated by stronger and more efficient fans, thus maintaining air flow. For optimal performance, filters require monitoring and replacement in accordance with the manufacturer's recommendations and standard preventive maintenance practices. 220 Upon removal, spent filters can be bagged and discarded with the routine solid waste, regardless of their patient-care area location. 221 Excess accumulation of dust and particulates increases filter efficiency, requiring more pressure to push the air through. The pressure differential across filters is measured by use of manometers or other gauges. A pressure reading that exceeds specifications indicates the need to change the filter. Filters also require regular inspection for other potential causes of decreased performance. Gaps in and around filter banks and heavy soil and debris upstream of poorly maintained filters have been implicated in health-care associated outbreaks of aspergillosis, especially when accompanied by construction activities at the facility. 17,18,106,222\n\n# c. Ultraviolet Germicidal Irradiation (UVGI)\nAs a supplemental air-cleaning measure, UVGI is effective in reducing the transmission of airborne bacterial and viral infections in hospitals, military housing, and classrooms, but it has only a minimal inactivating effect on fungal spores. UVGI is also used in air handling units to prevent or limit the growth of vegetative bacteria and fungi. Most commercially available UV lamps used for germicidal purposes are low-pressure mercury vapor lamps that emit radiant energy predominantly at a wave-length of 253.7 nm. 229,230 Two systems of UVGI have been used in health-care settings -duct irradiation and upper-room air irradiation. In duct irradiation systems, UV lamps are placed inside ducts that remove air from rooms to disinfect the air before it is recirculated. When properly designed, installed, and maintained, high levels of UVGI can be attained in the ducts with little or no exposure of persons in the rooms. 231,232 In upper-room air irradiation, UV lamps are either suspended from the ceiling or mounted on the wall. 4 Upper air UVGI units have two basic designs: a. a \"pan\" fixture with UVGI unshielded above the unit to direct the irradiation upward and b. a fixture with a series of parallel plates to columnize the irradiation outward while preventing the light from getting to the eyes of the room's occupants.\nThe germicidal effect is dependent on air mixing via convection between the room's irradiated upper zone and the lower patient-care zones. 233,234 Bacterial inactivation studies using BCG mycobacteria and Serratia marcescens have estimated the effect of UVGI as equivalent to 10 ACH-39 ACH. 235,236 Another study, however, suggests that UVGI may result in fewer equivalent ACH in the patient-care zone, especially if the mixing of air between zones is insufficient. 234 The use of fans or HVAC systems to generate air movement may increase the effectiveness of UVGI if airborne microorganisms are exposed to the light energy for a sufficient length of time. 233,235, The optimal relationship between ventilation and UVGI is not known.\nBecause the clinical effectiveness of UV systems may vary, UVGI is not recommended for air management prior to air recirculation from airborne isolation rooms. It is also not recommended as a substitute for HEPA filtration, local exhaust of air to the outside, or negative pressure. 4 The use of UV lamps and HEPA filtration in a single unit offers only minimal infection-control benefits over those provided by the use of a HEPA filter alone. 240 Duct systems with UVGI are not recommended as a substitute for HEPA filters if the air from isolation rooms must be recirculated to other areas of the facility. 4 Regular maintenance of UVGI systems is crucial and usually consists of keeping the bulbs free of dust and replacing old bulbs as necessary. Safety issues associated with the use of UVGI systems are described in other guidelines. 4\n\n# d. Conditioned Air in Occupied Spaces\nTemperature and humidity are two essential components of conditioned air. After outside air passes through a low-or medium-efficiency filter, the air undergoes conditioning for temperature and humidity control before it passes through high-efficiency or HEPA filtration.\ni. Temperature HVAC systems in health-care facilities are often single-duct or dual-duct systems. 35,241 A single-duct system distributes cooled air (55°F ) throughout the building and uses thermostatically controlled reheat boxes located in the terminal ductwork to warm the air for individual or multiple rooms. The dual-duct system consists of parallel ducts, one with a cold air stream and the other with a hot air stream. A mixing box in each room or group of rooms mixes the two air streams to achieve the desired temperature. Temperature standards are given as either a single temperature or a range, depending on the specific health-care zone. Cool temperature standards (68°F-73°F ) usually are associated with operating rooms, clean workrooms, and endoscopy suites. 120 A warmer temperature (75°F ) is needed in areas requiring greater degrees of patient comfort. Most other zones use a temperature range of 70°F-75°F (21°C-24°C). 120 Temperatures outside of these ranges may be needed occasionally in limited areas depending on individual circumstances during patient care (e.g., cooler temperatures in operating rooms during specialized operations).\nii. Humidity Four measures of humidity are used to quantify different physical properties of the mixture of water vapor and air. The most common of these is relative humidity, which is the ratio of the amount of water vapor in the air to the amount of water vapor air can hold at that temperature. 242 The other measures of humidity are specific humidity, dew point, and vapor pressure. 242 Relative humidity measures the percentage of saturation. At 100% relative humidity, the air is saturated. For most areas within health-care facilities, the designated comfort range is 30%-60% relative humidity. 120,214 Relative humidity levels >60%, in addition to being perceived as uncomfortable, promote fungal growth. 243 Humidity levels can be manipulated by either of two mechanisms. 244 In a water-wash unit, water is sprayed and drops are taken up by the filtered air; additional heating or cooling of this air sets the humidity levels. The second mechanism is by means of water vapor created from steam and added to filtered air in humidifying boxes. Reservoir-type humidifiers are not allowed in health-care facilities as per AIA guidelines and many state codes. 120 Cool-mist humidifiers should be avoided, because they can disseminate aerosols containing allergens and microorganisms. 245 Additionally, the small, personal-use versions of this equipment can be difficult to clean.\n\n# iii. Ventilation\nThe control of air pollutants (e.g., microorganisms, dust, chemicals, and smoke) at the source is the most effective way to maintain clean air. The second most effective means of controlling indoor air pollution is through ventilation. Ventilation rates are voluntary unless a state or local government specifies a standard in health-care licensing or health department requirements. These standards typically apply to only the design of a facility, rather than its operation. 220,246 Health-care facilities without specific ventilation standards should follow the AIA guideline specific to the year in which the building was 120, 214, 241 built or the ANSI/ASHRAE Standard 62, Ventilation for Acceptable Indoor Air Quality.\nVentilation guidelines are defined in terms of air volume per minute per occupant and are based on the assumption that occupants and their activities are responsible for most of the contaminants in the conditioned space. 215 Most ventilation rates for health-care facilities are expressed as room ACH. Peak efficiency for particle removal in the air space occurs between 12 ACH-15 ACH. 35,247,248 Ventilation rates vary among the different patient-care areas of a health-care facility (Appendix B). 120 Health-care facilities generally use recirculated air. 35,120,241,249,250 Fans create sufficient positive pressure to force air through the building duct work and adequate negative pressure to evacuate air from the conditioned space into the return duct work and/or exhaust, thereby completing the circuit in a sealed system (Figure 1). However, because gaseous contaminants tend to accumulate as the air recirculates, a percentage of the recirculated air is exhausted to the outside and replaced by fresh outdoor air. In hospitals, the delivery of filtered air to an occupied space is an engineered system design issue, the full discussion of which is beyond the scope of this document.\nHospitals with areas not served by central HVAC systems often use through-the-wall or fan coil air conditioning units as the sole source of room ventilation. AIA guidelines for newly installed systems stipulate that through-the-wall fan-coil units be equipped with permanent (i.e., cleanable) or replaceable filters with a minimum efficiency of 68% weight arrestance. 120 These units may be used only as recirculating units; all outdoor air requirements must be met by a separate central air handling system with proper filtration, with a minimum of two outside air changes in general patient rooms (D. Erickson, ASHE, 2000). 120 If a patient room is equipped with an individual through-the-wall fan coil unit, the room should not be used as either AII or as PE. 120 These requirements, although directed to new HVAC installations also are appropriate for existing settings. Non-central air-handling systems are prone to problems associated with excess condensation accumulating in drip pans and improper filter maintenance; health-care facilities should clean or replace the filters in these units on a regular basis while the patient is out of the room.\nLaminar airflow ventilation systems are designed to move air in a single pass, usually through a bank of HEPA filters either along a wall or in the ceiling, in a one-way direction through a clean zone with parallel streamlines. Laminar airflow can be directed vertically or horizontally; the unidirectional system optimizes airflow and minimizes air turbulence. 63,241 Delivery of air at a rate of 0.5 meters per second (90 ± 20 ft/min) helps to minimize opportunities for microorganism proliferation. 63,251,252 Laminar airflow systems have been used in PE to help reduce the risk for health-care associated airborne infections (e.g., aspergillosis) in high-risk patients. 63,93,253,254 However, data that demonstrate a survival benefit for patients in PE with laminar airflow are lacking. Given the high cost of installation and apparent lack of benefit, the value of laminar airflow in this setting is questionable. 9,37 Few data support the use of laminar airflow systems elsewhere in a hospital. 255 iv. Pressurization Positive and negative pressures refer to a pressure differential between two adjacent air spaces (e.g., rooms and hallways). Air flows away from areas or rooms with positive pressure (pressurized), while air flows into areas with negative pressure (depressurized). AII rooms are set at negative pressure to prevent airborne microorganisms in the room from entering hallways and corridors. PE rooms housing severely neutropenic patients are set at positive pressure to keep airborne pathogens in adjacent spaces or corridors from coming into and contaminating the airspace occupied by such high-risk patients. Selfclosing doors are mandatory for both of these areas to help maintain the correct pressure differential. 4,6,120 Older health-care facilities may have variable pressure rooms (i.e., rooms in which the ventilation can be manually switched between positive and negative pressure). These rooms are no longer permitted in the construction of new facilities or in renovated areas of the facility, 120 and their use in existing facilities has been discouraged because of difficulties in assuring the proper pressure differential, especially for the negative pressure setting, and because of the potential for error associated with switching the pressure differentials for the room. Continued use of existing variable pressure rooms depends on a partnership between engineering and infection control. Both positive-and negativepressure rooms should be maintained according to specific engineering specifications (Table 6). Health-care professionals (e.g., infection control, hospital epidemiologists) must perform a risk assessment to determine the appropriate number of AII rooms (negative pressure) and/or PE rooms (positive pressure) to serve the patient population. The AIA guidelines require a certain number of AII rooms as a minimum, and it is important to refer to the edition under which the building was built for appropriate guidance. 120 In large health-care facilities with central HVAC systems, sealed windows help to ensure the efficient operation of the system, especially with respect to creating and maintaining pressure differentials. Sealing the windows in PE areas helps minimize the risk of airborne contamination from the outside. One outbreak of aspergillosis among immunosuppressed patients in a hospital was attributed in part to an open window in the unit during a time when both construction and a fire happened nearby; sealing the window prevented further entry of fungal spores into the unit from the outside air. 111 Additionally, all emergency exits (e.g., fire escapes and emergency doors) in PE wards should be kept closed (except during emergencies) and equipped with alarms.\n\n# e. Infection Control Impact of HVAC System Maintenance and Repair\nA failure or malfunction of any component of the HVAC system may subject patients and staff to discomfort and exposure to airborne contaminants. Only limited information is available from formal studies on the infection-control implications of a complete air-handling system failure or shutdown for maintenance. Most experience has been derived from infectious disease outbreaks and adverse outcomes among high-risk patients when HVAC systems are poorly maintained. (See Table 7 for potential ventilation hazards, consequences, and correction measures.)\nAIA guidelines prohibit U.S. hospitals and surgical centers from shutting down their HVAC systems for purposes other than required maintenance, filter changes, and construction. 120 Airflow can be reduced; however, sufficient supply, return, and exhaust must be provided to maintain required pressure relationships when the space is not occupied. Maintaining these relationships can be accomplished with special drives on the air-handling units (i.e., a variable air ventilation system).\nMicroorganisms proliferate in environments wherever air, dust, and water are present, and air-handling systems can be ideal environments for microbial growth. 35 Properly engineered HVAC systems require routine maintenance and monitoring to provide acceptable indoor air quality efficiently and to minimize conditions that favor the proliferation of health-care associated pathogens. 35,249 Performance monitoring of the system includes determining pressure differentials across filters, regular inspection of system filters, DOP testing of HEPA filters, testing of low-or medium efficiency filters, and manometer tests for positive-and negative-pressure areas in accordance with nationally recognized standards, guidelines, and manufacturers' recommendations. The use of hand-held, calibrated equipment that can provide a numerical reading on a daily basis is preferred for engineering purposes (A.Streifel, University of Minnesota, 2000). 256 Several methods that provide a visual, qualitative measure of pressure differentials (i.e., airflow direction) include smoke-tube tests or placing flutter strips, ping-pong balls, or tissue in the air stream.\nPreventive filter and duct maintenance (e.g., cleaning ductwork vents, replacing filters as needed, and properly disposing spent filters into plastic bags immediately upon removal) is important to prevent potential exposures of patients and staff during HVAC system shut-down. The frequency of filter inspection and the parameters of this inspection are established by each facility to meet their unique needs. Ductwork in older health-care facilities may have insulation on the interior surfaces that can trap contaminants. This insulation material tends to break down over time to be discharged from the HVAC system. Additionally, a malfunction of the air-intake system can overburden the filtering system and permit aerosolization of fungal pathogens. Keeping the intakes free from bird droppings, especially those from pigeons, helps to minimize the concentration of fungal spores entering from the outside. 98 Accumulation of dust and moisture within HVAC systems increases the risk for spread of health-careassociated environmental fungi and bacteria. Clusters of infections caused by Aspergillus spp., P. aeruginosa, S. aureus, and Acinetobacter spp. have been linked to poorly maintained and/or malfunctioning air conditioning systems. 68,161,257,258 Efforts to limit excess humidity and moisture in the infrastructure and on air-stream surfaces in the HVAC system can minimize the proliferation and dispersion of fungal spores and waterborne bacteria throughout indoor air. Within the HVAC system, water is present in water-wash units, humidifying boxes, or cooling units. The dual-duct system may also create conditions of high humidity and excess moisture that favor fungal growth in drain pans as well as in fibrous insulation material that becomes damp as a result of the humid air passing over the hot stream and condensing.\nIf moisture is present in the HVAC system, periods of stagnation should be avoided. Bursts of organisms can be released upon system start-up, increasing the risk of airborne infection. 206 Proper engineering of the HVAC system is critical to preventing dispersal of airborne organisms. In one hospital, endophthalmitis caused by Acremonium kiliense infection following cataract extraction in an ambulatory surgical center was traced to aerosols derived from the humidifier water in the ventilation system. 206 The organism proliferated because the ventilation system was turned off routinely when the center was not in operation; the air was filtered before humidification, but not afterwards.\nMost health-care facilities have contingency plans in case of disruption of HVAC services. These plans include back-up power generators that maintain the ventilation system in high-risk areas (e.g., operating rooms, intensive-care units, negative-and positive-pressure rooms, transplantation units, and oncology units). Alternative generators are required to engage within 10 seconds of a loss of main power. If the ventilation system is out of service, rendering indoor air stagnant, sufficient time must be allowed to clean the air and re-establish the appropriate number of ACH once the HVAC system begins to function again.\nAir filters may also need to be changed, because reactivation of the system can dislodge substantial amounts of dust and create a transient burst of fungal spores.\nDuct cleaning in health-care facilities has benefits in terms of system performance, but its usefulness for infection control has not been conclusively determined. Duct cleaning typically involves using specialized tools to dislodge dirt and a high-powered vacuum cleaner to clean out debris. 263 Some duct-cleaning services also apply chemical biocides or sealants to the inside surfaces of ducts to minimize fungal growth and prevent the release of particulate matter. The U.S. Environmental Protection Agency (EPA), however, has concerns with the use of sanitizers and/or disinfectants to treat the surfaces of ductwork, because the label indications for most of these products may not specifically include the use of the product in HVAC systems. 264 Further, EPA has not evaluated the potency of disinfectants in such applications, nor has the agency examined the potential attendant health and safety risks. The EPA recommends that companies use only those chemical biocides that are registered for use in HVAC systems. 264 Although infrequent cleaning of the exhaust ducts in AII areas has been documented as a cause of diminishing negative pressure and a decrease in the air exchange rates, 214 no data indicate that duct cleaning, beyond what is recommended for optimal performance, improves indoor air quality or reduces the risk of infection. Exhaust return systems should be cleaned as part of routine system maintenance. Duct cleaning has not been shown to prevent any health problems, 265 and EPA studies indicate that airborne particulate levels do not increase as a result of dirty air ducts, nor do they diminish after cleaning, presumably because much of the dirt inside air ducts adheres to duct surfaces and does not enter the conditioned space. 265 Additional research is needed to determine if air-duct contamination can significantly increase the airborne infection risk in general areas of health-care facilities.\n\n# Construction, Renovation, Remediation, Repair, and Demolition\n\n# a. General Information\nEnvironmental disturbances caused by construction and/or renovation and repair activities (e.g., disruption of the above-ceiling area, running cables through the ceiling, and structural repairs) in and near health-care facilities markedly increase the airborne Aspergillus spp. spore counts in the indoor air of such facilities, thereby increasing the risk for health-care associated aspergillosis among high-risk patients.\nAlthough one case of health-care associated aspergillosis is often difficult to link to a specific environmental exposure, the occurrence of temporarily clustered cases increase the likelihood that an environmental source within the facility may be identified and corrected. Construction, renovation, repair, and demolition activities in health-care facilities require substantial planning and coordination to minimize the risk for airborne infection both during projects and after their completion. Several organizations and experts have endorsed a multi-disciplinary team approach (Box 4) to coordinate the various stages of construction activities (e.g., project inception, project implementation, final walk-through, and completion). 120,249,250, Environmental services, employee health, engineering, and infection control must be represented in construction planning and design meetings should be convened with architects and design engineers. The number of members and disciplines represented is a function of the complexity of a project. Smaller, less complex projects and maintenance may require a minimal number of members beyond the core representation from engineering, infection control, environmental services, and the directors of the specialized departments.\n\n# Box 4. Suggested members and functions of a multi-disciplinary coordination team for construction, renovation, repair, and demolition projects\n\n# Members\n- Infection-control personnel, including hospital epidemiologists - Laboratory personnel - Facility administrators or their designated representatives, facility managers - Director of engineering - Risk-management personnel - Directors of specialized programs (e.g., transplantation, oncology and ICU programs) - Employee safety personnel, industrial hygienists, and regulatory affairs personnel - Environmental services personnel Information systems personnel - Construction administrators or their designated representatives - Architects, design engineers, project managers, and contractors\n\n# Functions and responsibilities\nCoordinate members' input in developing a comprehensive project management plan.\nConduct a risk assessment of the project to determine potential hazards to susceptible patients.\nPrevent unnecessary exposures of patients, visitors, and staff to infectious agents.\nOversee all infection-control aspects of construction activities.\nEstablish site-specific infection-control protocols for specialized areas.\nProvide education about the infection-control impact of construction to staff and construction workers.\nEnsure compliance with technical standards, contract provisions, and regulations.\nEstablish a mechanism to address and correct problems quickly.\nDevelop contingency plans for emergency response to power failures, water supply disruptions, and fires.\nProvide a water-damage management plan (including drying protocols) for handling water intrusion from floods, leaks, and condensation.\nDevelop a plan for structural maintenance.\nEducation of maintenance and construction workers, health-care staff caring for high-risk patients, and persons responsible for controlling indoor air quality heightens awareness that minimizing dust and moisture intrusion from construction sites into high-risk patient-care areas helps to maintain a safe environment. 120,250,271, Visual and printed educational materials should be provided in the language spoken by the workers. Staff and construction workers also need to be aware of the potentially catastrophic consequences of dust and moisture intrusion when an HVAC system or water system fails during construction or repair; action plans to deal quickly with these emergencies should be developed in advance and kept on file. Incorporation of specific standards into construction contracts may help to prevent departures from recommended practices as projects progress. Establishing specific lines of communication is important to address problems (e.g., dust control, indoor air quality, noise levels, and vibrations), resolve complaints, and keep projects moving toward completion. Health-care facility staff should develop a mechanism to monitor worker adherence to infection-control guidelines on a daily basis in and around the construction site for the duration of the project.\n\n# b. Preliminary Considerations\nThe three major topics to consider before initiating any construction or repair activity are as follows: a. design and function of the new structure or area, b. assessment of environmental risks for airborne disease and opportunities for prevention, and c. measures to contain dust and moisture during construction or repairs.\nA checklist of design and function considerations can help to ensure that a planned structure or area can be easily serviced and maintained for environmental infection control (Box 5) . 17,250,273, Specifications for the construction, renovation, remodeling, and maintenance of health-care facilities are outlined in the AIA document, Guidelines for Design and Construction of Hospitals and Health Care Facilities. 120,275 Box 5. Construction design and function considerations for environmental infection control Proactive strategies can help prevent environmentally mediated airborne infections in health-care facilities during demolition, construction, and renovation. The potential presence of dust and moisture and their contribution to health-care associated infections must be critically evaluated early in the planning of any demolition, construction, renovation, and repairs. 120,250,251,273,274, Consideration must extend beyond dust generated by major projects to include dust that can become airborne if disturbed during routine maintenance and minor renovation activities (e.g., exposure of ceiling spaces for inspection; installation of conduits, cable, or sprinkler systems; rewiring; and structural repairs or replacement). 273,276,277 Other projects that can compromise indoor air quality include construction and repair jobs that inadvertently allow substantial amounts of raw, unfiltered outdoor air to enter the facility (e.g., repair of elevators and elevator shafts) and activities that dampen any structure, area, or item made of porous materials or characterized by cracks and crevices (e.g., sink cabinets in need of repair, carpets, ceilings, floors, walls, vinyl wall coverings, upholstery, drapes, and countertops). 18,273,277 Molds grow and proliferate on these surfaces when they become and remain wet. 21,120,250,266,270,272,280 Scrubbable materials are preferred for use in patient-care areas.\nContainment measures for dust and/or moisture control are dictated by the location of the construction site. Outdoor demolition and construction require actions to keep dust and moisture out of the facility (e.g., sealing windows and vents and keeping doors closed or sealed). Containment of dust and moisture generated from construction inside a facility requires barrier structures (either pre-fabricated or constructed of more durable materials as needed) and engineering controls to clean the air in and around the construction or repair site.\n\n# c. Infection-Control Risk Assessment\nAn infection-control risk assessment (ICRA) conducted before initiating repairs, demolition, construction, or renovation activities can identify potential exposures of susceptible patients to dust and moisture and determine the need for dust and moisture containment measures. This assessment centers on the type and extent of the construction or repairs in the work area but may also need to include adjacent patient-care areas, supply storage, and areas on levels above and below the proposed project. An example of designing an ICRA as a matrix, the policy for performing an ICRA and implementing its results, and a sample permit form that streamlines the communication process are available. 281 Knowledge of the air flow patterns and pressure differentials helps minimize or eliminate the inadvertent dispersion of dust that could contaminate air space, patient-care items, and surfaces. 57,282,283 A recent aspergillosis outbreak among oncology patients was attributed to depressurization of the building housing the HSCT unit while construction was underway in an adjacent building. Pressure readings in the affected building (including 12 of 25 HSCT-patient rooms) ranged from 0.1 Pa-5.8 Pa. Unfiltered outdoor air flowed into the building through doors and windows, exposing patients in the HSCT unit to fungal spores. 283 During long-term projects, providing temporary essential services (e.g., toilet facilities) and conveniences (e.g., vending machines) to construction workers within the site will help to minimize traffic in and out of the area. The type of barrier systems necessary for the scope of the project must be defined. 12,120,250,279,284 Depending on the location and extent of the construction, patients may need to be relocated to other areas in the facility not affected by construction dust. 51,285 Such relocation might be especially prudent when construction takes place within units housing immunocompromised patients (e.g., severely neutropenic patients and patients on corticosteroid therapy). Advance assessment of high-risk locations and planning for the possible transport of patients to other departments can minimize delays and waiting time in hallways. 51 Although hospitals have provided immunocompromised patients with some form of respiratory protection for use outside their rooms, the issue is complex and remains unresolved until more research can be done. Previous guidance on this issue has been inconsistent. 9 Protective respirators (i.e., N95) were well tolerated by patients when used to prevent further cases of construction-related aspergillosis in a recent outbreak. 283 The routine use of the N95 respirator by patients, however, has not been evaluated for preventing exposure to fungal spores during periods of non-construction. Although health-care workers who would be using the N95 respirator for personal respiratory protect must be fittested, there is no indication that either patients or visitors should undergo fit-testing.\nSurveillance activities should augment preventive strategies during construction projects. 3,4,20,110,286,287 By determining baseline levels of health-care acquired airborne and waterborne infections, infectioncontrol staff can monitor changes in infection rates and patterns during and immediately after construction, renovations, or repairs. 3\n\n# d. Air Sampling\nAir sampling in health-care facilities may be conducted both during periods of construction and on a periodic basis to determine indoor air quality, efficacy of dust-control measures, or air-handling system performance via parametric monitoring. Parametric monitoring consists of measuring the physical periodic assessment of the system (e.g., air flow direction and pressure, ACH, and filter efficiency) can give assurance of proper ventilation, especially for special care areas and operating rooms. 288 Air sampling is used to detect aerosols (i.e., particles or microorganisms). Particulate sampling (i.e., total numbers and size range of particulates) is a practical method for evaluating the infection-control performance of the HVAC system, with an emphasis on filter efficiency in removing respirable particles (<5 μm in diameter) or larger particles from the air. Particle size is reported in terms of the mass median aerodynamic diameter (MMAD), whereas count median aerodynamic diameter (CMAD) is useful with respect to particle concentrations.\nParticle counts in a given air space within the health-care facility should be evaluated against counts obtained in a comparison area. Particle counts indoors are commonly compared with the particulate levels of the outdoor air. This approach determines the \"rank order\" air quality from \"dirty\" (i.e., the outdoor air) to \"clean\" (i.e., air filtered through high-efficiency filters ) to \"cleanest\" (i.e., HEPA-filtered air). 288 Comparisons from one indoor area to another may also provide useful information about the magnitude of an indoor air-quality problem. Making rank-order comparisons between clean, highly-filtered areas and dirty areas and/or outdoors is one way to interpret sampling results in the absence of air quality and action level standards. 35,289 In addition to verifying filter performance, particle counts can help determine if barriers and efforts to control dust dispersion from construction are effective. This type of monitoring is helpful when performed at various times and barrier perimeter locations during the project. Gaps or breaks in the barriers' joints or seals can then be identified and repaired. The American Conference of Governmental Industrial Hygienists (ACGIH) has set a threshold limit value-time weighted average (TLV®-TWA) of 10 mg/m 3 for nuisance dust that contains no asbestos and <1% crystalline silica. 290 Alternatively, OSHA has set permissible exposure limits (PELs) for inert or nuisance dust as follows: respirable fraction at 5 mg/m 3 and total dust at 15 mg/m 3 . 291 Although these standards are not measures of a bioaerosol, they are used for indoor air quality assessment in occupational settings and may be useful criteria in construction areas. Application of ACGIH guidance to health-care settings has not been standardized, but particulate counts in health-care facilities are likely to be well below this threshold value and approaching cleanroom standards in certain care areas (e.g., operating rooms). 100 Particle counters and anemometers are used in particulate evaluation. The anemometer measures air flow velocity, which can be used to determine sample volumes. Particulate sampling usually does not require microbiology laboratory services for the reporting of results.\nMicrobiologic sampling of air in health-care facilities remains controversial because of currently unresolved technical limitations and the need for substantial laboratory support (Box 6). Infection-control professionals, laboratorians, and engineers should determine if microbiologic and/or particle sampling is warranted and assess proposed methods for sampling. The most significant technical limitation of air sampling for airborne fungal agents is the lack of standards linking fungal spore levels with infection rates. Despite this limitation, several health-care institutions have opted to use microbiologic sampling when construction projects are anticipated and/or underway in efforts to assess the safety of the environment for immunocompromised patients. 35,289 Microbiologic air sampling should be limited to assays for airborne fungi; of those, the thermotolerant fungi (i.e., those capable of growing at 95°F-98.6°F ) are of particular concern because of their pathogenicity in immunocompromised hosts. 35 Use of selective media (e.g., Sabouraud dextrose agar and inhibitory mold agar) helps with the initial identification of recovered organisms.\nMicrobiologic sampling for fungal spores performed as part of various airborne disease outbreak investigations has also been problematic. 18,49,106,111,112,289 The precise source of a fungus is often difficult to trace with certainty, and sampling conducted after exposure may neither reflect the circumstances that were linked to infection nor distinguish between health-care acquired and community-acquired infections.\nBecause fungal strains may fluctuate rapidly in the environment, health-care acquired Aspergillus spp. infection cannot be confirmed or excluded if the infecting strain is not found in the health-care setting. 287 Sensitive molecular typing methods (e.g., randomly amplified polymorphic DNA (RAPD) techniques and a more recent DNA fingerprinting technique that detects restriction fragment length polymorphisms in fungal genomic DNA) to identify strain differences among Aspergillus spp., however, are becoming increasingly used in epidemiologic investigations of health-care acquired fungal infection (A.Streifel, University of Minnesota, 2000). 68,110,286,287, During case cluster evaluation, microbiologic sampling may provide an isolate from the environment for molecular typing and comparison with patient isolates.\nTherefore, it may be prudent for the clinical laboratory to save Aspergillus spp. isolated from colonizations and invasive disease cases among patients in PE, oncology, and transplant services for these purposes. Sedimentation methods using settle plates and volumetric sampling methods using solid impactors are commonly employed when sampling air for bacteria and fungi. Settle plates have been used by numerous investigators to detect airborne bacteria or to measure air quality during medical procedures (e.g., surgery). 17,60,97,151,161,287 Settle plates, because they rely on gravity during sampling, tend to select for larger particles and lack sensitivity for respirable particles (e.g., individual fungal spores), especially in highly-filtered environments. Therefore, they are considered impractical for general use. 35,289, Settle plates, however, may detect fungi aerosolized during medical procedures (e.g., during wound dressing changes), as described in a recent outbreak of aspergillosis among liver transplant patients. 302 The use of slit or sieve impactor samplers capable of collecting large volumes of air in short periods of time are needed to detect low numbers of fungal spores in highly filtered areas. 35,289 In some outbreaks, aspergillosis cases have occurred when fungal spore concentrations in PE ambient air ranged as low as 0.9-2.2 colony-forming units per cubic meter (CFU/m 3 ) of air. 18,94 On the basis of the expected spore counts in the ambient air and the performance parameters of various types of volumetric air samplers, investigators of a recent aspergillosis outbreak have suggested that an air volume of at least 1000 L (1 m 3 ) should be considered when sampling highly filtered areas. 283 Investigators have also suggested limits of 15 CFU/m 3 for gross colony counts of fungal organisms and <0.1 CFU/m 3 for Aspergillus fumigatus and other potentially opportunistic fungi in heavily filtered areas (≥12 ACH and filtration of ≥99.97% efficiency). 120 No correlation of these values with the incidence of health-care-associated fungal infection rates has been reported.\nAir sampling in health-care facilities, whether used to monitor air quality during construction, to verify filter efficiency, or to commission new space prior to occupancy, requires careful notation of the circumstances of sampling. Most air sampling is performed under undisturbed conditions. However, when the air is sampled during or after human activity (e.g., walking and vacuuming), a higher number of airborne microorganisms likely is detected. 297 The contribution of human activity to the significance of air sampling and its impact on health-care associated infection rates remain to be defined. Comparing microbiologic sampling results from a target area (e.g., an area of construction) to those from an unaffected location in the facility can provide information about distribution and concentration of potential airborne pathogens. A comparison of microbial species densities in outdoor air versus indoor air has been used to help pinpoint fungal spore bursts. Fungal spore densities in outdoor air are variable, although the degree of variation with the seasons appears to be more dramatic in the United States than in Europe. 92,287,303 Particulate and microbiologic air sampling have been used when commissioning new HVAC system installations; however, such sampling is particularly important for newly constructed or renovated PE or operating rooms. Particulate sampling is used as part of a battery of tests to determine if a new HVAC system is performing to specifications for filtration and the proper number of ACH. 268,288,304 Microbiologic air sampling, however, remains controversial in this application, because no standards for comparison purposes have been determined. If performed, sampling should be limited to determining the density of fungal spores per unit volume of air space. High numbers of spores may indicate contamination of air-handling system components prior to installation or a system deficiency when culture results are compared with known filter efficiencies and rates of air exchange.\n\n# e. External Demolition and Construction\nExternal demolition, planned building implosions, and dirt excavation generate considerable dust and debris that can contain airborne microorganisms. In one study, peak concentrations in outdoor air at grade level and HVAC intakes during site excavation averaged 20,000 CFU/m 3 for all fungi and 500 CFU/m 3 for Aspergillus fumigatus, compared with 19 CFU/m 3 and 4 CFU/m 3 , respectively, in the absence of construction. 280 Many health-care institutions are located in large, urban areas; building implosions are becoming a more frequent concern. Infection-control risk assessment teams, particularly those in facilities located in urban renewal areas, would benefit by developing risk management strategies for external demolition and construction as a standing policy. In light of the events of 11 September 2001, it may be necessary for the team to identify those dust exclusion measures that can be implemented rapidly in response to emergency situations (Table 8). Issues to be reviewed prior to demolition include a. proximity of the air intake system to the work site, b. adequacy of window seals and door seals, c. proximity of areas frequented by immunocompromised patients, and d. location of the underground utilities (D. Erickson, ASHE, 2000). 120,250,273,276,277,280,305 Minimizing the entry of outside dust into the HVAC system is crucial in reducing the risk for airborne contaminants. Facility engineers should be consulted about the potential impact of shutting down the system or increasing the filtration. Selected air handlers, especially those located close to excavation sites, may have to be shut off temporarily to keep from overloading the system with dust and debris. Care is needed to avoid significant facility-wide reductions in pressure differentials that may cause the building to become negatively pressured relative to the outside. To prevent excessive particulate overload and subsequent reductions in effectiveness of intake air systems that cannot be shut off temporarily, air filters must be inspected frequently for proper installation and function. Excessive dust penetration can be avoided if recirculated air is maximally utilized while outdoor air intakes are shut down. Scheduling demolition and excavation during the winter, when Aspergillus spp. spores may be present in lower numbers, can help, although seasonal variations in spore density differ around the world. 92,287,303 Dust control can be managed by misting the dirt and debris during heavy dust-generating activities. To decrease the amount of aerosols from excavation and demolition projects, nearby windows, especially in areas housing immunocompromised patients, can be sealed and window and door frames caulked or weatherstripped to prevent dust intrusion. 50,301,306 Monitoring for adherence to these control measures throughout demolition or excavation is crucial. Diverting pedestrian traffic away from the construction sites decreases the amount of dust tracked back into the health-care facility and minimizes exposure of high-risk patients to environmental pathogens. Additionally, closing entrances near construction or demolition sites might be beneficial; if this is not practical, creating an air lock (i.e., pressurizing the entry way) is another option.\n\n# f. Internal Demolition, Construction, Renovations, and Repairs\nThe focus of a properly implemented infection-control program during interior construction and repairs is containment of dust and moisture. This objective is achieved by a. educating construction workers about the importance of control measures b. preparing the site; c. notifying and issuing advisories for staff, patients, and visitors; d. moving staff and patients and relocating patients as needed; e. issuing standards of practice and precautions during activities and maintenance; f. monitoring for adherence to control measures during construction and providing prompt feedback about lapses in control g. monitoring HVAC performance; h. implementing daily clean-up, terminal cleaning and removal of debris upon completion; and i. ensuring the integrity of the water system during and after construction. These activities should be coordinated with engineering staff and infection-control professionals.\nPhysical barriers capable of containing smoke and dust will confine dispersed fungal spores to the construction zone. 279,284,307,308 The specific type of physical barrier required depends on the project's scope and duration and on local fire codes. Short-term projects that result in minimal dust dispersion (e.g., installation of new cables or wiring above ceiling tiles) require only portable plastic enclosures with negative pressure and HEPA filtration of the exhaust air from the enclosed work area. The placement of a portable industrial-grade HEPA filter device capable of filtration rate of 300-800 ft 3 /min. adjacent to the work area will help to remove fungal spores, but its efficacy is dependent on the supplied ACH and size of the area. If the project is extensive but short-term, dust-abatement, fire-resistant plastic curtains (e.g., Visqueen®) may be adequate. These should be completely airtight and sealed from ceiling to floor with overlapping curtains; 276,277,309 holes, tears, or other perforations should be repaired promptly with tape. A portable, industrial-grade HEPA filter unit on continuous operation is needed within the contained area, with the filtered air exhausted to the outside of the work zone. Patients should not remain in the room when dust-generating activities are performed. Tools to assist the decision-making process regarding selection of barriers based on an ICRA approach are available. 281 More elaborate barriers are indicated for long-term projects that generate moderate to large amounts of dust. These barrier structures typically consist of rigid, noncombustible walls constructed from sheet rock, drywall, plywood, or plaster board and covered with sheet plastic (e.g., Visqueen®). Barrier requirements to prevent the intrusion of dust into patient-care areas include a. installing a plastic dust abatement curtain before construction of the rigid barrier b. sealing and taping all joint edges including the top and bottom; c. extending the barrier from floor to floor, which takes into account the space above the finished, lay-down ceiling; and d. fitting or sealing any temporary doors connecting the construction zone to the adjacent area. (See Box 7 for a list of the various construction and repair activities that require the use of some type of barrier.) Dust and moisture abatement and control rely primarily on the impermeable barrier containment approach; as construction continues, numerous opportunities can lead to dispersion of dust to other areas of the health-care facility. Infection-control measures that augment the use of barrier containment should be undertaken (Table 9).\nDust-control measures for clinical laboratories are an essential part of the infection-control strategy during hospital construction or renovation. Use of plastic or solid barriers may be needed if the ICRA determines that air flow from construction areas may introduce airborne contaminants into the laboratory space. In one facility, pseudofungemia clusters attributed to Aspergillus spp. and Penicillium spp. were linked to improper air flow patterns and construction projects adjacent to the laboratory; intrusion of dust and spores into a biological safety cabinet from construction activity immediately next to the cabinet resulted in a cluster of cultures contaminated with Aspergillus niger. 310,311 Reportedly, no barrier containment was used and the HEPA filtration system was overloaded with dust. In addition, an outbreak of pseudobacteremia caused by Bacillus spp. occurred in another hospital during construction above a storage area for blood culture bottles. 207 Airborne spread of Bacillus spp. spores resulted in contamination of the bottles' plastic lids, which were not disinfected or handled with proper aseptic technique prior to collection of blood samples. 1. Monitor the construction area daily for compliance with the infection-control plan. 2. Protective outer clothing for construction workers should be removed before entering clean areas. 3. Use mats with tacky surfaces within the construction zone at the entry; cover sufficient area so that both feet make contact with the mat while walking through the entry. 4. Construct an anteroom as needed where coveralls can be donned and removed. 5. Clean the construction zone and all areas used by construction workers with a wet mop. 6. If the area is carpeted, vacuum daily with a HEPA-filtered-equipped vacuum. 7. Provide temporary essential services (e.g., toilets) and worker conveniences (e.g, vending machines) in the construction zone as appropriate. 8. Damp-wipe tools if removed from the construction zone or left in the area. 9. Ensure that construction barriers remain well sealed; use particle sampling as needed. 10. Ensure that the clinical laboratory is free from dust contamination.\n\n# Infection-control measure\nSteps for implementation Complete the project.\n1. Flush the main water system to clear dust-contaminated lines.\n\n# Environmental Infection-Control Measures for Special Health-Care Settings\nAreas in health-care facilities that require special ventilation include a. operating rooms b. PE rooms used by high-risk, immunocompromised patients; and c. AII rooms for isolation of patients with airborne infections (e.g., those caused by M. tuberculosis, VZV, or measles virus).\nThe number of rooms required for PE and AII are determined by a risk assessment of the health-care facility. 6 Continuous, visual monitoring of air flow direction is required for new or renovated pressurized rooms. 120,256\n\n# a. Protective Environments (PE)\nAlthough the exact configuration and specifications of PEs might differ among hospitals, these care areas for high-risk, immunocompromised patients are designed to minimize fungal spore counts in air by maintaining a. filtration of incoming air by using central or point-of-use HEPA filters b. directed room air flow ; c. positive room air pressure of 2.5 Pa relative to the corridor; d. well-sealed rooms; and e. ≥12 ACH. 44,120,251,254, Air flow rates must be adjusted accordingly to ensure sufficient ACH, and these rates vary depending on certain factors (e.g., room air leakage area). For example, to provide ≥12 ACH in a typical patient room with 0.5 sq. ft. air leakage, the air flow rate will be minimally 125 cubic feet/min (cfm). 320,321 Higher air flow rates may be needed. A general ventilation diagram for a positive-pressure room is given in Figure 2. Directed room air flow in PE rooms is not laminar; parallel air streams are not generated. Studies attempting to demonstrate patient benefit from laminar air flow in a PE setting are equivocal. 316, 318, 319, 322 -327 Air flow direction at the entrances to these areas should be maintained and verified, preferably on a daily basis, using either a visual means of indication (e.g., smoke tubes and flutter strips) or manometers. Permanent installation of a visual monitoring device is indicated for new PE construction and renovation. 120 Facility service structures can interfere with the proper unidirectional air flow from the patients' rooms to the adjacent corridor. In one outbreak investigation, Aspergillus spp. infections in a critical care unit may have been associated with a pneumatic specimen transport system, a textile disposal duct system, and central vacuum lines for housekeeping, all of which disrupted proper air flow from the patients' rooms to the outside and allowed entry of fungal spores into the unit (M. McNeil, CDC, 2000). The use of surface fungicide treatments is becoming more common, especially for building materials. 329 Copper-based compounds have demonstrated anti-fungal activity and are often applied to wood or paint.\nCopper-8-quinolinolate was used on environmental surfaces contaminated with Aspergillus spp. to control one reported outbreak of aspergillosis.310 The compound was also incorporated into the fireproofing material of a newly constructed hospital to help decrease the environmental spore burden. 316\n\n# b. Airborne Infection Isolation (AII)\nAcute-care inpatient facilities need at least one room equipped to house patients with airborne infectious disease. Every health-care facility, including ambulatory and long-term care facilities, should undertake an ICRA to identify the need for AII areas. Once the need is established, the appropriate ventilation equipment can be identified. Air handling systems for this purpose need not be restricted to central systems. Guidelines for the prevention of health-care acquired TB have been published in response to multiple reports of health-care associated transmission of multi-drug resistant strains. 4,330 In reports documenting health-care acquired TB, investigators have noted a failure to comply fully with prevention measures in established guidelines. 331 -345 These gaps highlight the importance of prompt recognition of the disease, isolation of patients, proper treatment, and engineering controls. AII rooms are also appropriate for the care and management of smallpox patients. 6 Environmental infection control with respect to smallpox is currently being revisited (see Appendix E).\nSalient features of engineering controls for AII areas include a. use of negative pressure rooms with close monitoring of air flow direction using manometers or temporary or installed visual indicators placed in the room with the door closed b. minimum 6 ACH for existing facilities, ≥12 ACH for areas under renovation or for new construction; and c. air from negative pressure rooms and treatment rooms exhausted directly to the outside if possible. 4,120,248 As with PE, airflow rates need to be determined to ensure the proper numbers of ACH. 320,321 AII rooms can be constructed either with (Figure 3) or without (Figure 4) an anteroom. When the recirculation of air from AII rooms is unavoidable, HEPA filters should be installed in the exhaust duct leading from the room to the general ventilation system. In addition to UVGI fixtures in the room, UVGI can be placed in the ducts as an adjunct measure to HEPA filtration, but it can not replace the HEPA filter. 4 One of the components of airborne infection isolation is respiratory protection for health-care workers and visitors when entering AII rooms. 4,6,347 Recommendations of the type of respiratory protection are dependent on the patient's airborne infection (indicating the need for AII) and the risk of infection to persons entering the AII room. A more in-depth discussion of respiratory protection in this instance is presented in the current isolation guideline; 6 a revision of this guideline is in development. Coughinducing procedures (e.g., endotracheal intubation and suctioning of known or suspected TB patients, diagnostic sputum induction, aerosol treatments, and bronchoscopy) require similar precautions. Additional engineering measures are necessary for the management of patients requiring PE (i.e., allogeneic HSCT patients) who concurrently have airborne infection. For this type of patient treatment, an anteroom (Figure 4) is required in new construction and renovation as per AIA guidelines. 120 The pressure differential of an anteroom can be positive or negative relative to the patient in the room. 120 An anteroom can act as an airlock (Figure 4). If the anteroom is positive relative to the air space in the patient's room, staff members do not have to mask prior to entry into the anteroom if air is directly exhausted to the outside and a minimum of 10 ACH (Figure 4, top diagram). 120 When an anteroom is negative relative to both the AII room and the corridor, health-care workers must mask prior to entering the anteroom (Figure 4, bottom diagram). If an AII room with an anteroom is not available, use of a portable, industrial-grade HEPA filter unit may help to increase the number of ACHs while facilitating the removal of fungal spores; however, a fresh air source must be present to achieve the proper air exchange rate. Incoming ambient air should receive HEPA filtration.\n\n# c. Operating Rooms\nOperating room air may contain microorganisms, dust, aerosol, lint, skin squamous epithelial cells, and respiratory droplets. The microbial level in operating room air is directly proportional to the number of people moving in the room. 351 One study documented lower infection rates with coagulase-negative staphylococci among patients when operating room traffic during the surgical procedure was limited. 352 Therefore, efforts should be made to minimize personnel traffic during operations. Outbreaks of SSIs caused by group A beta-hemolytic streptococci have been traced to airborne transmission from colonized operating-room personnel to patients. Several potential health-care associated pathogens (e.g., Staphylococcus aureus and Staphylococcus epidermidis) and drug-resistant organisms have also been recovered from areas adjacent to the surgical field, 353 but the extent to which the presence of bacteria near the surgical field influences the development of postoperative SSIs is not clear. 354 Proper ventilation, humidity (<68%), and temperature control in the operating room is important for the comfort of surgical personnel and patients, but also in preventing environmental conditions that encourage growth and transmission of microorganisms. 355 Operating rooms should be maintained at positive pressure with respect to corridors and adjacent areas. 356 Operating rooms typically do not have a variable air handling system. Variable air handling systems are permitted for use in operating rooms only if they continue to provide a positive pressure with respect to the corridors and adjacent areas and the proper ACHs are maintained when the room is occupied. Conventional operating-room ventilation systems produce a minimum of about 15 ACH of filtered air for thermal control, three (20%) of which must be fresh air. 120,357,358 Air should be introduced at the ceiling and exhausted near the floor. 357,359 Laminar airflow and UVGI have been suggested as adjunct measures to reduce SSI risk for certain operations. Laminar airflow is designed to move particle-free air over the aseptic operating field at a uniform velocity (0.3-0.5 m/sec), sweeping away particles in its path. This air flow can be directed vertically or horizontally, and recirculated air is passed through a HEPA filter. Neither laminar airflow nor UV light, however, has been conclusively shown to decrease overall SSI risk. 356, Elective surgery on infectious TB patients should be postponed until such patients have received adequate drug therapy. The use of general anesthesia in TB patients poses infection-control challenges because intubation can induce coughing, and the anesthesia breathing circuit apparatus potentially can become contaminated. 371 Although operating room suites at 15 ACH exceed the air exchanges required transmission of TB to operating-room personnel. If feasible, intubation and extubation of the TB surgical patient should be performed in AII. AIA currently does not recommend changing pressure from positive to negative or setting it to neutral; most facilities lack the capability to do so. 120 When emergency surgery is indicated for a suspected/diagnosed infectious TB patient, taking specific infection-control measures is prudent (Box 8). + The placement of portable HEPA filter units in the operating room must be carefully evaluated for potential disruptions in normal air flow. The portable unit should be turned off while the surgical procedure is underway and turned on following extubation. Portable HEPA filter units previously placed in construction areas may be used in subsequent patient care, provided that all internal and external surfaces are cleaned and the filter's performance is verified with appropriate particle testing and is changed, if needed.\n\n# Other Aerosol Hazards in Health-Care Facilities\nIn addition to infectious bioaerosols, several crucial non-infectious, indoor air-quality issues must be addressed by health-care facilities. The presence of sensitizing and allergenic agents and irritants in the workplace (e.g., ethylene oxide, glutaraldehyde, formaldehyde, hexachlorophene, and latex allergens 375 ) is increasing. Asthma and dermatologic and systemic reactions often result with exposure to these chemicals. Anesthetic gases and aerosolized medications (e.g., ribavirin, pentamidine, and aminoglycosides) represent some of the emerging potentially hazardous exposures to health-care workers. Containment of the aerosol at the source is the first level of engineering control, but personal protective equipment (e.g., masks, respirators, and glove liners) that distances the worker from the hazard also may be needed.\nLaser plumes and surgical smoke represent another potential risk for health-care workers. Lasers transfer electromagnetic energy into tissues, resulting in the release of a heated plume that includes particles, gases, tissue debris, and offensive smells. One concern is that aerosolized infectious material in the laser plume might reach the nasal mucosa of surgeons and adjacent personnel. Although some viruses (i.e., varicella-zoster virus, pseudorabies virus, and herpes simplex virus) do not aerosolize efficiently, 379,380 other viruses and bacteria (e.g., human papilloma virus , HIV, coagulasenegative Staphylococcus, Corynebacterium spp., and Neisseria spp.) have been detected in laser plumes. The presence of an infectious agent in a laser plume may not, however, be sufficient to cause disease from airborne exposure, especially if the normal mode of transmission for the agent is not airborne. No evidence indicated that HIV or hepatitis B virus (HBV) has been transmitted via aerosolization and inhalation. 388 Although continuing studies are needed to fully evaluate the risk of laser plumes to surgical personnel, the prevention measures in these other guidelines should be followed: a. NIOSH recommendations, 378 b. the Recommended Practices for Laser Safety in Practice Settings developed by the Association of periOperative Registered Nurses , 389 c. the assessments of ECRI, 390-392 and d. the ANSI standard. 393 These guidelines recommend the use of a. respirators (N95 or N100) or full face shields and masks, 260 b. central wall-suction units with in-line filters to collect particulate matter from minimal plumes, and c. dedicated mechanical smoke exhaust systems with a high-efficiency filter to remove large amounts of laser plume.\nAlthough transmission of TB has occurred as a result of abscess management practices that lacked airborne particulate control measures and respiratory protection, use of a smoke evacuator or needle aspirator and a high degree of clinical awareness can help protect healthcare workers when excising and draining an extrapulmonary TB abscess. 137\n\n# D. Water 1. Modes of Transmission of Waterborne Diseases\nMoist environments and aqueous solutions in health-care settings have the potential to serve as reservoirs for waterborne microorganisms. Under favorable environmental circumstances (e.g., warm temperature and the presence of a source of nutrition), many bacterial and some protozoal microorganisms can either proliferate in active growth or remain for long periods in highly stable, environmentally resistant (yet infectious) forms. Modes of transmission for waterborne infections include direct contact ; ingestion of water ; indirect-contact transmission ; 6 inhalation of aerosols dispersed from water sources; 3 and aspiration of contaminated water.\nThe first three modes of transmission are commonly associated with infections caused by gram-negative bacteria and nontuberculous mycobacteria (NTM). Aerosols generated from water sources contaminated with Legionella spp. often serve as the vehicle for introducing legionellae to the respiratory tract. 394\n\n# Waterborne Infectious Diseases in Health-Care Facilities a. Legionellosis\nLegionellosis is a collective term describing infection produced by Legionella spp., whereas Legionnaires disease is a multi-system illness with pneumonia. 395 The clinical and epidemiologic aspects of these diseases (Table 11) are discussed extensively in another guideline. 3 Although Legionnaires disease is a respiratory infection, infection-control measures intended to prevent healthcare-associated cases center on the quality of water-the principal reservoir for Legionella spp.\n\n# Format Change :\nThe format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Table 11. Clinical and epidemiologic characteristics of legionellosis/Legionnaires disease\n\n# Modes of transmission\n- Aspiration of water, direct inhalation or water aerosols. 3,400 Causative agent - Legionella pneumophila (90% of infections); L. micdadei, L. bozemanii, L. dumoffii, L. longbeachii, (14 additional species can cause infection in humans). Source of exposure - Exposure to environmental sources of Legionella spp. (i.e., water or water aerosols). 31,33, Clinical syndromes and diseases Two distinct illnesses: - Pontiac fever ; and - progressive pneumonia that may be accompanied by cardiac, renal, and gastrointestinal involvement 3\nPatient populations at greatest risk - Immunosuppressed patients (e.g., transplant patients, cancer patients, and patients receiving corticosteroid therapy); - Immunocompromised patients (e.g., surgical patients, patients with underlying chronic lung disease, and dialysis patients); - Elderly persons; and - Patients who smoke. \n\n# Occurrence\n- Proportion of community-acquired pneumonia caused by Legionella spp. ranges from 1%-5%; estimated annual incidence among the general population is 8,000-18,000 cases in the United States; the incidence of healthcare-associated pneumonia (0%-14%) may be underestimated if appropriate laboratory diagnostic methods are unavailable. 396,397, Mortality rate - Mortality declined markedly during 1980-1998, from 34% to 12% for all cases; the mortality rate is higher among persons with health-care associated pneumonia compared with the rate among community-acquired pneumonia patients (14% for health-care associated pneumonia versus 10% for community-acquired pneumonia ). 445 Legionella spp. are commonly found in various natural and man-made aquatic environments 446,447 and can enter health-care facility water systems in low or undetectable numbers. 448,449 Cooling towers, evaporative condensers, heated potable water distribution systems, and locally-produced distilled water can provide environments for multiplication of legionellae. In several hospital outbreaks, patients have been infected through exposure to contaminated aerosols generated by cooling towers, showers, faucets, respiratory therapy equipment, and room-air humidifiers. 455 Factors that enhance colonization and amplification of legionellae in man-made water environments include a. temperatures of 77°F-107.6°F , b. stagnation, 461 c. scale and sediment, 462 and d. presence of certain free-living aquatic amoebae that can support intracellular growth of legionellae. 462,463 The bacteria multiply within single-cell protozoa in the environment and within alveolar macrophages in humans.\n\n# b. Other Gram-Negative Bacterial Infections\nOther gram-negative bacteria present in potable water also can cause health-care associated infections.\nClinically important, opportunistic organisms in tap water include Pseudomonas aeruginosa, Pseudomonas spp., Burkholderia cepacia, Ralstonia pickettii, Stenotrophomonas maltophilia, and Sphingomonas spp.\n(Tables 12 and 13). Immunocompromised patients are at greatest risk of developing infection. Medical conditions associated with these bacterial agents range from colonization of the respiratory and urinary tracts to deep, disseminated infections that can result in pneumonia and bloodstream bacteremia. Colonization by any of these organisms often precedes the development of infection. The use of tap water in medical care (e.g., in direct patient care, as a diluent for solutions, as a water source for medical instruments and equipment, and during the final stages of instrument disinfection) therefore presents a potential risk for exposure. Colonized patients also can serve as a source of contamination, particularly for moist environments of medical equipment (e.g., ventilators).\nIn addition to Legionella spp., Pseudomonas aeruginosa and Pseudomonas spp. are among the most clinically relevant, gram-negative, health-care associated pathogens identified from water. These and other gram-negative, non-fermentative bacteria have minimal nutritional requirements (i.e., these organisms can grow in distilled water) and can tolerate a variety of physical conditions. These attributes are critical to the success of these organisms as health-care associated pathogens. Measures to prevent the spread of these organisms and other waterborne, gram-negative bacteria include hand hygiene, glove use, barrier precautions, and eliminating potentially contaminated environmental reservoirs. 464,465 Format Change : The format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Table 12. Pseudomonas aeruginosa infections\n\n# Modes of transmission\n- Direct contact with water, aerosols; aspiration of water and inhalation of water aerosols; and indirect transfer from moist environmental surfaces via hands of health-care workers. 28, Clinical syndromes and diseases - Septicemia, pneumonia (particularly ventilator-associated), chronic respiratory infections among cystic fibrosis patients, urinary tract infections, skin and soft-tissue infections (e.g., tissue necrosis and hemorrhage), burn-wound infections, folliculitis, endocarditis, central nervous system infections (e.g., meningitis and abscess), eye infections, and bone and joint infections. Environmental sources of pseudomonads in healthcare settings - Potable (tap) water, distilled water, antiseptic solutions contaminated with tap water, sinks, hydrotherapy pools, whirlpools and whirlpool spas, water baths, lithotripsy therapy tanks, dialysis water, eyewash stations, flower vases, and endoscopes with residual moisture in the channels. 28,29,466,468, Environmental sources of pseudomonads in the community - Fomites (e.g., drug injection equipment stored in contaminated water). 494,495 Patient populations at greatest risk - Intensive care unit (ICU) patients (including neonatal ICU), transplant patients (organ and hematopoietic stem cell), neutropenic patients, burn therapy and hydrotherapy patients, patients with malignancies, cystic fibrosis patients, patients with underlying medical conditions, and dialysis patients. 28, 466, 467, 472, 477, 493, 506-508, 511, 512, 521-526 Format Change : The format of this section was changed to improve readability and accessibility. The content is unchanged. 527 - Contaminated solutions and disinfectants 528,529 - Dialysis machines 527 - Nebulizers - Water baths 533 - Intrinsically-contaminated mouthwash 534 (This report describes contamination occurring during manufacture prior to use by the health-care facility staff. All other entries reflect extrinsic sources of contamination.) - Ventilator temperature probes 535\n\n# Stenotrophomonas maltophlia, Sphingomonas spp.\n- Distilled water 536,537 - Contaminated solutions and disinfectants 529 - Dialysis machines 527 - Nebulizers - Water 538 - Ventilator temperature probes 539\n\n# Ralstonia pickettii\n- Fentanyl solutions 540 - Chlorhexidine 541\n- Distilled water 541 - Contaminated respiratory therapy solution 541,542 Serratia marcescens\n- Potable water 543 - Contaminated antiseptics (i.e., benzalkonium chloride and chlorhexidine) - Contaminated disinfectants (i.e., quaternary ammonium compounds and glutaraldehyde) 547,548 Acinetobacter spp.\n- Medical equipment that collects moisture (e.g., mechanical ventilators, cool mist humidifiers, vaporizers, and mist tents) - Room humidifiers 553,555 - Environmental surfaces Enterobacter spp.\n- Humidifier water 565 - Intravenous fluids - Unsterilized cotton swabs 573 - Ventilators 565,569 - Rubber piping on a suctioning machine 565,569 - Blood gas analyzers 570 Two additional gram-negative bacterial pathogens that can proliferate in moist environments are Acinetobacter spp. and Enterobacter spp. 571,572 Members of both genera are responsible for healthcareassociated episodes of colonization, bloodstream infections, pneumonia, and urinary tract infections among medically compromised patients, especially those in ICUs and burn therapy units. 566, Infections caused by Acinetobacter spp. represent a significant clinical problem. Average infection rates are higher from July through October compared with rates from November through June. 584 Mortality rates associated with Acinetobacter bacteremia are 17%-52%, and rates as high as 71% have been reported for pneumonia caused by infection with either Acinetobacter spp. or Pseudomonas spp.Multidrug resistance, especially in third generation cephalosporins for Enterobacter spp., contributes to increased morbidity and mortality. 569,572 Patients and health-care workers contribute significantly to the environmental contamination of surfaces and equipment with Acinetobacter spp. and Enterobacter spp., especially in intensive care areas, because of the nature of the medical equipment (e.g., ventilators) and the moisture associated with this equipment. 549,571,572,585 Hand carriage and hand transfer are commonly associated with health-care-associated transmission of these organisms and for S. marcescens. 586 Enterobacter spp. are primarily spread in this manner among patients by the hands of health-care workers. 567,587 Acinetobacter spp. have been isolated from the hands of 4%-33% of health-care workers in some studies, and transfer of an epidemic strain of Acinetobacter from patients' skin to health-care workers' hands has been demonstrated experimentally. 591 Acinetobacter infections and outbreaks have also been attributed to medical equipment and materials (e.g., ventilators, cool mist humidifiers, vaporizers, and mist tents) that may have contact with water of uncertain quality (e.g., rinsing a ventilator circuit in tap water). Strict adherence to hand hygiene helps prevent the spread of both Acinetobacter spp. and Enterobacter spp. 577,592 Acinetobacter spp. have also been detected on dry environmental surfaces (e.g., bed rails, counters, sinks, bed cupboards, bedding, floors, telephones, and medical charts) in the vicinity of colonized or infected patients; such contamination is especially problematic for surfaces that are frequently touched. In two studies, the survival periods of Acinetobacter baumannii and Acinetobacter calcoaceticus on dry surfaces approximated that for S. aureus (e.g., 26-27 days). 593,594 Because Acinetobacter spp. may come from numerous sources at any given time, laboratory investigation of health-care associated Acinetobacter infections should involve techniques to determine biotype, antibiotype, plasmid profile, and genomic fingerprinting (i.e., macrorestriction analysis) to accurately identify sources and modes of transmission of the organism(s). 595\n\n# c. Infections and Pseudo-Infections Due to Nontuberculous Mycobacteria\nNTM are acid-fast bacilli (AFB) commonly found in potable water. NTM include both saprophytic and opportunistic organisms. Many NTM are of low pathogenicity, and some measure of host impairment is necessary to enhance clinical disease. 596 The four most common forms of human disease associated with NTM are pulmonary disease in adults; cervical lymph node disease in children; skin, soft tissue, and bone infections; and disseminated disease in immunocompromised patients. 596,597 Person-to-person acquisition of NTM infection, especially among immunocompetent persons, does not appear to occur, and close contacts of patients are not readily infected, despite the high numbers of organisms harbored by such patients. 596, NTM are spread via all modes of transmission associated with water. In addition to health-care associated outbreaks of clinical disease, NTM can colonize patients in health-care facilities through consumption of contaminated water or ice or through inhalation of aerosols. Colonization following NTM exposure, particularly of the respiratory tract, occurs when a patient's local defense mechanisms are impaired; overt clinical disease does not develop. 606 The format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Table 14a. Infections or colonizations\n\n# Pathogen Vehicles associated with infections or colonizations\n\n# Mycobacterium abscessus\n- Inadequately sterilized medical instruments 613\n\n# Mycobacterium avium complex (MAC)\n- Potable water \n\n# Mycobacterium chelonae\n- Dialysis, reprocessed dialyzers 31,32 - Inadequately-sterilized medical instruments, jet injectors 617,618 - Contaminated solutions 619,620 - Hydrotherapy tanks 621\n\n# Mycobacterium fortuitum\n- Aerosols from showers or other water sources 605,606 - Ice 602\n- Inadequately sterilized medical instruments 603 - Hydrotherapy tanks 622\n\n# Mycobacterium marinum\n- Hydrotherapy tanks 623\n\n# Mycobacterium ulcerans\n- Potable water 624 - Laboratory solution (intrinsically contaminated 625 - Potable water ingestion prior to sputum specimen collection 626\n\n# Mycobacterium kansasii\n- Potable water 627\n\n# Mycobacterium terrae\n- Potable water 608\n\n# Mycobacterium xenopi\n- Potable water 609,612,627 NTM can be isolated from both natural and man-made environments. Numerous studies have identified 632 Some NTM species (e.g., Mycobacterium xenopi) can survive in water at 113°F (45°C), and can be isolated from hot water taps, which can pose a problem for hospitals that lower the temperature of their hot water systems. 627 Other NTM (e.g., Mycobacterium kansasii, M. gordonae, M. fortuitum, and M. chelonae) cannot tolerate high temperatures and are associated more often with cold water lines and taps. 629 NTM have a high resistance to chlorine; they can tolerate free chlorine concentrations of 0.05-0.2 mg/L (0.05-0.2 ppm) found at the tap. 598,633,634 They are 20-100 times more resistant to chlorine compared with coliforms; slow-growing strains of NTM (e.g., Mycobacterium avium and M. kanasii) appear to be more resistant to chorine inactivation compared to fast-growing NTM. 635 Slow-growing NTM species have also demonstrated some resistance to formaldehyde and glutaraldehyde, which has posed problems for reuse of hemodialyzers. 31 The ability of NTM to form biofilms at fluid-surface interfaces (e.g., interior surfaces of water pipes) contributes to the organisms' resistance to chemical inactivation and provides a microenvironment for growth and proliferation. 636,637\n\n# d. Cryptosporidiosis\nCryptosporidium parvum is a protozoan parasite that causes self-limiting gastroenteritis in normal hosts but can cause severe, life-threatening disease in immunocompromised patients. First recognized as a human pathogen in 1976, C. parvum can be present in natural and finished waters after fecal contamination from either human or animal sources. The health risks associated with drinking potable water contaminated with minimal numbers of C. parvum oocysts are unknown. 642 It remains to be determined if immunosuppressed persons are more susceptible to lower doses of oocysts than are immunocompetent persons. One study demonstrated that a median 50% infectious dose (ID50) of 132 oocysts of calf origin was sufficient to cause infection among healthy volunteers. 643 In a second study, the same researchers found that oocysts obtained from infected foals (newborn horses) were infectious for human volunteers at median ID50 of 10 oocysts, indicating that different strains or species of Cryptosporidium may vary in their infectivity for humans. 644 In a small study population of 17 healthy adults with pre-existing antibody to C. parvum, the ID50 was determined to be 1,880 oocysts, more than 20-fold higher than in seronegative persons. 645 These data suggest that pre-existing immunity derived from previous exposures to Cryptosporidium offers some protection from infection and illness that ordinarily would result from exposure to low numbers of oocysts. 645,646 Oocysts, particularly those with thick walls, are environmentally resistant, but their survival under natural water conditions is poorly understood. Under laboratory conditions, some oocysts remain viable and infectious in cold (41°F ) for months. 641 The prevalence of Cryptosporidium in the U.S. drinking water supply is notable. Two surveys of approximately 300 surface water supplies revealed that 55%-77% of the water samples contained Cryptosporidium oocysts. 647,648 Because the oocysts are highly resistant to common disinfectants (e.g., chlorine) used to treat drinking water, filtration of the water is important in reducing the risk of waterborne transmission. Coagulation-floculation and sedimentation, when used with filtration, can collectively achieve approximately a 2.5 log10 reduction in the number of oocysts. 649 However, outbreaks have been associated with both filtered and unfiltered drinking water systems (e.g., the 1993 outbreak in Milwaukee, Wisconsin that affected 400,000 people). 641, The presence of oocysts in the water is not an absolute indicator that infection will occur when the water is consumed, nor does the absence of detectable oocysts guarantee that infection will not occur. Healthcare associated outbreaks of cryptosporidiosis primarily have been described among groups of elderly patients and immunocompromised persons. 653\n\n# Water Systems in Health-Care Facilities a. Basic Components and Point-of-Use Fixtures\nTreated municipal water enters a health-care facility via the water mains and is distributed throughout the building(s) by a network of pipes constructed of galvanized iron, copper, and polyvinylchloride (PVC). The pipe runs should be as short as is practical. Where recirculation is employed, the pipe runs should be insulated and long dead legs avoided in efforts to minimize the potential for water stagnation, which favors the proliferation of Legionella spp. and NTM. In high-risk applications (e.g., PE areas for severely immunosuppressed patients), insulated recirculation loops should be incorporated as a design minimal loss.\nEach water service main, branch main, riser, and branch (to a group of fixtures) has a valve and a means to reach the valves via an access panel. 120 Each fixture has a stop valve. Valves permit the isolation of a portion of the water system within a facility during repairs or maintenance. Vacuum breakers and other similar devices in the lines prevent water from back-flowing into the system. All systems that supply water should be evaluated to determine risk for potential back siphonage and cross connections.\nHealth-care facilities generate hot water from municipal water using a boiler system. Hot water heaters and storage vessels for such systems should have a drainage facility at the lowest point, and the heating element should be located as close as possible to the bottom of the vessel to facilitate mixing and to prevent water temperature stratification. Those hot or cold water systems that incorporate an elevated holding tank should be inspected and cleaned annually. Lids should fit securely to exclude foreign materials.\nThe most common point-of-use fixtures for water in patient-care areas are sinks, faucets, aerators, showers, and toilets; eye-wash stations are found primarily in laboratories. The potential for these fixtures to serve as a reservoir for pathogenic microorganisms has long been recognized (Table 15). 509, Wet surfaces and the production of aerosols facilitate the multiplication and dispersion of microbes. The level of risk associated with aerosol production from point-of-use fixtures varies. Aerosols from shower heads and aerators have been linked to a limited number of clusters of gram-negative bacterial colonizations and infections, including Legionnaires disease, especially in areas where immunocompromised patients are present (e.g., surgical ICUs, transplant units, and oncology units). 412, 415,\nIn one report, clinical infection was not evident among immunocompetent persons (e.g., hospital staff) who used hospital showers when Legionella pneumophila was present in the water system. 660 Given the infrequency of reported outbreaks associated with faucet aerators, consensus has not been reached regarding the disinfection of or removal of these devices from general use. If additional clusters of infections or colonizations occur in high-risk patient-care areas, it may be prudent to clean and decontaminate the aerators or to remove them. 658,659 ASHRAE recommends cleaning and monthly disinfection of aerators in high-risk patient-care areas as part of Legionella control measures. 661 Although aerosols are produced with toilet flushing, 662,663 no epidemiologic evidence suggests that these aerosols pose a direct infection hazard.\nAlthough not considered a standard point-of-use fixture, decorative fountains are being installed in increasing numbers in health-care facilities and other public buildings. Aerosols from a decorative fountain have been associated with transmission of Legionella pneumophila serogroup 1 infection to a small cluster of older adults. 664 This hotel lobby fountain had been irregularly maintained, and water in the fountain may have been heated by submersed lighting, all of which favored the proliferation of Legionella in the system. 664 Because of the potential for generations of infectious aerosols, a prudent prevention measure is to avoid locating these fixtures in or near high-risk patient-care areas and to adhere to written policies for routine fountain maintenance. 120 Follow public health guidelines.\n(See Tables 12-14)\n\n# Potable water Legionella Aerosol inhalation\nModerate: occasional welldescribed outbreaks.\nProvide supplemental treatment for water.\n(See\n\n# b. Water Temperature and Pressure\nHot water temperature is usually measured at the point of use or at the point at which the water line enters equipment requiring hot water for proper operation. 120 Generally, the hot water temperature in hospital patient-care areas is no greater than a temperature within the range of 105°F-120°F (40.6°C-49°C), depending on the AIA guidance issued at the year in which the facility was built. 120 Hot water temperature in patient-care areas of skilled nursing-care facilities is set within a slightly lower range of 95°F-110°F (35°C-43.3°C) depending on the AIA guidance at the time of facility construction. 120 Many states have adopted a temperature setting in these ranges into their health-care regulations and building codes. ASHRAE, however, has recommended higher settings. 661 Steam jets or booster heaters are usually needed to meet the hot water temperature requirements in certain service areas of the hospital (e.g., the kitchen or the laundry ). 120 Additionally, water lines may need to be heated to a particular temperature specified by manufacturers of specific hospital equipment. Hot-water distribution systems serving patient-care areas are generally operated under constant recirculation to provide continuous hot water at each hot-water outlet. 120 If a facility is or has a hemodialysis unit, then continuously circulated, cold treated water is provided to that unit. 120 To minimize the growth and persistence of gram-negative waterborne bacteria (e.g., thermophilic NTM and Legionella spp.), 627, cold water in health-care facilities should be stored and distributed at temperatures below 68°F (20°C); hot water should be stored above 140°F (60°C) and circulated with a minimum return temperature of 124°F (51°C), 661 or the highest temperature specified in state regulations and building codes. If the return temperature setting of 124°F (51°C) is permitted, then installation of preset thermostatic mixing valves near the point-of-use can help to prevent scalding. Valve maintenance is especially important in preventing valve failure, which can result in scalding. New shower systems in large buildings, hospitals, and nursing homes should be designed to permit mixing of hot and cold water near the shower head. The warm water section of pipe between the control valve and shower head should be self-draining. Where buildings can not be retrofitted, other approaches to minimize the growth of Legionella spp. include periodically increasing the temperature to at least 150°F at the point of use and adding additional chlorine and flushing the water. 661,710,711 Systems should be inspected annually to ensure that thermostats are functioning properly. Maintaining adequate pressure also helps to ensure the integrity of the piping system.\n\n# c. Infection-Control Impact of Water System Maintenance and Repair\nCorrective measures for water-system failures have not been studied in well-designed experiments; these measures are instead based on empiric engineering and infection-control principles. Health-care facilities can occasionally sustain both intentional cut-offs by the municipal water authority to permit new construction project tie-ins and unintentional disruptions in service when a water main breaks as a result of aging infrastructure or a construction accident. Vacuum breakers or other similar devices can prevent backflow of water in the facility's distribution system during water-disruption emergencies. 11 To be prepared for such an emergency, all health-care facilities need contingency plans that identify the total demand for potable water, the quantity of replacement water required for a minimum of 24 hours when the water system is down, mechanisms for emergency water distribution, and procedures for correcting drops in water pressure that affect operation of essential devices and equipment that are driven or cooled by a water system . 713\n\n# Format Change :\nThe format of this section was changed to improve readability and accessibility. The content is unchanged. Detailed, up-to-date plans for hot and cold water piping systems should be readily available for maintenance and repair purposes in case of system problems. Opening potable water systems for repair or construction and subjecting systems to water-pressure changes can result in water discoloration and dramatic increases in the concentrations of Legionella spp. and other gram-negative bacteria. The maintenance of a chlorine residual at all points within the piping system also offers some protection from entry of contamination to the pipes in the event of inadvertent cross-connection between potable and nonpotable water lines. As a minimum preventive measure, ASHRAE recommends a thorough flushing of the system. 661 High-temperature flushing or hyperchlorination may also be appropriate strategies to decrease potentially high concentrations of waterborne organisms. The decision to pursue either of these remediation strategies, however, should be made on a case-by-case basis. If only a portion of the system is involved, high temperature flushing or chlorination can be used on only that portion of the system. 661 When shock decontamination of hot water systems is necessary (e.g., after disruption caused by construction and after cross-connections), the hot water temperature should be raised to 160°F-170°F (71°C-77°C) and maintained at that level while each outlet around the system is progressively flushed. A minimum flush time of 5 minutes has been recommended; 3 the optimal flush time is not known, however, and longer flush times may be necessary. 714 The number of outlets that can be flushed simultaneously depends on the capacity of the water heater and the flow capability of the system. Appropriate safety procedures to prevent scalding are essential. When possible, flushing should be performed when the fewest building occupants are present (e.g., during nights and weekends).\nWhen thermal shock treatment is not possible, shock chlorination may serve as an alternative method. 661 Experience with this method of decontamination is limited, however, and high levels of free chlorine can corrode metals. Chlorine should be added, preferably overnight, to achieve a free chlorine residual of at least 2 mg/L (2 ppm) throughout the system. 661 This may require chlorination of the water heater or tank to levels of 20-50 mg/L (20-50 ppm). The pH of the water should be maintained at 7.0-8.0. 661 After completion of the decontamination, recolonization of the hot water system is likely to occur unless proper temperatures are maintained or a procedure such as continuous supplemental chlorination is continued.\nInterruptions of the water supply and sewage spills are situations that require immediate recovery and remediation measures to ensure the health and safety of patients and staff. 715 When delivery of potable water through the municipal distribution system has been disrupted, the public water supplier must issue a \"boil water\" advisory if microbial contamination presents an immediate public health risk to customers. The hospital engineer should oversee the restoration of the water system in the facility and clear it for use when appropriate. Hospitals must maintain a high level of surveillance for waterborne disease among patients and staff after the advisory is lifted. 642 Flooding from either external (e.g., from a hurricane) or internal sources (e.g., a water system break) usually results in property damage and a temporary loss of water and sanitation. JCAHO requires all hospitals to have plans that address facility response for recovery from both internal and external disasters. 713,719 The plans are required to discuss a. general emergency preparedness, b. staffing, c. regional planning among area hospitals, d. emergency supply of potable water, e. infection control and medical services needs, f. climate control, and g. remediation.\nThe basic principles of structural recovery from flooding are similar to those for recovery from sewage contamination (Box 9 and 10). Following a major event (e.g., flooding), facilities may elect to conduct microbial sampling of water after the system is restored to verify that water quality has been returned to safe levels (<500 CFU/mL, heterotrophic plate count). This approach may help identify point-of-use fixtures that may harbor contamination as a result of design or engineering features. 720 Medical records should be allowed to dry and then either photocopied or placed in plastic covers before returning them to the record.\nMoisture meters can be used to assess water-damaged structural materials. If porous structural materials for walls have a moisture content of >20% after 72 hours, the affected material should be removed. 266,278,313 The management of water-damaged structural materials is not strictly limited to major water catastrophes (e.g., flooding and sewage intrusions); the same principles are used to evaluate the damage from leaking roofs, point-of-use fixtures, and equipment. Additional sources of moisture include condensate on walls from boilers and poorly engineered humidification in HVAC systems. An exception to these recommendations is made for hemodialysis units where water is further treated either by portable water treatment or large-scale water treatment systems usually involving reverse osmosis (RO). In the United States, >97% of dialysis facilities use RO treatment for their water. 721 However, changing pre-treatment filters and disinfecting the system to prevent colonization of the RO membrane and microbial contamination down-stream of the pre-treatment filter are prudent measures.\n\n# Box 10. Contingency planning for flooding\nGeneral emergency preparedness - Ensure that emergency electrical generators are not located in flood-prone areas of the facility.\n- Develop alternative strategies for moving patients, water containers, medical records, equipment, and supplies in the event that the elevators are inoperable. - Establish in advance a centralized base of operations with batteries, flashlights, and cellular phones.\n- Ensure sufficient supplies of sandbags to place at the entrances and the area around boilers, incinerators, and generators. - Establish alternative strategies for bringing core employees to the facility if high water prevents travel.\n\n# Staffing Patterns\n- Temporarily reassign licensed staff as needed to critical care areas to provide manual ventilation and to perform vital assessments on patients. - Designate a core group of employees to remain on site to keep all services operational if the facility remains open. - Train all employees in emergency preparedness procedures.\n\n# Regional planning among are facilities for disaster management\n- Incorporate community support and involvement (e.g., media alerts, news, and transportation).\n- Develop in advance strategies for transferring patients, as needed.\n- Develop strategies for sharing supplies and providing essential services among participating facilities (e.g., central sterile department services, and laundry services). - Identify sources for emergency provisions (e.g., blood, emergency vehicles, and bottled water).\n\n# Medical services and infection control\n- Use alcohol-based hand rubs in general patient-care areas.\n- Postpone elective surgeries until full services are restored, or transfer these patients to other facilities.\n- Consider using portable dialysis machines. (Portable dialysis machines require less water compared to the larger units situated in dialysis settings.) - Provide an adequate supply of tetanus and hepatitis A immunizations for patients and staff.\n\n# Climate control\n- Provide adequate water for cooling towers. (Water for cooling towers may need to be trucked in, especially if the tower uses a potable water source.) - Material in this box was compiled from references 713, 716-719.\n\n# Strategies for Controlling Waterborne Microbial Contamination a. Supplemental Treatment of Water with Heat and/or Chemicals\nIn addition to using supplemental treatment methods as remediation measures after inadvertent contamination of water systems, health-care facilities sometimes use special measures to control waterborne microorganisms on a sustained basis. This decision is most often associated with outbreaks of legionellosis and subsequent efforts to control legionellae, 722 although some facilities have tried supplemental measures to better control thermophilic NTM. 627 The primary disinfectant for both cold and hot water systems is chlorine. However, chlorine residuals are expected to be low, and possibly nonexistent, in hot water tanks because of extended retention time in the tank and elevated water temperature. Flushing, especially that which removes sludge from the bottom of the tank, probably provides the most effective treatment of water systems. Unlike the situation for disinfecting cooling towers, no equivalent recommendations have been made for potable water systems, although specific intervention strategies have been published. 403,723 The principal approaches to disinfection of potable systems are heat flushing using temperatures 160°F-170°F (71°-77°C), hyperchlorination, and physical cleaning of hot-water tanks. 3,403,661 Potable systems are easily recolonized and may require continuous intervention (e.g., raising of hot water temperatures or continuous chlorination). 403,711 Chlorine solutions lose potency over time, thereby rendering the stocking of large quantities of chlorine impractical.\nSome hospitals with hot water systems identified as the source of Legionella spp. have performed emergency decontamination of their systems by pulse (i.e., one-time) thermal disinfection/superheating or hyperchlorination. 711,714,724,725 After either of these procedures, hospitals either maintain their heated water with a minimum return temperature of 124°F (51°C) and cold water at <68°F (<20°C) or chlorinate their hot water to achieve 1-2 mg/L (1-2 ppm) of free residual chlorine at the tap. 26, 437, 709-711, 726, 727 Additional measures (e.g., physical cleaning or replacement of hot-water storage tanks, water heaters, faucets, and shower heads) may be required to help eliminate accumulations of scale and sediment that protect organisms from the biocidal effects of heat and chlorine. 457,711 Alternative methods for controlling and eradicating legionellae in water systems (e.g., treating water with chlorine dioxide, heavy metal ions , ozone, and UV light) have limited the growth of legionellae under laboratory and operating conditions. Further studies on the long-term efficacy of these treatments are needed before these methods can be considered standard applications.\nRenewed interest in the use of chloramines stems from concerns about adverse health effects associated with disinfectants and disinfection by-products. 743 Monochloramine usage minimizes the formation of disinfection by-products, including trihalomethanes and haloacetic acids. Monochloramine can also reach distal points in a water system and can penetrate into bacterial biofilms more effectively than free chlorine. 744 However, monochloramine use is limited to municipal water treatment plants and is currently not available to health-care facilities as a supplemental water-treatment approach. A recent study indicated that 90% of Legionnaires disease outbreaks associated with drinking water could have been prevented if monochloramine rather than free chlorine has been used for residual disinfection. 745 In a retrospective comparison of health-care associated Legionnaires disease incidence in central Texas hospitals, the same research group documented an absence of cases in facilities located in communities with monochloramine-treated municipal water. 746 Additional data are needed regarding the effectiveness of using monochloramine before its routine use as a disinfectant in water systems can be recommended.\nNo data have been published regarding the effectiveness of monochloramine installed at the level of the health-care facility.\nAdditional filtration of potable water systems is not routinely necessary. Filters are used in water lines in dialysis units, however, and may be inserted into the lines for specific equipment (e.g., endoscope washers and disinfectors) for the purpose of providing bacteria-free water for instrument reprocessing. Additionally, an RO unit is usually added to the distribution system leading to PE areas.\n\n# b. Primary Prevention of Legionnaires Disease (No Cases Identified)\nThe primary and secondary environmental infection-control strategies described in this section on the guideline pertain to health-care facilities without transplant units. Infection-control measures specific to PE or transplant units (i.e., patient-care areas housing patients at the highest risk for morbidity and mortality from Legionella spp. infection) are described in the subsection titled Preventing Legionnaires Disease in Protective Environments.\nHealth-care facilities use at least two general strategies to prevent health-care associated legionellosis when no cases or only sporadic cases have been detected. The first is an environmental surveillance approach involving periodic culturing of water samples from the hospital's potable water system to monitor for Legionella spp. If any sample is culture-positive, diagnostic testing is recommended for all patients with health-care associated pneumonia. 748,749 In-house testing is recommended for facilities with transplant programs as part of a comprehensive treatment/management program. If ≥30% of the samples are culture-positive for Legionella spp., decontamination of the facility's potable water system is warranted. 748 The premise for this approach is that no cases of health-care associated legionellosis can occur if Legionella spp. are not present in the potable water system, and, conversely, cases of health-care associated legionellosis could potentially occur if Legionella spp. are cultured from the water. 26,751 Physicians who are informed that the hospital's potable water system is culture-positive for Legionella spp. are more likely to order diagnostic tests for legionellosis.\nA potential advantage of the environmental surveillance approach is that periodic culturing of water is less costly than routine laboratory diagnostic testing for all patients who have health-care associated pneumonia. The primary argument against this approach is that, in the absence of cases, the relationship between water-culture results and legionellosis risk remains undefined. 3 Legionnella spp. can be present in the water systems of buildings 752 without being associated with known cases of disease. 437,707,753 In a study of 84 hospitals in Québec, 68% of the water systems were found to be colonized with Legionella spp., and 26% were colonized at >30% of sites sampled; cases of Legionnaires disease, however, were infrequently reported from these hospitals. 707 Other factors also argue against environmental surveillance. Interpretation of results from periodic water culturing might be confounded by differing results among the sites sampled in a single water system and by fluctuations in the concentration of Legionella spp. at the same site. 709,754 In addition, the risk for illness after exposure to a given source might be influenced by several factors other than the presence or concentration of organisms, including a. the degree to which contaminated water is aerosolized into respirable droplets, b. the proximity of the infectious aerosol to the potential host, c. the susceptibility of the host, and d. the virulence properties of the contaminating strain. Thus, data are insufficient to assign a level of disease risk even on the basis of the number of colonyforming units detected in samples from areas for immunocompetent patients. Conducting environmental surveillance would obligate hospital administrators to initiate water-decontamination programs if Legionella spp. are identified. Therefore, periodic monitoring of water from the hospital's potable water system and from aerosol-producing devices is not widely recommended in facilities that have not experienced cases of health-care associated legionellosis. 661,758 The second strategy to prevent and control health-care associated legionellosis is a clinical approach, in which providers maintain a high index of suspicion for legionellosis and order appropriate diagnostic tests (i.e., culture, urine antigen, and direct fluorescent antibody serology) for patients with health-care associated pneumonia who are at high risk for legionellosis and its complications. 437,759,760 The testing of autopsy specimens can be included in this strategy should a death resulting from healthcare-associated pneumonia occur. Identification of one case of definite or two cases of possible healthcare-associated Legionnaires disease should prompt an epidemiologic investigation for a hospital source of Legionella spp., which may involve culturing the facility's water for Legionella. Routine maintenance of cooling towers, and use of sterile water for the filling and terminal rinsing of nebulization devices and ventilation equipment can help to minimize potential sources of contamination. Circulating potable water temperatures should match those outlined in the subsection titled Water Temperature and Pressure, as permitted by state code.\n\n# c. Secondary Prevention of Legionnaires Disease (With Identified Cases)\nThe indications for a full-scale environmental investigation to search for and subsequently decontaminate identified sources of Legionella spp. in health-care facilities without transplant units have not been clarified; these indications would likely differ depending on the facility. Case categories for health-care associated Legionnaires disease in facilities without transplant units include definite cases (i.e., laboratory-confirmed cases of legionellosis that occur in patients who have been hospitalized continuously for ≥10 days before the onset of illness) and possible cases (i.e., laboratory-confirmed infections that occur 2-9 days after hospital admission). 3 In settings in which as few as one to three health-care associated cases are recognized over several months, intensified surveillance for Legionnaires disease has frequently identified numerous additional cases. 405,408,432,453,739,759,760 This finding suggests the need for a low threshold for initiating an investigation after laboratory confirmation of cases of healthcare associated legionellosis. When developing a strategy for responding to such a finding, however, infection-control personnel should consider the level of risk for health-care-associated acquisition of, and mortality from, Legionella spp. infection at their particular facility.\nAn epidemiologic investigation conducted to determine the source of Legionella spp. involves several important steps (Box 11). Laboratory assessment is crucial in supporting epidemiologic evidence of a link between human illness and a specific environmental source. 761 Strain determination from subtype analysis is most frequently used in these investigations. 410, Once the environmental source is established and confirmed with laboratory support, supplemental water treatment strategies can be initiated as appropriate.\n\n# Box 11. Steps in an epidemiologic investigation for legionellosis\n- Review medical and microbiologic records.\n\n# d. Preventing Legionnaires Disease in Protective Environments\nThis subsection outlines infection-control measures applicable to those health-care facilities providing care to severely immunocompromised patients. Indigenous microorganisms in the tap water of these facilities may pose problems for such patients. These measures are designed to prevent the generation of potentially infectious aerosols from water and the subsequent exposure of PE patients or other immunocompromised patients (e.g., transplant patients) (Table 17). Infection-control measures that address the use of water with medical equipment (e.g., ventilators, nebulizers, and equipment humidifiers) are described in other guidelines and publications. 3,455 If one case of laboratory-confirmed, health-care associated Legionnaires disease is identified in a patient in a solid-organ transplant program or in PE (i.e., an inpatient in PE for all or part of the 2-10 days prior to onset of illness) or if two or more laboratory-confirmed cases occur among patients who had visited an outpatient PE setting, the hospital should report the cases to the local and state health departments. The hospital should then initiate a thorough epidemiologic and environmental investigation to determine the likely environmental sources of Legionella spp. 9 The source of Legionella should be decontaminated or removed. Isolated cases may be difficult to investigate. Because transplant recipients are at substantially higher risk for disease and death from legionellosis compared with other hospitalized patients, periodic culturing for Legionella spp. in water samples from the potable water in the solid-organ transplant and/or PE unit can be performed as part of an overall strategy to prevent Legionnaires disease in PE units. 9,431,710,769 The optimal methodology (i.e., frequency and number of sites) for environmental surveillance cultures in PE units has not been determined, and the cost-effectiveness of this strategy has not been evaluated. Because transplant recipients are at high risk for Legionnaires disease and because no data are available to determine a safe concentration of legionellae organisms in potable water, the goal of environmental surveillance for Legionella spp. should be to maintain water systems with no detectable organisms. 9,431 Culturing for legionellae may be used to assess the effectiveness of water treatment or decontamination methods, a practice that provides benefits to both patients and health-care workers. 767,770 Format Change : The format of this section was changed to improve readability and accessibility. The content is unchanged. - Use water that is not contaminated with Legionella spp. for patients' sponge baths. 9 - Provide sterile water for drinking, tooth brushing, or for flushing nasogastric tubes. 9,412 - Perform supplemental treatment of the water for the unit. 732 - Consider periodic monitoring (i.e., culturing) of the unit water supply for Legionella spp. Protecting patient-care devices and instruments from inadvertent tap water contamination during room cleaning procedures is also important in any immunocompromised patient-care area. In a recent outbreak of gram-negative bacteremias among open-heart-surgery patients, pressure-monitoring equipment that was assembled and left uncovered overnight prior to the next day's surgeries was inadvertently contaminated with mists and splashing water from a hose-disinfectant system used for cleaning. 771\n\n# Cooling Towers and Evaporative Condensers\nModern health-care facilities maintain indoor climate control during warm weather by use of cooling towers (large facilities) or evaporative condensers (smaller buildings). A cooling tower is a wet-type, evaporative heat transfer device used to discharge to the atmosphere waste heat from a building's air conditioning condensers (Figure 5). 772,773 Warm water from air-conditioning condensers is piped to the cooling tower where it is sprayed downward into a counter-or cross-current air flow. To accelerate heat transfer to the air, the water passes over the fill, which either breaks water into droplets or causes it to spread into a thin film. 772,773 Most systems use fans to move air through the tower, although some large industrial cooling towers rely on natural draft circulation of air. The cooled water from the tower is piped back to the condenser, where it again picks up heat generated during the process of chilling the system's refrigerant. The water is cycled back to the cooling tower to be cooled. Closed-circuit cooling towers and evaporative condensers are also evaporative heat-transfer devices. In these systems, the process fluid (e.g., water, ethylene glycol/water mixture, oil, or a condensing refrigerant) does not directly contact the cooling air, but is contained inside a coil assembly. 661 Water temperatures are approximate and may differ substantially according to system use and design. Warm water from the condenser (or chiller) is sprayed downward into a counter-or cross-current air flow. Water passes over the fill (a component of the system designed to increase the surface area of the water exposed to air), and heat from the water is transferred to the air. Some of the water becomes aerosolized during this process, although the volume of aerosol discharged to the air can be reduced by the placement of a drift eliminator. Water cooled in the tower returns to the heat source to cool refrigerant from the air conditioning unit.\nCooling towers and evaporative condensers incorporate inertial stripping devices called drift eliminators to remove water droplets generated within the unit. Although the effectiveness of these eliminators varies substantially depending on design and condition, some water droplets in the size range of <5 μm will likely leave the unit, and some larger droplets leaving the unit may be reduced to ≤5 μm by evaporation. Thus, even with proper operation, a cooling tower or evaporative condenser can generate and expel respirable water aerosols. If either the water in the unit's basin or the make-up water (added to replace water lost to evaporation) contains Legionella spp. or other waterborne microorganisms, these organisms can be aerosolized and dispersed from the unit. 774 Clusters of both Legionnaires disease and Pontiac fever have been traced to exposure to infectious water aerosols originating from cooling towers and evaporative condensers contaminated with Legionella spp. Although most of these outbreaks have been community-acquired episodes of pneumonia, health-care associated Legionnaires disease has been linked to cooling tower aerosol exposure. 404,405 Contaminated aerosols from cooling towers on hospital premises gained entry to the buildings either through open windows or via air handling system intakes located near the tower equipment.\nCooling towers and evaporative condensers provide ideal ecological niches for Legionella spp. The typical temperature of the water in cooling towers ranges from 85°F-95°F (29°C-35°C), although temperatures can be above 120°F (49°C) and below 70°F (21°C) depending on system heat load, ambient temperature, and operating strategy. 661 An Australian study of cooling towers found that legionellae colonized or multiplied in towers with basin temperatures above 60.8°F (16°C), and multiplication became explosive at temperatures above 73.4°F (23°C). 783 Water temperature in closed-circuit cooling towers and evaporative condensers is similar to that in cooling towers. Considerable variation in the piping arrangement occurs. In addition, stagnant areas or dead legs may be difficult to clean or penetrate with biocides.\nSeveral documents address the routine maintenance of cooling towers, evaporative condensers, and whirlpool spas. 661, 784-787 They suggest following manufacturer's recommendations for cleaning and biocide treatment of these devices; all health-care facilities should ensure proper maintenance for their cooling towers and evaporative condensers, even in the absence of Legionella spp (Appendix C). Because cooling towers and evaporative condensers can be shut down during periods when air conditioning is not needed, this maintenance cleaning and treatment should be performed before starting up the system for the first time in the warm season. 782 Emergency decontamination protocols describing cleaning procedures and hyperchlorination for cooling towers have been developed for towers implicated in the transmission of legionellosis. 786, 787\n\n# Dialysis Water Quality and Dialysate\n\n# a. Rationale for Water Treatment in Hemodialysis\nHemodialysis, hemofiltration, and hemodiafiltration require special water-treatment processes to prevent adverse patient outcomes of dialysis therapy resulting from improper formulation of dialysate with water containing high levels of certain chemical or biological contaminants. The Association for the Advancement of Medical Instrumentation (AAMI) has established chemical and microbiologic standards for the water used to prepare dialysate, substitution fluid, or to reprocess hemodialyzers for renal replacement therapy. The AAMI standards address: a. equipment and processes used to purify water for the preparation of concentrates and dialysate and the reprocessing of dialyzers for multiple use and b. the devices used to store and distribute this water. Future revisions to these standards may include hemofiltration and hemodiafiltration.\nWater treatment systems used in hemodialysis employ several physical and/or chemical processes either singly or in combination (Figure 6). These systems may be portable units or large systems that feed several rooms. In the United States, >97% of maintenance hemodialysis facilities use RO alone or in combination with deionization. 793 Many acute-care facilities use portable hemodialysis machines with attached portable water treatment systems that use either deionization or RO. These machines were exempted from earlier versions of AAMI recommendations, but given current knowledge about toxic exposures to and inflammatory processes in patients new to dialysis, these machines should now come into compliance with current AAMI recommendations for hemodialysis water and dialysate quality. 788,789 Previous recommendations were based on the assumption that acute-care patients did not experience the same degree of adverse effects from short-term, cumulative exposures to either chemicals or microbiologic agents present in hemodialysis fluids compared with the effects encountered by patients during chronic, maintenance dialysis. 788,789 Additionally, JCAHO is reviewing inpatient practices and record-keeping for dialysis (acute and maintenance) for adherence to AAMI standards and recommended practices. Neither the water used to prepare dialysate nor the dialysate itself needs to be sterile, but tap water can not be used without additional treatment. Infections caused by rapid-growing NTM (e.g., Mycobacterium chelonae and M. abscessus) present a potential risk to hemodialysis patients (especially those in hemodialyzer reuse programs) if disinfection procedures to inactivate mycobacteria in the water (lowlevel disinfection) and the hemodialyzers (high-level disinfection) are inadequate. 31,32,633 Other factors associated with microbial contamination in dialysis systems could involve the water treatment system, the water and dialysate distribution systems, and the type of hemodialyzer. 666,667, Understanding the various factors and their influence on contamination levels is the key to preventing high levels of microbial contamination in dialysis therapy.\nIn several studies, pyrogenic reactions were demonstrated to have been caused by lipopolysaccharide or endotoxin associated with gram-negative bacteria. 794, Early studies demonstrated that parenteral exposure to endotoxin at a concentration of 1 ng/kg body weight/hour was the threshold dose for producing pyrogenic reactions in humans, and that the relative potencies of endotoxin differ by bacterial species. 804,805 Gram-negative water bacteria (e.g., Pseudomonas spp.) have been shown to multiply rapidly in a variety of hospital-associated fluids that can be used as supply water for hemodialysis (e.g., distilled water, deionized water, RO water, and softened water) and in dialysate (a balanced salt solution made with this water). 806 Several studies have demonstrated that the attack rates of pyrogenic reactions are directly associated with the number of bacteria in dialysate. 666,667,807 These studies provided the rationale for setting the heterotrophic bacteria standards in the first AAMI hemodialysis guideline at ≤2,000 CFU/mL in dialysate and one log lower (≤200 CFU/mL) for the water used to prepare dialysate. 668,788 If the level of bacterial contamination exceeded 200 CFU/mL in water, this level could be amplified in the system and effectively constitute a high inoculum for dialysate at the start of a dialysis treatment. 807,808 Pyrogenic reactions did not appear to occur when the level of contamination was below 2,000 CFU/mL in dialysate unless the source of the endotoxin was exogenous to the dialysis system (i.e., present in the community water supply). Endotoxins in a community water supply have been linked to the development of pyrogenic reactions among dialysis patients. 794 Whether endotoxin actually crosses the dialyzer membrane is controversial. Several investigators have shown that bacteria growing in dialysate-generated products that could cross the dialyzer membrane. 809,810 Gram-negative bacteria growing in dialysate have produced endotoxins that in turn stimulated the production of anti-endotoxin antibodies in hemodialysis patients; 801,811 these data suggest that bacterial endotoxins, although large molecules, cross dialyzer membranes either intact or as fragments. The use of the very permeable membranes known as high-flux membranes (which allow large molecules to traverse the membrane) increases the potential for passage of endotoxins into the blood path. Several studies support this contention. In one such study, an increase in plasma endotoxin concentrations during dialysis was observed when patients were dialyzed against dialysate containing 10 3 -10 4 CFU/mL Pseudomonas spp. 812 In vitro studies using both radiolabeled lipopolysaccharide and biologic assays have demonstrated that biologically active substances derived from bacteria found in dialysate can cross a variety of dialyzer membranes. 802, Patients treated with high-flux membranes have had higher levels of anti-endotoxin antibodies than subjects or patients treated with conventional membranes. 817 Finally, since 1989, 19%-22% of dialysis centers have reported pyrogenic reactions in the absence of septicemia. 818,819 Investigations of adverse outcomes among patients using reprocessed dialyzers have demonstrated a greater risk for developing pyrogenic reactions when the water used to reprocess these devices contained >6 ng/mL endotoxin and >10 4 CFU/mL bacteria. 820 In addition to the variability in endotoxin assays, host factors also are involved in determining whether a patient will mount a response to endotoxin. 803 Outbreak investigations of pyrogenic reactions and bacteremias associated with hemodialyzer reuse have demonstrated that pyrogenic reactions are prevented once the endotoxin level in the water used to reprocess the dialyzers is returned to below the AAMI standard level. 821 Reuse of dialyzers and use of bicarbonate dialysate, high-flux dialyzer membranes, or high-flux dialysis may increase the potential for pyrogenic reactions if the water in the dialysis setting does not meet standards. Although investigators have been unable to demonstrate endotoxin transfer across dialyzer membranes, 803,822,823 the preponderance of reports now supports the ability of endotoxin to transfer across at least some high-flux membranes under some operating conditions. In addition to the acute risk of pyrogenic reactions, indirect evidence in increasingly demonstrating that chronic exposure to low amounts of endotoxin may play a role in some of the long-term complications of hemodialysis therapy. Patients treated with ultrafiltered dialysate for 5-6 months have demonstrated a decrease in serum β2 microglobulin concentrations and a decrease in markers of an inflammatory response. In studies of longer duration, use of microbiologically ultrapure dialysate has been associated with a decreased incidence of β2 microglobulin-associated amyloidosis. 827,828 Although patient benefit likely is associated with the use of ultrapure dialysate, no consensus has been reached regarding the potential adoption of this as standard in the United States. Debate continues regarding the bacterial and endotoxin limits for dialysate. As advances in water treatment and hemodialysis processes occur, efforts are underway to move improved technology from the manufacturer out into the user community. Cost-benefit studies, however, have not been done, and substantially increased costs to implement newer water treatment modalities are anticipated.\nTo reconcile AAMI documents with current International Organization for Standardization (ISO) format, AAMI has determined that its hemodialysis standards will be discussed in the following four installments: RD 5 for hemodialysis equipment, RD 62 for product water quality, RD 47 for dialyzer reprocessing, and RD 52 for dialysate quality. The Renal Diseases and Dialysis Committee of AAMI is expected to finalize and promulgated the dialysate standard pertinent to the user community (RD 52), adopting by reference the bacterial and endotoxin limits in product water as currently outlined in the AAMI standard that applies to systems manufacturers (RD 62). At present, the user community should continue to observe water quality and dialysate standards as outlined in AAMI RD 5 (Hemodialysis Systems, 1992) and AAMI RD 47 (Reuse of Hemodialyzers, 1993) until the new RD 52 standard becomes available (Table 18). 789, 791 RD 47-1993).\nThe current AAMI standard directed at systems manufacturers (RD 62 ) now specifies that all product water used to prepare dialysate or to reprocess dialyzers for multiple use should contain <2 endotoxin units per milliliter (EU/mL). 792 A level of 2 EU/mL was chosen as the upper limit for endotoxin because this level is easily achieved with contemporary water treatment systems using RO and/or ultrafiltration. CDC has advocated monthly endotoxin testing along with microbiologic assays of water, because endotoxin activity may not correspond to the total heterotrophic plate counts. 829 Additionally, the current AAMI standard RD 62 for manufacturers includes action levels for product water. Because 48 hours can elapse between the time of sampling water for microbial contamination and the time when results are received, and because bacterial proliferation can be rapid, action levels for microbial counts and endotoxin concentrations are reported as 50 CFU/mL and 1 EU/mL, respectively, in this revision of the standard. 792 These recommendations will allow users to initiate corrective action before levels exceed the maximum levels established by the standard.\nIn hemodialysis, the net movement of water is from the blood to the dialysate, although within the dialyzer, local movement of water from the dialysate to the blood through the phenomenon of backfiltration may occur, particularly in dialyzers with highly permeable membranes. 830 In contrast, hemofiltration and hemodiaflltration feature infusion of large volumes of electrolyte solution (20-70 L) into the blood. Increasingly, this electrolyte solution is being prepared on-line from water and concentrate. Because of the large volumes of fluid infused, AAMI considered the necessity of setting more stringent requirements for water to be used in this application, but this organization has not yet established these because of lack of expert consensus and insufficient experience with on-line therapies in the United States. On-line hemofiltration and hemodiafiltration systems use sequential ultrafiltration as the final step in the preparation of infusion fluid. Several experts from AAMI concur that these point-ofuse ultrafiltration systems should be capable of further reducing the bacteria and endotoxin burden of solutions prepared from water meeting the requirements of the AAMI standard to a safe level for infusion.\n\n# b. Microbial Control Strategies\nThe strategy for controlling massive accumulations of gram-negative water bacteria and NTM in dialysis systems primarily involves preventing their growth through proper disinfection of water-treatment systems and hemodialysis machines. Gram-negative water bacteria, their associated lipopolysaccharides (bacterial endotoxins), and NTM ultimately come from the community water supply, and levels of these bacteria can be amplified depending on the water treatment system, dialysate distribution system, type of dialysis machine, and method of disinfection (Table 19). 634,794,831 Control strategies are designed to reduce levels of microbial contamination in water and dialysis fluid to relatively low levels but not to completely eradicate it.\n\n# Format Change :\nThe format of this section was changed to improve readability and accessibility. The content is unchanged. - Size Oversized diameter and length decrease fluid flow and increase bacterial reservoir for both treated water and centrally-prepared dialysate.\n\n# Construction\nRough joints, dead ends, unused branches, and polyvinyl chloride (PVC) piping can act as bacterial reservoirs.\n\n# Elevation\nOutlet taps should be located at the highest elevation to prevent loss of disinfectant; keep a recirculation loop in the system; flush unused ports routinely.\n\n# Storage tanks\nTanks are undesirable because they act as a reservoir for water bacteria; if tanks are present, they must be routinely scrubbed and disinfected.\n\n# Dialysis machines\n- Single-pass Disinfectant should have contact with all parts of the machine that are exposed to water or dialysis fluid.\n\n# Recirculating single-pass or recirculating (batch)\nRecirculating pumps and machine design allow for massive contamination levels if not properly disinfected; overnight chemical germicide treatment is recommended.\nTwo components of hemodialysis water distribution systems -pipes (particularly those made of polyvinyl chloride ) and storage tanks -can serve as reservoirs of microbial contamination. Hemodialysis systems frequently use pipes that are wider and longer than are needed to handle the required flow, which slows the fluid velocity and increases both the total fluid volume and the wetted surface area of the system. Gram-negative bacteria in fluids remaining in pipes overnight multiply rapidly and colonize the wet surfaces, producing bacterial populations and endotoxin quantities in proportion to the volume and surface area. Such colonization results in formation of protective biofilm that is difficult to remove and protects the bacteria from disinfection. 832 Routine (i.e., monthly), low-level disinfection of the pipes can help to control bacterial contamination of the distribution system. Additional measures to protect pipes from contaminations include a. situating all outlet taps at equal elevation and at the highest point of the system so that the disinfectant cannot drain from pipes by gravity before adequate contact time has elapsed and b. eliminating rough joints, dead-end pipes, and unused branches and taps that can trap fluid and serve as reservoirs of bacteria capable of continuously inoculating the entire volume of the system. 800\nMaintain a flow velocity of 3-5 ft/sec.\nA storage tank in the distribution system greatly increases the volume of fluid and surface area available and can serve as a niche for water bacteria. Storage tanks are therefore not recommended for use in dialysis systems unless they are frequently drained and adequately disinfected, including scrubbing the sides of the tank to remove bacterial biofilm. An ultrafilter should be used distal to the storage tank. 808,833 Microbiologic sampling of dialysis fluids is recommended because gram-negative bacteria can proliferate rapidly in water and dialysate in hemodialysis systems; high levels of these organisms place patients at risk for pyrogenic reactions or health-care associated infection. 667,668,808 Health-care facilities are advised to sample dialysis fluids at least monthly using standard microbiologic assay methods for waterborne microorganisms. 788,793,799, Product water used to prepare dialysate and to reprocess hemodialyzers for reuse on the same patient should also be tested for bacterial endotoxin on a monthly basis. 792,829,837 (See Appendix C for information about water sampling methods for dialysis.)\nCross-contamination of dialysis machines and inadequate disinfection measures can facilitate the spread of waterborne organisms to patients. Steps should be taken to ensure that dialysis equipment is performing correctly and that all connectors, lines, and other components are specific for the equipment, in good repair, and properly in place. A recent outbreak of gram-negative bacteremias among dialysis patients was attributed to faulty valves in a drain port of the machine that allowed backflow of saline used to flush the dialyzer before patient use. 838,839 This backflow contaminated the drain priming connectors, which contaminated the blood lines and exposed the patients to high concentrations of gram-negative bacteria. Environmental infection control in dialysis settings also includes low-level disinfection of housekeeping surfaces and spot decontamination of spills of blood (see Environmental Services in Part I of this guideline for further information).\n\n# c. Infection-Control Issues in Peritoneal Dialysis\nPeritoneal dialysis (PD), most commonly administered as continuous ambulatory peritoneal dialysis (CAPD) and continual cycling peritoneal dialysis (CCPD), is the third most common treatment for end-stage renal disease (ESRD) in the United States, accounting for 12% of all dialysis patients. 840 Peritonitis is the primary complication of CAPD, with coagulase-negative staphylococci the most clinically significant causative organisms. 841 Other organisms that have been found to produce peritonitis include Staphylococcus aureus, Mycobacterium fortuitum, M. mucogenicum, Stenotrophomonas maltophilia, Burkholderia cepacia, Corynebacterium jeikeium, Candida spp., and other fungi. Substantial morbidity is associated with peritoneal dialysis infections. Removal of peritoneal dialysis catheters usually is required for treatment of peritonitis caused by fungi, NTM, or other bacteria that are not cleared within the first several days of effective antimicrobial treatment. Furthermore, recurrent episodes of peritonitis may lead to fibrosis and loss of the dialysis membrane.\nMany reported episodes of peritonitis are associated with exit-site or tunneled catheter infections. Risk factors for the development of peritonitis in PD patients include 1. under dialysis, 2. immune suppression, 3. prolonged antimicrobial treatment, 4. patient age , 5. length of hospital stay, and 6. hypoalbuminemia. 844,851,852 Concern has been raised about infection risk associated with the use of automated cyclers in both inpatient and outpatient settings; however, studies suggest that PD patients who use automated cyclers have much lower infection rates. 853 One study noted that a closed-drainage system reduced the incidence of systemrelated peritonitis among intermittent peritoneal dialysis (IPD) patients from 3.6 to 1.5 cases/100 patient days. 854 The association of peritonitis with management of spent dialysate fluids requires additional study. Therefore, ensuring that the tip of the waste line is not submerged beneath the water level in a toilet or in a drain is prudent.\n\n# Ice Machines and Ice\nMicroorganisms may be present in ice, ice-storage chests, and ice-making machines. The two main sources of microorganisms in ice are the potable water from which it is made and a transferral of organisms from hands (Table 20). Ice from contaminated ice machines has been associated with patient colonization, blood stream infections, pulmonary and gastrointestinal illnesses, and pseudoinfections. 602,603,683,684,854,855 Microorganisms in ice can secondarily contaminate clinical specimens and medical solutions that require cold temperatures for either transport or holding. 601,620 An outbreak of surgical-site infections was interrupted when sterile ice was used in place of tap water ice to cool cardioplegia solutions. 601 Format Change : The format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Table 20. Microorganisms and their sources in ice and ice machines\nFrom potable water - Legionella spp. 684,685,857,858 - Nontuberculous mycobacteria (NTM) 602,603,859 - Pseudomonas aeruginosa 859 - Burkholderia cepacia 859,860 - Stenotrophomonas maltophilia 860 - Flavobacterium spp. 860 From fecally-contaminated water - Norwalk virus - Giardia lamblia 864 - Cryptosporidium parvum 685 From hand-transfer of organisms - Acinetobacter spp. 859 - Coagulase-negative staphylococci 859 - Salmonella enteriditis 865 - Cryptosporidium parvum 685 In a study comparing the microbial populations of hospital ice machines with organisms recovered from ice samples gathered from the community, samples from 27 hospital ice machines yielded low numbers (<10 CFU/mL) of several potentially opportunistic microorganisms, mainly gram-negative bacilli. 859 During the survey period, no health-care associated infections were attributed to the use of ice. Ice from community sources had higher levels of microbial contamination (75%-95% of 194 samples had total heterotrophic plate counts <500 CFU/mL, with the proportion of positive cultures dependent on the incubation temperature) and showed evidence of fecal contamination from the source water. 859 Thus, ice machines in health-care settings are no more heavily contaminated compared with ice machines in the community. If the source water for ice in a health-care facility is not fecally contaminated, then ice from clean ice machines and chests should pose no increased hazard for immunocompetent patients. Some waterborne bacteria found in ice could potentially be a risk to immunocompromised patients if they consume ice or drink beverages with ice. For example, Burkholderia cepacia in ice could present an infection risk for cystic fibrosis patients. 859,860 Therefore, protecting immunosuppressed and otherwise medically at-risk patients from exposure to tap water and ice potentially contaminated with opportunistic pathogens is prudent. 9 No microbiologic standards for ice, ice-making machines, or ice storage equipment have been established, although several investigators have suggested the need for such standards. 859,866 Culturing of ice machines is not routinely recommended, but it may be useful as part of an epidemiologic investigation. Sampling might also help determine the best schedule for cleaning open ice-storage chests. Recommendations for a regular program of maintenance and disinfection have been published. Health-care facilities are advised to clean ice-storage chests on a regular basis. Open ice chests may require a more frequent cleaning schedule compared with chests that have covers. Portable ice chests and containers require cleaning and low-level disinfection before the addition of ice intended for consumption. Ice-making machines may require less frequent cleaning, but their maintenance is important to proper performance. The manufacturer's instructions for both the proper method of cleaning and/or maintenance should be followed. These instructions may also recommend an EPA-registered disinfectant to ensure chemical potency, materials compatibility, and safety. In the event that instructions and suitable EPA-registered disinfectants are not available for this process, then a generic approach to cleaning, disinfecting, and maintaining ice machines and dispensers can be used (Box 12).\nIce and ice-making machines also may be contaminated via improper storage or handling of ice by patients and/or staff. 684-686, 855-858, 870 Suggested steps to avoid this means of contamination include a. minimizing or avoiding direct hand contact with ice intended for consumption, b. using a hard-surface scoop to dispense ice, and c. installing machines that dispense ice directly into portable containers at the touch of a control. 687,869 Box 12. General steps for cleaning and maintaining ice machines, dispensers, and storage chests*+ 1. Disconnect unit from power supply. 2. Remove and discard ice from bin or storage chest. 3. Allow unit to warm to room temperature. 4. Disassemble removable parts of machine that make contact with water to make ice. 5. Thoroughly clean machine and parts with water and detergent. 6. Dry external surfaces of removable parts before reassembling. 7. Check for any needed repair. 8. Replace feeder lines, as appropriate (e.g., when damaged, old, or difficult to clean). 9. Ensure presence of an air space in tubing leading from water inlet into water distribution system of machine. 10. Inspect for rodent or insect infestations under the unit and treat, as needed. 11. Check door gaskets (open compartment models) for evidence of leakage or dripping into the storage chest. 12. Clean the ice-storage chest or bin with fresh water and detergent; rinse with fresh tap water. 13. Sanitize machine by circulating a 50-100 parts per million (ppm) solution of sodium hypochlorite (i.e., 4-8 mL sodium hypochlorite/gallon of water) through the ice-making and storage systems for 2 hours (100 ppm solution), or 4 hours (50 ppm solution). 14. Drain sodium hypochlorite solutions and flush with fresh tap water. 15. Allow all surfaces of equipment to dry before returning to service. - Material in this box is adapted from reference 869. + These general guidelines should be used only where manufacturer-recommended methods and EPA-registered disinfectants are not available.\n\n# Hydrotherapy Tanks and Pools\n\n# a. General Information\nHydrotherapy equipment (e.g., pools, whirlpools, whirlpool spas, hot tubs, and physiotherapy tanks) traditionally has been used to treat patients with certain medical conditions (e.g., burns, 871,872 septic ulcers, lesions, amputations, 873 orthopedic impairments and injuries, arthritis, 874 and kidney lithotripsy). 654 Wound-care medicine is increasingly moving away from hydrotherapy, however, in favor of bedside pulsed-lavage therapy using sterile solutions for cleaning and irrigation. 492, Several episodes of health-care associated infections have been linked to use of hydrotherapy equipment ( Infection control for hydrotherapy tanks, pools, or birthing tanks presents unique challenges because indigenous microorganisms are always present in the water during treatments. In addition, some studies have found free living amoebae (i.e., Naegleria lovaniensis), which are commonly found in association with Naegleria fowleri, in hospital hydrotherapy pools. 890 Although hydrotherapy is at times appropriate for patients with wounds, burns, or other types of non-intact skin conditions (determined on a case-bycase basis), this equipment should not be considered \"semi-critical\" in accordance with the Spaulding classification. 891 Microbial data to evaluate the risk of infection to patients using hydrotherapy pools and birthing tanks are insufficient. Nevertheless, health-care facilities should maintain stringent cleaning and disinfection practices in accordance with the manufacturer's instructions and with relevant scientific literature until data supporting more rigorous infection-control measures become available. Factors that should be considered in therapy decisions in this situation would include a. availability of alternative aseptic techniques for wound management and b. a risk-benefit analysis of using traditional hydrotherapy.\n\n# b. Hydrotherapy Tanks\nHydrotherapy tanks (e.g., whirlpools, Hubbard tanks and whirlpool bath tubs) are shallow tanks constructed of stainless steel, plexiglass, or tile. They are closed-cycle water systems with hydrojets to circulate, aerate, and agitate the water. The maximum water temperature range is 50°F-104°F (10°C-40°C). The warm water temperature, constant agitation and aeration, and design of the hydrotherapy tanks provide ideal conditions for bacterial proliferation if the equipment is not properly maintained, cleaned, and disinfected. The design of the hydrotherapy equipment should be evaluated for potential infection-control problems that can be associated with inaccessible surfaces that can be difficult to clean and/or remain wet in between uses (i.e., recessed drain plates with fixed grill plates). 887 Associated equipment (e.g., parallel bars, plinths, Hoyer lifts, and wheelchairs) can also be potential reservoirs of microorganisms, depending on the materials used in these items (i.e., porous vs. non-porous materials) and the surfaces that may become wet during use. Patients with active skin colonizations and wound infections can serve as sources of contamination for the equipment and the water. Contamination from spilled tub water can extend to drains, floors, and walls. Health-care associated colonization or infection can result from exposure to endogenous sources of microorganisms (autoinoculation) or exogenous sources (via cross-contamination from other patients previously receiving treatment in the unit).\nAlthough some facilities have used tub liners to minimize environmental contamination of the tanks, the use of a tub liner does not eliminate the need for cleaning and disinfection. Draining these small pools and tanks after each patient use, thoroughly cleaning with a detergent, and disinfecting according to manufacturers' instructions have reduced bacterial contamination levels in the water from 10 4 CFU/mL to <10 CFU/mL. 892 A chlorine residual of 15 ppm in the water should be obtained prior to the patient's therapy session (e.g., by adding 15 grams of calcium hypochlorite 70% per 100 gallons of water). 892 A study of commercial and residential whirlpools found that superchlorination or draining, cleaning, disinfection, and refilling of whirlpools markedly reduced densities of Pseudomonas aeruginosa in whirlpool water. 893 The bacterial populations were rapidly replenished, however, when disinfectant concentrations dropped below recommended levels for recreational use (i.e., chlorine at 3.0 ppm or bromine at 6.0 ppm). When using chlorine, however, knowing whether the community drinking-water system is disinfected with chloramine is important, because municipal utilities adjust the pH of the water to the basic side to enhance chloramine formation. Because chlorine is not very effective at pH levels above 8, it may be necessary to re-adjust the pH of the water to a more acidic level. 894 A few reports describe the addition of antiseptic chemicals to hydrotherapy tank water, especially for burn patient therapy. One study involving a minimal number of participants demonstrated a reduction in the number of Pseudomonas spp. and other gram-negative bacteria from both patients and equipment surfaces when chloramine-T (\"chlorazene\") was added to the water. 898 Chloramine-T has not, however, been approved for water treatment in the United States.\n\n# c. Hydrotherapy Pools\nHydrotherapy pools typically serve large numbers of patients and are usually heated to 91.4°F-98.6°F (31°C-37°C). The temperature range is more narrow (94°F-96.8°F ) for pediatric and geriatric patient use. 899 Because the size of hydrotherapy pools precludes draining after patient use, proper management is required to maintain the proper balance of water conditioning (i.e., alkalinity, hardness, and temperature) and disinfection. The most widely used chemicals for disinfection of pools are chlorine and chlorine compounds -calcium hypochlorite, sodium hypochlorite, lithium hypochlorite, chloroisocyanurates, and chlorine gas. Solid and liquid formulations of chlorine chemicals are the easiest and safest to use. 900 Other halogenated compounds have also been used for pool-water disinfection, albeit on a limited scale. Bromine, which forms bactericidal bromamines in the presence of ammonia, has limited use because of its association with contact dermatitis. 901 Iodine does not bleach hair, swim suits, or cause eye irritation, but when introduced at proper concentrations, it gives water a greenish-yellowish cast. 892 In practical terms, maintenance of large hydrotherapy pools (e.g., those used for exercise) is similar to that for indoor public pools (i.e., continuous filtration, chlorine residuals no less than 0.4 ppm, and pH of 7.2-7.6). 902,903 Supply pipes and pumps also need to be maintained to eliminate the possibility of this equipment serving as a reservoir for waterborne organisms. 904 Specific standards for chlorine residual and pH of the water are addressed in local and state regulations. Patients who are fecally incontinent or who have draining wounds should refrain from using these pools until their condition improves.\n\n# d. Birthing Tanks and Other Equipment\nThe use of birthing tanks, whirlpool spas, and whirlpools is a recent addition to obstetrical practice. 905 Few studies on the potential risks associated with these pieces of equipment have been conducted. In one study of 32 women, a newborn contracted a Pseudomonas infection after being birthed in such a tank, the strain of which was identical to the organism isolated from the tank water. 906 Another report documented identical strains of P. aeruginosa isolates from a newborn with sepsis and on the environmental surfaces of a tub that the mother used for relaxation while in labor. 907 Other studies have shown no significant increases in the rates of post-immersion infections among mothers and infants. 908,909 Because the water and the tub surfaces routinely become contaminated with the mother's skin flora and blood during labor and delivery, birthing tanks and other tub equipment must be drained after each patient use and the surfaces thoroughly cleaned and disinfected. Health-care facilities are advised to follow the manufacturer's instructions for selection of disinfection method and chemical germicide. The range of chlorine residuals for public whirlpools and whirlpool spas is 2-5 ppm. 910 Use of an inflatable tub is an alternative solution, but this item must be cleaned and disinfected between patients if it is not considered a single-use unit.\nRecreational tanks and whirlpool spas are increasingly being used as hydrotherapy equipment. Although such home equipment appears to be suitable for hydrotherapy, they are neither designed nor constructed to function in this capacity. Additionally, manufacturers generally are not obligated to provide the healthcare facility with cleaning and disinfecting instructions appropriate for medical equipment use, and the U.S. Food and Drug Administration (FDA) does not evaluate recreational equipment. Health-care facilities should therefore carefully evaluate this \"off-label\" use of home equipment before proceeding with a purchase.\n\n# Miscellaneous Medical/Dental Equipment Connected to Main Water Systems a. Automated Endoscope Reprocessors\nThe automated endoscopic reprocessor (AER) is classified by the FDA as an accessory for the flexible endoscope. 654 A properly operating AER can provide a more consistent, reliable method of decontaminating and terminal reprocessing for endoscopes between patient procedures than manual reprocessing methods alone. 911 An endoscope is generally subjected to high-level disinfection using a liquid chemical sterilant or a high-level disinfectant. Because the instrument is a semi-critical device, the optimal rinse fluid for a disinfected endoscope would be sterile water. 3 Sterile water, however, is expensive and difficult to produce in sufficient quantities and with adequate quality assurance for instrument rinsing in an AER. 912,913 Therefore, one option to be used for AERs is rinse water that has been passed through filters with a pore size of 0.1-0.2 μm to render the water \"bacteria-free.\" These filters usually are located in the water line at or near the port where the mains water enters the equipment. The product water (i.e., tap water passing through these filters) in these applications is not considered equivalent in microbial quality to that for membrane-filtered water as produced by pharmaceutical firms. Membrane filtration in pharmaceutical applications is intended to ensure the microbial quality of polished product water.\nWater has been linked to the contamination of flexible fiberoptic endoscopes in the following two scenarios: a. rinsing a disinfected endoscope with unfiltered tap water, followed by storage of the instrument without drying out the internal channels and b. contamination of AERs from tap water inadvertently introduced into the equipment.\nIn the latter instance, the machine's water reservoirs and fluid circuitry become contaminated with waterborne, heterotrophic bacteria (e.g., Pseudomonas aeruginosa and NTM), which can survive and persist in biofilms attached to these components. Colonization of the reservoirs and water lines of the AER becomes problematic if the required cleaning, disinfection, and maintenance are not performed on the equipment as recommended by the manufacturer. 669,916,917 Use of the 0.1-0.2-μm filter in the water line helps to keep bacterial contamination to a minimum, 670,911,917 but filters may fail and allow bacteria to pass through to the equipment and then to the instrument undergoing reprocessing. 671-674, 913, 918 Filters also require maintenance for proper performance. 670,911,912,918,919 Heightened awareness of the proper disinfection of the connectors that hook the instrument to the AER may help to further reduce the potential for contaminating endoscopes during reprocessing. 920 An emerging issue in the field of endoscopy is that of the possible role of rinse water monitoring and its potential to help reduce endoscopy/bronchoscopyassociated infections. 918 Studies have linked deficiencies in endoscope cleaning and/or disinfecting processes to the incidence of post-endoscopic adverse outcomes. Several clusters have been traced to AERs of older designs and these were associated with water quality. 675, Regardless of whether manual or automated terminal reprocessing is used for endoscopes, the internal channels of the instrument should be dried before storage. 925 The presence of residual moisture in the internal channels encourages the proliferation of waterborne microorganisms, some of which may be pathogenic. One of the most frequently used methods employs 70% isopropyl alcohol to flush the internal channels, followed by forced air drying of these channels and hanging the endoscope vertically in a protected cabinet; this method ensures internal drying of the endoscope, lessens the potential for proliferation of waterborne microorganisms, 669,913,917,922,926,927 and is consistent with professional organization guidance for endoscope reprocessing. 928 An additional problem with waterborne microbial contamination of AERs centers on increased microbial resistance to alkaline glutaraldehyde, a widely used liquid chemical sterilant/high-level disinfectant. 669,929 Opportunistic waterborne microorganisms (e.g., Mycobacterium chelonae, Methylobacterium spp.) have been associated with pseudo-outbreaks and colonization; infection caused by these organisms has been associated with procedures conducted in clinical settings (e.g., bronchoscopy). 669,913, Increasing microbial resistance to glutaraldehyde has been attributed to improper use of the disinfectant in the equipment, allowing the dilution of glutaraldehyde to fall below the manufacturer's recommended minimal use concentration. 929\n\n# b. Dental Unit Water Lines\nDental unit water lines (DUWLs) consist of small-bore plastic tubing that delivers water used for general, non-surgical irrigation and as a coolant to dental handpieces, sonic and ultrasonic scalers, and air-water syringes; municipal tap water is the source water for these lines. The presence of biofilms of waterborne bacteria and fungi (e.g., Legionella spp., Pseudomonas aeruginosa, and NTM) in DUWLs has been established. 636,637,694,695, Biofilms continually release planktonic microorganisms into the water, the titers of which can exceed 1H10 6 CFU/mL. 694 However, scientific evidence indicates that immunocompetent persons are only at minimal risk for substantial adverse health effects after contact with water from a dental unit. Nonetheless, exposing patients or dental personnel to water of uncertain microbiological quality is not consistent with universally accepted infection-control principles. 935 In 1993, CDC issued guidelines relative to water quality in a dental setting. These guidelines recommend that all dental instruments that use water (including high-speed handpieces) should be run to discharge water for 20-30 seconds after each patient and for several minutes before the start of each clinic day. 936 This practice can help to flush out any patient materials that many have entered the turbine, air, or waterlines. 937,938 The 1993 guidance also indicated that waterlines be flushed at the beginning of the clinic day. Although these guidelines are designed to help reduce the number of microorganisms present in treatment water, they do not address the issue of reducing or preventing biofilm formation in the waterlines. Research published subsequent to the 1993 dental infection control guideline suggests that flushing the lines at the beginning of the day has only minimal effect on the status of the biofilm in the lines and does not reliably improve the quality of water during dental treatment. Updated recommendations on infection-control practices for water line use in dentistry will be available in late 2003. 942 The numbers of microorganisms in water used as coolant or irrigant for non-surgical dental treatment should be as low as reasonably achievable and, at a minimum, should meet nationally recognized standards for safe drinking water. 935,943 Only minimal evidence suggests that water meeting drinking water standards poses a health hazard for immunocompetent persons. The EPA, the American Public Health Association (APHA), and the American Water Works Association (AWWA) have set a maximum limit of 500 CFU/mL for aerobic, heterotrophic, mesophilic bacteria in drinking water in municipal distribution systems. 944,945 This standard is achievable, given improvements in water-line technology. Dentists should consult with the manufacturer of their dental unit to determine the best equipment and method for maintaining and monitoring good water quality. 935,946\n\n# E. Environmental Services 1. Principles of Cleaning and Disinfecting Environmental Surfaces\nAlthough microbiologically contaminated surfaces can serve as reservoirs of potential pathogens, these surfaces generally are not directly associated with transmission of infections to either staff or patients. The transferral of microorganisms from environmental surfaces to patients is largely via hand contact with the surface. 947,948 Although hand hygiene is important to minimize the impact of this transfer, cleaning and disinfecting environmental surfaces as appropriate is fundamental in reducing their potential contribution to the incidence of healthcare-associated infections.\nThe principles of cleaning and disinfecting environmental surfaces take into account the intended use of the surface or item in patient care. CDC retains the Spaulding classification for medical and surgical instruments, which outlines three categories based on the potential for the instrument to transmit infection if the instrument is microbiologically contaminated before use. 949,950 These categories are \"critical,\" \"semicritical,\" and \"noncritical.\" In 1991, CDC proposed an additional category designated \"environmental surfaces\" to Spaulding's original classification 951 to represent surfaces that generally do not come into direct contact with patients during care. Environmental surfaces carry the least risk of disease transmission and can be safely decontaminated using less rigorous methods than those used on medical instruments and devices. Environmental surfaces can be further divided into medical equipment surfaces (e.g., knobs or handles on hemodialysis machines, x-ray machines, instrument carts, and dental units) and housekeeping surfaces (e.g., floors, walls, and tabletops). 951 The following factors influence the choice of disinfection procedure for environmental surfaces: a. the nature of the item to be disinfected, b. the number of microorganisms present, c. the innate resistance of those microorganisms to the inactivating effects of the germicide, d. the amount of organic soil present, e. the type and concentration of germicide used, f. duration and temperature of germicide contact, and g. if using a proprietary product, other specific indications and directions for use. 952,953 Cleaning is the necessary first step of any sterilization or disinfection process. Cleaning is a form of decontamination that renders the environmental surface safe to handle or use by removing organic matter, salts, and visible soils, all of which interfere with microbial inactivation. The physical action of scrubbing with detergents and surfactants and rinsing with water removes large numbers of microorganisms from surfaces. 957 If the surface is not cleaned before the terminal reprocessing procedures are started, the success of the sterilization or disinfection process is compromised.\nSpaulding proposed three levels of disinfection for the treatment of devices and surfaces that do not require sterility for safe use. These disinfection levels are \"high-level,\" \"intermediate-level,\" and \"low level.\" 949,950 The basis for these levels is that microorganisms can usually be grouped according to their innate resistance to a spectrum of physical or chemical germicidal agents (Table 22). This information, coupled with the instrument/surface classification, determines the appropriate level of terminal disinfection for an instrument or surface. The process of high-level disinfection, an appropriate standard of treatment for heat-sensitive, semicritical medical instruments (e.g., flexible, fiberoptic endoscopes), inactivates all vegetative bacteria, mycobacteria, viruses, fungi, and some bacterial spores. High-level disinfection is accomplished with powerful, sporicidal chemicals (e.g., glutaraldehyde, peracetic acid, and hydrogen peroxide) that are not appropriate for use on housekeeping surfaces. These liquid chemical sterilants/high-level disinfectants are highly toxic. Use of these chemicals for applications other than those indicated in their label instructions (i.e., as immersion chemicals for treating heat-sensitive medical instruments) is not appropriate. 964 Intermediate-level disinfection does not necessarily kill bacterial spores, but it does inactivate Mycobacterium tuberculosis var. bovis, which is substantially more resistant to chemical germicides than ordinary vegetative bacteria, fungi, and medium to small viruses (with or without lipid envelopes). Chemical germicides with sufficient potency to achieve intermediate-level disinfection include chlorine-containing compounds (e.g., sodium hypochlorite), alcohols, some phenolics, and some iodophors. Low-level disinfection inactivates vegetative bacteria, fungi, enveloped viruses (e.g., human immunodeficiency virus , and influenza viruses), and some non-enveloped viruses (e.g., adenoviruses). Low-level disinfectants include quaternary ammonium compounds, some phenolics, and some iodophors. Sanitizers are agents that reduce the numbers of bacterial contaminants to safe levels as judged by public health requirements, and are used in cleaning operations, particularly in food service and dairy applications. Germicidal chemicals that have been approved by FDA as skin antiseptics are not appropriate for use as environmental surface disinfectants. 951 The selection and use of chemical germicides are largely matters of judgment, guided by product label instructions, information, and regulations. Liquid sterilant chemicals and high-level disinfectants intended for use on critical and semi-critical medical/dental devices and instruments are regulated exclusively by the FDA as a result of recent memoranda of understanding between FDA and the EPA that delineates agency authority for chemical germicide regulation. 965,966 A common misconception in the use of surface disinfectants in health-care settings relates to the underlying purpose for use of proprietary products labeled as a \"tuberculocidal\" germicide. Such products will not interrupt and prevent the transmission of TB in health-care settings because TB is not acquired from environmental surfaces. The tuberculocidal claim is used as a benchmark by which to measure germicidal potency. Because mycobacteria have the highest intrinsic level of resistance among the vegetative bacteria, viruses, and fungi, any germicide with a tuberculocidal claim on the label (i.e., an intermediate-level disinfectant) is considered capable of inactivating a broad spectrum of pathogens, including much less resistant organisms such the bloodborne pathogens (e.g., hepatitis B virus , hepatitis C virus , and HIV). It is this broad spectrum capability, rather than the product's specific potency against mycobacteria, that is the basis for protocols and OSHA regulations indicating the appropriateness of using tuberculocidal chemicals for surface disinfection. 967\n\n# General Cleaning Strategies for Patient-Care Areas\nThe number and types of microorganisms present on environmental surfaces are influenced by the following factors: a. number of people in the environment, b. amount of activity, c. amount of moisture, d. presence of material capable of supporting microbial growth, e. rate at which organisms suspended in the air are removed, and f. type of surface and orientation . 968 Strategies for cleaning and disinfecting surfaces in patient-care areas take into account a. potential for direct patient contact, b. degree and frequency of hand contact, and c. potential contamination of the surface with body substances or environmental sources of microorganisms (e.g., soil, dust, and water).\n\n# a. Cleaning of Medical Equipment\nManufacturers of medical equipment should provide care and maintenance instructions specific to their equipment. These instructions should include information about a. the equipments' compatibility with chemical germicides, b. whether the equipment is water-resistant or can be safely immersed for cleaning, and c. how the equipment should be decontaminated if servicing is required. 967 In the absence of manufacturers' instructions, non-critical medical equipment (e.g., stethoscopes, blood pressure cuffs, dialysis machines, and equipment knobs and controls) usually only require cleansing followed by low-to intermediate-level disinfection, depending on the nature and degree of contamination.\nEthyl alcohol or isopropyl alcohol in concentrations of 60%-90% (v/v) is often used to disinfect small surfaces (e.g., rubber stoppers of multiple-dose medication vials, and thermometers) 952, 969 and occasionally external surfaces of equipment (e.g., stethoscopes and ventilators). However, alcohol evaporates rapidly, which makes extended contact times difficult to achieve unless items are immersed, a factor that precludes its practical use as a large-surface disinfectant. 951 Alcohol may cause discoloration, swelling, hardening, and cracking of rubber and certain plastics after prolonged and repeated use and may damage the shellac mounting of lenses in medical equipment. 970 Barrier protection of surfaces and equipment is useful, especially if these surfaces are a. touched frequently by gloved hands during the delivery of patient care, b. likely to become contaminated with body substances, or c. difficult to clean. Impervious-backed paper, aluminum foil, and plastic or fluid-resistant covers are suitable for use as barrier protection.\nAn example of this approach is the use of plastic wrapping to cover the handle of the operatory light in dental-care settings. 936,942 Coverings should be removed and discarded while the health-care worker is still gloved. 936,942 The health-care worker, after ungloving and performing hand hygiene, must cover these surfaces with clean materials before the next patient encounter.\n\n# b. Cleaning Housekeeping Surfaces\nHousekeeping surfaces require regular cleaning and removal of soil and dust. Dry conditions favor the persistence of gram-positive cocci (e.g., coagulase-negative Staphylococcus spp.) in dust and on surfaces, whereas moist, soiled environments favor the growth and persistence of gram-negative bacilli. 948,971,972 Fungi are also present on dust and proliferate in moist, fibrous material.\nMost, if not all, housekeeping surfaces need to be cleaned only with soap and water or a detergent/disinfectant, depending on the nature of the surface and the type and degree of contamination.\nCleaning and disinfection schedules and methods vary according to the area of the health-care facility, type of surface to be cleaned, and the amount and type of soil present. Disinfectant/detergent formulations registered by EPA are used for environmental surface cleaning, but the actual physical removal of microorganisms and soil by wiping or scrubbing is probably as important, if not more so, than any antimicrobial effect of the cleaning agent used. 973 Therefore, cost, safety, product-surface compatibility, and acceptability by housekeepers can be the main criteria for selecting a registered agent. If using a proprietary detergent/disinfectant, the manufacturers' instructions for appropriate use of the product should be followed. 974 Consult the products' material safety data sheets (MSDS) to determine appropriate precautions to prevent hazardous conditions during product application. Personal protective equipment (PPE) used during cleaning and housekeeping procedures should be appropriate to the task.\nHousekeeping surfaces can be divided into two groups -those with minimal hand-contact (e.g., floors, and ceilings) and those with frequent hand-contact (\"high touch surfaces\"). The methods, thoroughness, and frequency of cleaning and the products used are determined by health-care facility policy. 6 However, high-touch housekeeping surfaces in patient-care areas (e.g., doorknobs, bedrails, light switches, wall areas around the toilet in the patient's room, and the edges of privacy curtains) should be cleaned and/or disinfected more frequently than surfaces with minimal hand contact. Infection-control practitioners typically use a risk-assessment approach to identify high-touch surfaces and then coordinate an appropriate cleaning and disinfecting strategy and schedule with the housekeeping staff.\nHorizontal surfaces with infrequent hand contact (e.g., window sills and hard-surface flooring) in routine patient-care areas require cleaning on a regular basis, when soiling or spills occur, and when a patient is discharged from the facility. 6 Regular cleaning of surfaces and decontamination, as needed, is also advocated to protect potentially exposed workers. 967 Cleaning of walls, blinds, and window curtains is recommended when they are visibly soiled. 972,973,975 Disinfectant fogging is not recommended for general infection control in routine patient-care areas. 2,976 Further, paraformaldehyde, which was once used in this application, is no longer registered by EPA for this purpose. Use of paraformaldehyde in these circumstances requires either registration or an exemption issued by EPA under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). Infection control, industrial hygienists, and environmental services supervisors should assess the cleaning procedures, chemicals used, and the safety issues to determine if a temporary relocation of the patient is needed when cleaning in the room.\nExtraordinary cleaning and decontamination of floors in health-care settings is unwarranted. Studies have demonstrated that disinfection of floors offers no advantage over regular detergent/water cleaning and has minimal or no impact on the occurrence of health-care associated infections. 947,948, Additionally, newly cleaned floors become rapidly recontaminated from airborne microorganisms and those transferred from shoes, equipment wheels, and body substances. 971,975,981 Nevertheless, healthcare institutions or contracted cleaning companies may choose to use an EPA-registered detergent/disinfectant for cleaning low-touch surfaces (e.g., floors) in patient-care areas because of the difficulty that personnel may have in determining if a spill contains blood or body fluids (requiring a detergent/disinfectant for clean-up) or when a multi-drug resistant organism is likely to be in the environment. Methods for cleaning non-porous floors include wet mopping and wet vacuuming, dry dusting with electrostatic materials, and spray buffing. 973, Methods that produce minimal mists and aerosols or dispersion of dust in patient-care areas are preferred. 9,20,109,272 Part of the cleaning strategy is to minimize contamination of cleaning solutions and cleaning tools. Bucket solutions become contaminated almost immediately during cleaning, and continued use of the solution transfers increasing numbers of microorganisms to each subsequent surface to be cleaned. 971,981,985 Cleaning solutions should be replaced frequently. A variety of \"bucket\" methods have been devised to address the frequency with which cleaning solutions are replaced. 986,987 Another source of contamination in the cleaning process is the cleaning cloth or mop head, especially if left soaking in dirty cleaning solutions. 971, Laundering of cloths and mop heads after use and allowing them to dry before re-use can help to minimize the degree of contamination. 990 A simplified approach to cleaning involves replacing soiled cloths and mop heads with clean items each time a bucket of detergent/disinfectant is emptied and replaced with fresh, clean solution (B. Stover, Kosair Children's Hospital, 2000). Disposable cleaning cloths and mop heads are an alternative option, if costs permit.\nAnother reservoir for microorganisms in the cleaning process may be dilute solutions of the detergents or disinfectants, especially if the working solution is prepared in a dirty container, stored for long periods of time, or prepared incorrectly. 547 Gram-negative bacilli (e.g., Pseudomonas spp. and Serratia marcescens) have been detected in solutions of some disinfectants (e.g., phenolics and quaternary ammonium compounds). 547,991 Contemporary EPA registration regulations have helped to minimize this problem by asking manufacturers to provide potency data to support label claims for detergent/disinfectant properties under real-use conditions (e.g., diluting the product with tap water instead of distilled water). Application of contaminated cleaning solutions, particularly from small-quantity aerosol spray bottles or with equipment that might generate aerosols during operation, should be avoided, especially in high-risk patient areas. 992,993 Making sufficient fresh cleaning solution for daily cleaning, discarding any remaining solution, and drying out the container will help to minimize the degree of bacterial contamination. Containers that dispense liquid as opposed to spray-nozzle dispensers (e.g., quart-sized dishwashing liquid bottles) can be used to apply detergent/disinfectants to surfaces and then to cleaning cloths with minimal aerosol generation. A pre-mixed, \"ready-to-use\" detergent/disinfectant solution may be used if available.\n\n# c. Cleaning Special Care Areas\nGuidelines have been published regarding cleaning strategies for isolation areas and operating rooms. 6,7 The basic strategies for areas housing immunosuppressed patients include a. wet dusting horizontal surfaces daily with cleaning cloths pre-moistened with detergent or an EPAregistered hospital disinfectant or disinfectant wipes; 94, 98463 b. using care when wet dusting equipment and surfaces above the patient to avoid patient contact with the detergent/disinfectant; c. avoiding the use of cleaning equipment that produces mists or aerosols; d. equipping vacuums with HEPA filters, especially for the exhaust, when used in any patient-care area housing immunosuppressed patients; 9, 94, 986 and e. regular cleaning and maintenance of equipment to ensure efficient particle removal.\nWhen preparing the cleaning cloths for wet-dusting, freshly prepared solutions of detergents or disinfectants should be used rather than cloths that have soaked in such solutions for long periods of time. Dispersal of microorganisms in the air from dust or aerosols is more problematic in these settings than elsewhere in health-care facilities. Vacuum cleaners can serve as dust disseminators if they are not operating properly. 994 Doors to immunosuppressed patients' rooms should be closed when nearby areas are being vacuumed. 9 Bacterial and fungal contamination of filters in cleaning equipment is inevitable, and these filters should be cleaned regularly or replaced as per equipment manufacturer instructions.\nMats with tacky surfaces placed in operating rooms and other patient-care areas only slightly minimize the overall degree of contamination of floors and have little impact on the incidence rate of health-careassociated infection in general. 351,971,983 An exception, however, is the use of tacky mats inside the entry ways of cordoned-off construction areas inside the health-care facility; these mats help to minimize the intrusion of dust into patient-care areas.\nSpecial precautions for cleaning incubators, mattresses, and other nursery surfaces have been recommended to address reports of hyperbilirubinemia in newborns linked to inadequately diluted solutions of phenolics and poor ventilation. These medical conditions have not, however, been associated with the use of properly prepared solutions of phenolics. Non-porous housekeeping surfaces in neonatal units can be disinfected with properly diluted or pre-mixed phenolics, followed by rinsing with clean water. 997 However, phenolics are not recommended for cleaning infant bassinets and incubators during the stay of the infant. Infants who remain in the nursery for an extended period should be moved periodically to freshly cleaned and disinfected bassinets and incubators. 997 If phenolics are used for cleaning bassinets and incubators after they have been vacated, the surfaces should be rinsed thoroughly with water and dried before either piece of equipment is reused. Cleaning and disinfecting protocols should allow for the full contact time specified for the product used. Bassinet mattresses should be replaced, however, if the mattress cover surface is broken. 997\n\n# Cleaning Strategies for Spills of Blood and Body Substances\nNeither HBV, HCV, nor HIV has ever been transmitted from a housekeeping surface (i.e., floors, walls, or countertops). Nonetheless, prompt removal and surface disinfection of an area contaminated by either blood or body substances are sound infection-control practices and OSHA requirements. 967 Studies have demonstrated that HIV is inactivated rapidly after being exposed to commonly used chemical germicides at concentrations that are much lower than those used in practice. HBV is readily inactivated with a variety of germicides, including quaternary ammonium compounds. 1004 Embalming fluids (e.g., formaldehyde) are also capable of completely inactivating HIV and HBV. 1005,1006 OSHA has revised its regulation for disinfecting spills of blood or other potentially infectious material to include proprietary products whose label includes inactivation claims for HBV and HIV, provided that such surfaces have not become contaminated with agent(s) or volumes of or concentrations of agent(s) for which a higher level of disinfection is recommended. 1007 These registered products are listed in EPA's List D -Registered Antimicrobials Effective Against Hepatitis B Virus and Human HIV-1, which may include products tested against duck hepatitis B virus (DHBV) as a surrogate for HBV. 1008,1009 Additional lists of interest include EPA's List C -Registered Antimicrobials Effective Against Human HIV-1 and EPA's List E -Registered Antimicrobials Effective Against Mycobacterium spp., Hepatitis B Virus, and Human HIV-1.\nSodium hypochlorite solutions are inexpensive and effective broad-spectrum germicidal solutions. 1010,1011 Generic sources of sodium hypochlorite include household chlorine bleach or reagent grade chemical. Concentrations of sodium hypochlorite solutions with a range of 5,000-6,150 ppm (1:10 v/v dilution of household bleaches marketed in the United States) to 500-615 ppm (1:100 v/v dilution) free chlorine are effective depending on the amount of organic material (e.g., blood, mucus, and urine) present on the surface to be cleaned and disinfected. 1010, 1011 EPA-registered chemical germicides may be more compatible with certain materials that could be corroded by repeated exposure to sodium hypochlorite, especially the 1:10 dilution. Appropriate personal protective equipment (e.g., gloves and goggles) should be worn when preparing and using hypochlorite solutions or other chemical germicides. 967 Despite laboratory evidence demonstrating adequate potency against bloodborne pathogens (e.g., HIV and HBV), many chlorine bleach products available in grocery and chemical-supply stores are not registered by the EPA for use as surface disinfectants. Use of these chlorine products as surface disinfectants is considered by the EPA to be an \"unregistered use.\" EPA encourages the use of registered products because the agency reviews them for safety and performance when the product is used according to label instructions. When unregistered products are used for surface disinfection, users do so at their own risk.\nStrategies for decontaminating spills of blood and other body fluids differ based on the setting in which they occur and the volume of the spill. 1010 In patient-care areas, workers can manage small spills with cleaning and then disinfecting using an intermediate-level germicide or an EPA-registered germicide from the EPA List D or E. 967,1007 For spills containing large amounts of blood or other body substances, workers should first remove visible organic matter with absorbent material (e.g., disposable paper towels discarded into leak-proof, properly labeled containment) and then clean and decontaminate the area. 1002, 1003, 1012 If the surface is nonporous and a generic form of a sodium hypochlorite solution is used (e.g., household bleach), a 1:100 dilution is appropriate for decontamination assuming that a. the worker assigned to clean the spill is wearing gloves and other personal protective equipment appropriate to the task, b. most of the organic matter of the spill has been removed with absorbent material, and c. the surface has been cleaned to remove residual organic matter.\nA recent study demonstrated that even strong chlorine solutions (i.e., 1:10 dilution of chlorine bleach) may fail to totally inactivate high titers of virus in large quantities of blood, but in the absence of blood these disinfectants can achieve complete viral inactivation. 1011 This evidence supports the need to remove most organic matter from a large spill before final disinfection of the surface. Additionally, EPAregistered proprietary disinfectant label claims are based on use on a pre-cleaned surface. 951,954 Managing spills of blood, body fluids, or other infectious materials in clinical, public health, and research laboratories requires more stringent measures because of a. the higher potential risk of disease transmission associated with large volumes of blood and body fluids and b. high numbers of microorganisms associated with diagnostic cultures.\nThe use of an intermediate-level germicide for routine decontamination in the laboratory is prudent. 954 Recommended practices for managing large spills of concentrated infectious agents in the laboratory include a. confining the contaminated area, b. flooding the area with a liquid chemical germicide before cleaning, and c. decontaminating with fresh germicidal chemical of at least intermediate-level disinfectant potency. 1010 A suggested technique when flooding the spill with germicide is to lay absorbent material down on the spill and apply sufficient germicide to thoroughly wet both the spill and the absorbent material. 1013 If using a solution of household chlorine bleach, a 1:10 dilution is recommended for this purpose. EPAregistered germicides should be used according to the manufacturers' instructions for use dilution and contact time. Gloves should be worn during the cleaning and decontamination procedures in both clinical and laboratory settings. PPE in such a situation may include the use of respiratory protection (e.g., an N95 respirator) if clean-up procedures are expected to generate infectious aerosols. Protocols for cleaning spills should be developed and made available on record as part of good laboratory practice. 1013 Workers in laboratories and in patient-care areas of the facility should receive periodic training in environmentalsurface infection-control strategies and procedures as part of an overall infection-control and safety curriculum.\n\n# Carpeting and Cloth Furnishings a. Carpeting\nCarpeting has been used for more than 30 years in both public and patient-care areas of health-care facilities. Advantages of carpeting in patient-care areas include a. its noise-limiting characteristics b. the \"humanizing\" effect on health care; and c. its contribution to reductions in falls and resultant injuries, particularly for the elderly. Compared to hard-surface flooring, however, carpeting is harder to keep clean, especially after spills of blood and body substances. It is also harder to push equipment with wheels (e.g., wheelchairs, carts, and gurneys) on carpeting.\nSeveral studies have documented the presence of diverse microbial populations, primarily bacteria and fungi, in carpeting; 111, 1017-1024 the variety and number of microorganisms tend to stabilize over time. New carpeting quickly becomes colonized, with bacterial growth plateauing after about 4 weeks. 1019 Vacuuming and cleaning the carpeting can temporarily reduce the numbers of bacteria, but these populations soon rebound and return to pre-cleaning levels. 1019,1020,1023 Bacterial contamination tends to increase with higher levels of activity. 1025 Soiled carpeting that is or remains damp or wet provides an ideal setting for the proliferation and persistence of gram-negative bacteria and fungi. 1026 Carpeting that remains damp should be removed, ideally within 72 hours.\nDespite the evidence of bacterial growth and persistence in carpeting, only limited epidemiologic evidence demonstrates that carpets influence health-care associated infection rates in areas housing immunocompetent patients. 1023,1025,1027 This guideline, therefore, includes no recommendations against the use of carpeting in these areas. Nonetheless, avoiding the use of carpeting is prudent in areas where spills are likely to occur (e.g., laboratories, areas around sinks, and janitor closets) and where patients may be at greater risk of infection from airborne environmental pathogens (e.g., HSCT units, burn units, ICUs, and ORs). 111,1028 An outbreak of aspergillosis in an HSCT unit was recently attributed to carpet contamination and a particular method of carpet cleaning. 111 A window in the unit had been opened repeatedly during the time of a nearby building fire, which allowed fungal spore intrusion into the unit. After the window was sealed, the carpeting was cleaned using a \"bonnet buffing\" machine, which dispersed Aspergillus spores into the air. 111 Wet vacuuming was instituted, replacing the dry cleaning method used previously; no additional cases of invasive aspergillosis were identified.\nThe care setting and the method of carpet cleaning are important factors to consider when attempting to minimize or prevent production of aerosols and dispersal of carpet microorganisms into the air. 94,111 Both vacuuming and shampooing or wet cleaning with equipment can disperse microorganisms to the air. 111,994 Vacuum cleaners should be maintained to minimize dust dispersal in general, and be equipped with HEPA filters, especially for use in high-risk patient-care areas. 9, 94, 986 Some formulations of carpetcleaning chemicals, if applied or used improperly, can be dispersed into the air as a fine dust capable of causing respiratory irritation in patients and staff. 1029 Cleaning equipment, especially those that engage in wet cleaning and extraction, can become contaminated with waterborne organisms (e.g., Pseudomonas aeruginosa) and serve as a reservoir for these organisms if this equipment is not properly maintained. Substantial numbers of bacteria can then be transferred to carpeting during the cleaning process. 1030 Therefore, keeping the carpet cleaning equipment in good repair and allowing such equipment to dry between uses is prudent.\nCarpet cleaning should be performed on a regular basis determined by internal policy. Although spills of blood and body substances on non-porous surfaces require prompt spot cleaning using standard cleaning procedures and application of chemical germicides, 967 similar decontamination approaches to blood and body substance spills on carpeting can be problematic from a regulatory perspective. 1031 Most, if not all, modern carpet brands suitable for public facilities can tolerate the activity of a variety of liquid chemical germicides. However, according to OSHA, carpeting contaminated with blood or other potentially infectious materials cannot be fully decontaminated. 1032 Therefore, facilities electing to use carpeting for high-activity patient-care areas may choose carpet tiles in areas at high risk for spills. 967,1032 In the event of contamination with blood or other body substances, carpet tiles can be removed, discarded, and replaced. OSHA also acknowledges that only minimal direct skin contact occurs with carpeting, and therefore, employers are expected to make reasonable efforts to clean and sanitize carpeting using carpet detergent/cleaner products. 1032 Over the last few years, some carpet manufacturers have treated their products with fungicidal and/or bactericidal chemicals. Although these chemicals may help to reduce the overall numbers of bacteria or fungi present in carpet, their use does not preclude the routine care and maintenance of the carpeting. Limited evidence suggests that chemically treated carpet may have helped to keep health-care-associated aspergillosis rates low in one HSCT unit, 111 but overall, treated carpeting has not been shown to prevent the incidence of health-care associated infections in care areas for immunocompetent patients.\n\n# b. Cloth Furnishings\nUpholstered furniture and furnishings are becoming increasingly common in patient-care areas. These furnishings range from simple cloth chairs in patients' rooms to a complete decorating scheme that gives the interior of the facility more the look of an elegant hotel. 1033 Even though pathogenic microorganisms have been isolated from the surfaces of cloth chairs, no epidemiologic evidence suggests that general patient-care areas with cloth furniture pose increased risks of health-care associated infection compared with areas that contain hard-surfaced furniture. 1034,1035 Allergens (e.g., dog and cat dander) have been detected in or on cloth furniture in clinics and elsewhere in hospitals in concentrations higher than those found on bed linens. 1034,1035 These allergens presumably are transferred from the clothing of visitors. Researchers have therefore suggested that cloth chairs should be vacuumed regularly to keep the dust and allergen levels to a minimum. This recommendation, however, has generated concerns that aerosols created from vacuuming could place immunocompromised patients or patients with preexisting lung disease (e.g., asthma) at risk for development of health-care associated, environmental airborne disease. 9, 20, 109, 988 Recovering worn, upholstered furniture (especially the seat cushion) with covers that are easily cleaned (e.g., vinyl), or replacing the item is prudent; minimizing the use of upholstered furniture and furnishings in any patient-care areas where immunosuppressed patients are located (e.g., HSCT units) reduces the likelihood of disease. 9\n\n# Flowers and Plants in Patient-Care Areas\nFresh flowers, dried flowers, and potted plants are common items in health-care facilities. In 1974, clinicians isolated an Erwinia sp. post mortem from a neonate diagnosed with fulminant septicemia, meningitis, and respiratory distress syndrome. 1038 Because Erwinia spp. are plant pathogens, plants brought into the delivery room were suspected to be the source of the bacteria, although the case report did not definitively establish a direct link. Several subsequent studies evaluated the numbers and diversity of microorganisms in the vase water of cut flowers. These studies revealed that high concentrations of bacteria, ranging from 10 4 -10 10 CFU/mL, were often present, especially if the water was changed infrequently. 515,702,1039 The major group of microorganisms in flower vase water was gram-negative bacteria, with Pseudomonas aeruginosa the most frequently isolated organism. 515, 702, 1039, 1040 P. aeruginosa was also the primary organism directly isolated from chrysanthemums and other potted plants. 1041,1042 However, flowers in hospitals were not significantly more contaminated with bacteria compared with flowers in restaurants or in the home. 702 Additionally, no differences in the diversity and degree of antibiotic resistance of bacteria have been observed in samples isolated from hospital flowers versus those obtained from flowers elsewhere. 702 Despite the diversity and large numbers of bacteria associated with flower-vase water and potted plants, minimal or no evidence indicates that the presence of plants in immunocompetent patient-care areas poses an increased risk of health-care associated infection. 515 In one study involving a limited number of surgical patients, no correlation was observed between bacterial isolates from flowers in the area and the incidence and etiology of postoperative infections among the patients. 1040 Similar conclusions were reached in a study that examined the bacteria found in potted plants. 1042 Nonetheless, some precautions for general patient-care settings should be implemented, including a. limiting flower and plant care to staff with no direct patient contact, b. advising health-care staff to wear gloves when handling plants, c. washing hands after handling plants, d. changing vase water every 2 days and discharging the water into a sink outside the immediate patient environment, and e. cleaning and disinfecting vases after use. 702 Some researchers have examined the possibility of adding a chemical germicide to vase water to control bacterial populations. Certain chemicals (e.g., hydrogen peroxide and chlorhexidine) are well tolerated by plants. 1040,1043,1044 Use of these chemicals, however, was not evaluated in studies to assess impact on health-care associated infection rates. Modern florists now have a variety of products available to add to vase water to extend the life of cut flowers and to minimize bacterial clouding of the water.\nFlowers (fresh and dried) and ornamental plants, however, may serve as a reservoir of Aspergillus spp., and dispersal of conidiospores into the air from this source can occur. 109 Health-care associated outbreaks of invasive aspergillosis reinforce the importance of maintaining an environment as free of Aspergillus spp. spores as possible for patients with severe, prolonged neutropenia. Potted plants, fresh-cut flowers, and dried flower arrangements may provide a reservoir for these fungi as well as other fungal species (e.g., Fusarium spp.). 109,1045,1046 Researchers in one study of bacteria and flowers suggested that flowers and vase water should be avoided in areas providing care to medically at-risk patients (e.g., oncology patients and transplant patients), although this study did not attempt to correlate the observations of bacterial populations in the vase water with the incidence of health-care associated infections. 515 Another study using molecular epidemiology techniques demonstrated identical Aspergillus terreus types among environmental and clinical specimens isolated from infected patients with hematological malignancies. 1046 Therefore, attempts should be made to exclude flowers and plants from areas where immunosuppressed patients are be located (e.g., HSCT units). 9, 1046\n\n# Pest Control\nCockroaches, flies and maggots, ants, mosquitoes, spiders, mites, midges, and mice are among the typical arthropod and vertebrate pest populations found in health-care facilities. Insects can serve as agents for the mechanical transmission of microorganisms, or as active participants in the disease transmission process by serving as a vector. Arthropods recovered from health-care facilities have been shown to carry a wide variety of pathogenic microorganisms. Studies have suggested that the diversity of microorganisms associated with insects reflects the microbial populations present in the indoor health-care environment; some pathogens encountered in insects from hospitals were either absent from or present to a lesser degree in insects trapped from residential settings. Some of the microbial populations associated with insects in hospitals have demonstrated resistance to antibiotics. 1048,1059, Insect habitats are characterized by warmth, moisture, and availability of food. 1064 Insects forage in and feed on substrates, including but not limited to food scraps from kitchens/cafeteria, foods in vending machines, discharges on dressings either in use or discarded, other forms of human detritis, medical wastes, human wastes, and routine solid waste. Cockroaches, in particular, have been known to feed on fixed sputum smears in laboratories. 1065,1066 Both cockroaches and ants are frequently found in the laundry, central sterile supply departments, and anywhere in the facility where water or moisture is present (e.g., sink traps, drains and janitor closets). Ants will often find their way into sterile packs of items as they forage in a warm, moist environment. 1057 Cockroaches and other insects frequent loading docks and other areas with direct access to the outdoors.\nAlthough insects carry a wide variety of pathogenic microorganisms on their surfaces and in their gut, the direct association of insects with disease transmission (apart from vector transmission) is limited, especially in health-care settings; the presence of insects in itself likely does not contribute substantially to health-care associated disease transmission in developed countries. However, outbreaks of infection attributed to microorganisms carried by insects may occur because of infestation coupled with breaks in standard infection-control practices. 1063 Studies have been conducted to examine the role of houseflies as possible vectors for shigellosis and other forms of diarrheal disease in non-health-care settings. 1046, 1067 When control measures aimed at reducing the fly population density were implemented, a concomitant reduction in the incidence of diarrheal infections, carriage of Shigella organisms, and mortality caused by diarrhea among infants and young children was observed.\nMyiasis is defined as a parasitosis in which the larvae of any of a variety of flies use living or necrotic tissue or body substances of the host as a nutritional source. 1068 Larvae from health-care acquired myiasis have been observed in nares, wounds, eyes, ears, sinuses, and the external urogenital structures. Patients with this rare condition are typically older adults with underlying medical conditions (e.g., diabetes, chronic wounds, and alcoholism) who have a decreased capacity to ward off the flies. Persons with underlying conditions who live or travel to tropical regions of the world are especially at risk. 1070,1071 Cases occur in the summer and early fall months in temperate climates when flies are most active. 1071 An environmental assessment and review of the patient's history are necessary to verify that the source of the myiasis is health-care acquired and to identify corrective measures. 1069,1072 Simple prevention measures (e.g., installing screens on windows) are important in reducing the incidence of myiasis. 1072 From a public health and hygiene perspective, arthropod and vertebrate pests should be eradicated from all indoor environments, including health-care facilities. 1073,1074 Modern approaches to institutional pest management usually focus on a. eliminating food sources, indoor habitats, and other conditions that attract pests b. excluding pests from the indoor environments; and c. applying pesticides as needed. 1075 Sealing windows in modern health-care facilities helps to minimize insect intrusion. When windows need to be opened for ventilation, ensuring that screens are in good repair and closing doors to the outside can help with pest control. Insects should be kept out of all areas of the health-care facility, especially ORs and any area where immunosuppressed patients are located. A pest-control specialist with appropriate credentials can provide a regular insect-control program that is tailored to the needs of the facility and uses approved chemicals and/or physical methods. Industrial hygienists can provide information on possible adverse reactions of patients and staff to pesticides and suggest alternative methods for pest control, as needed. ) represent crucial and growing concerns for infection control. Although the term GISA is technically a more accurate description of the strains isolated to date (most of which are classified as having intermediate resistance to both vancomycin and teicoplanin), the term \"glycopeptide\" may not be recognized by many clinicians. Thus, the label of VISA, which emphasizes a change in minimum inhibitory concentration (MICs) to vancomycin, is similar to that of VRE and is more meaningful to clinicians. 1076 According to National Nosocomial Infection Surveillance (NNIS) statistics for infections acquired among ICU patients in the United States in 1999, 52.3% of infections resulting from S. aureus were identified as MRSA infections, and 25.2% of enterococcal infections were attributed to VRE. These figures reflect a 37% and a 43% increase, respectively, since 1994-1998. 1077 People represent the primary reservoir of S. aureus. 1078 Although S. aureus has been isolated from a variety of environmental surfaces (e.g., stethoscopes, floors, charts, furniture, dry mops, and hydrotherapy tanks), the role of environmental contamination in transmission of this organism in health care appears to be minimal. S. aureus contamination of surfaces and tanks within burn therapy units, however, may be a major factor in the transmission of infection among burn patients. 1083 Colonized patients are the principal reservoir of VRE, and patients who are immunosuppressed (e.g., transplant patients) or otherwise medically at-risk (e.g., ICU patients, cardio-thoracic surgical patients, patients previously hospitalized for extended periods, and those having received multi-antimicrobial or vancomycin therapy) are at greatest risk for VRE colonization. The mechanisms by which crosscolonization take place are not well defined, although recent studies have indicated that both MRSA and VRE may be transmitted either a. directly from patient to patient, b. indirectly by transient carriage on the hands of health-care workers, 1088-1091 or c. by hand transfer of these gram-positive organisms from contaminated environmental surfaces and patient-care equipment. 1084,1087, In one survey, hand carriage of VRE in workers in a long-term care facility ranged from 13%-41%. 1098 Many of the environmental surfaces found to be contaminated with VRE in outbreak investigations have been those that are touched frequently by the patient or the health-care worker. 1099 Such high-touch surfaces include bedrails, doorknobs, bed linens, gowns, overbed tables, blood pressure cuffs, computer table, bedside tables, and various medical equipment. 22,1087,1094,1095, Contamination of environmental surfaces with VRE generally occurs in clinical laboratories and areas where colonized patients are present, 1087, 1092, 1094, 1095, 1103 but the potential for contamination increases when such patients have diarrhea 1087 or have multiple body-site colonization. 1104 Additional factors that can be important in the dispersion of these pathogens to environmental surfaces are misuse of glove techniques by healthcare workers (especially when cleaning fecal contamination from surfaces) and patient, family, and visitor hygiene.\n\n# Special Pathogen Concerns a. Antibiotic-Resistant Gram-Positive Cocci\nInterest in the importance of environmental reservoirs of VRE increased when laboratory studies demonstrated that enterococci can persist in a viable state on dry environmental surfaces for extended periods of time (7 days to 4 months) 1099,1105 and multiple strains can be identified during extensive periods of surveillance. 1104 VRE can be recovered from inoculated hands of health-care workers (with or without gloves) for up to 60 minutes. 22 The presence of either MRSA, VISA, or VRE on environmental surfaces, however, does not mean that patients in the contaminated areas will become colonized. Strict adherence to hand hygiene/handwashing and the proper use of barrier precautions help to minimize the potential for spread of these pathogens. Published recommendations for preventing the spread of vancomycin resistance address isolation measures, including patient cohorting and management of patient-care items. 5 Direct patient-care items (e.g., blood pressure cuffs) should be disposable whenever possible when used in contact isolation settings for patients with multiply resistant microorganisms. 1102 1114,1115 These represented isolated cases, and neither the family members nor the health-care providers of these case-patients had evidence of colonization or infection with VRSA. Conventional environmental infection-control measures (i.e., cleaning and then disinfecting surfaces using EPA-registered disinfectants with label claims for S. aureus) were used during the environmental investigation of these two cases; 1110-1112 however, studies have yet to evaluate the potential intrinsic resistance of these VRSA strains to surface disinfectants.\nStandard procedures during terminal cleaning and disinfection of surfaces, if performed incorrectly, may be inadequate for the elimination of VRE from patient rooms. 1113, Given the sensitivity of VRE to hospital disinfectants, current disinfecting protocols should be effective if they are diligently carried out and properly performed. Health-care facilities should be sure that housekeeping staff use correct procedures for cleaning and disinfecting surfaces in VRE-contaminated areas, which include using sufficient amounts of germicide at proper use dilution and allowing adequate contact time. 1118\n\n# b. Clostridium difficile\nClostridium difficile is the most frequent etiologic agent for health-care associated diarrhea. 1119,1120 In one hospital, 30% of adults who developed health-care associated diarrhea were positive for C. difficile. 1121 One recent study employing PCR-ribotyping techniques demonstrated that cases of C. difiicile-acquired diarrhea occurring in the hospital included patients whose infections were attributed to endogenous C. difficile strains and patients whose illnesses were considered to be health-care-associated infections. 1122 Most patients remain asymptomatic after infection, but the organism continues to be shed in their stools. Risk factors for acquiring C. difficile-associated infection include a. exposure to antibiotic therapy, particularly with beta-lactam agents; 1123 b. gastrointestinal procedures and surgery; 1124 c. advanced age; and d. indiscriminate use of antibiotics. Of all the measures that have been used to prevent the spread of C. difficile-associated diarrhea, the most successful has been the restriction of the use of antimicrobial agents. 1129,1130 C. difficile is an anaerobic, gram-positive bacterium. Normally fastidious in its vegetative state, it is capable of sporulating when environmental conditions no longer support its continued growth. The capacity to form spores enables the organism to persist in the environment (e.g., in soil and on dry surfaces) for extended periods of time. Environmental contamination by this microorganism is well known, especially in places where fecal contamination may occur. 1131 The environment (especially housekeeping surfaces) rarely serves as a direct source of infection for patients. 1024, However, direct exposure to contaminated patient-care items (e.g., rectal thermometers) and high-touch surfaces in patients' bathrooms (e.g., light switches) have been implicated as sources of infection. 1130,1135,1136,1138 Transfer of the pathogen to the patient via the hands of health-care workers is thought to be the most likely mechanism of exposure. 24,1133,1139 Standard isolation techniques intended to minimize enteric contamination of patients, health-care-workers' hands, patient-care items, and environmental surfaces have been published. 1140 Handwashing remains the most effective means of reducing hand contamination. Proper use of gloves is an ancillary measure that helps to further minimize transfer of these pathogens from one surface to another.\nThe degree to which the environment becomes contaminated with C. difficile spores is proportional to the number of patients with C. difficile-associated diarrhea, 24,1132,1135 although asymptomatic, colonized patients may also serve as a source of contamination. Few studies have examined the use of specific chemical germicides for the inactivation of C. difficile spores, and no well-controlled trials have been conducted to determine efficacy of surface disinfection and its impact on health-care associated diarrhea. Some investigators have evaluated the use of chlorine-containing chemicals (e.g., 1,000 ppm hypochlorite at recommended use-dilution, 5,000 ppm sodium hypochlorite , 1:100 v/v dilutions of unbuffered hypochlorite, and phosphate-buffered hypochlorite ). One of the studies demonstrated that the number of contaminated environmental sites was reduced by half, 1135 whereas another two studies demonstrated declines in health-care associated C. difficile infections in a HSCT unit 1141 and in two geriatric medical units 1142 during a period of hypochlorite use. The presence of confounding factors, however, was acknowledged in one of these studies. 1142 The recommended approach to environmental infection control with respect to C. difficile is meticulous cleaning followed by disinfection using hypochlorite-based germicides as appropriate. 952,1130,1143 However, because no EPAregistered surface disinfectants with label claims for inactivation of C. difficile spores are available, the recommendation is based on the best available evidence from the scientific literature.\n\n# c. Respiratory and Enteric Viruses in Pediatric-Care Settings\nAlthough the viruses mentioned in this guideline are not unique to the pediatric-care setting in healthcare facilities, their prevalence in these areas, especially during the winter months, is substantial. Children (particularly neonates) are more likely to develop infection and substantial clinical disease from these agents compared with adults and therefore are more likely to require supportive care during their illness.\nCommon respiratory viruses in pediatric-care areas include rhinoviruses, respiratory syncytial virus (RSV), adenoviruses, influenza viruses, and parainfluenza viruses. Transmission of these viruses occurs primarily via direct contact with small-particle aerosols or via hand contamination with respiratory secretions that are then transferred to the nose or eyes. Because transmission primarily requires close personal contact, contact precautions are appropriate to interrupt transmission. 6 Hand contamination can occur from direct contact with secretions or indirectly from touching high-touch environmental surfaces that have become contaminated with virus from large droplets. The indirect transfer of virus from one persion to other via hand contact with frequently-touched fomites was demonstrated in a study using a bacteriophage whose environmental stability approximated that of human viral pathogens (e.g., poliovirus and parvovirus). 1144 The impact of this mode of transmission with respect to human respiratory-and enteric viruses is dependent on the ability of these agents to survive on environmental surfaces. Infectious RSV has been recovered from skin, porous surfaces, and non-porous surfaces after 30 minutes, 1 hour, and 7 hours, respectively. 1145 Parainfluenza viruses are known to persist for up to 4 hours on porous surfaces and up to 10 hours on non-porous surfaces. 1146 Rhinoviruses can persist on porous surfaces and non-porous surfaces for approximately 1 and 3 hours respectively; study participants in a controlled environment became infected with rhinoviruses after first touching a surface with dried secretions and then touching their nasal or conjunctival mucosa. 1147 Although the efficiency of direct transmission of these viruses from surfaces in uncontrolled settings remains to be defined, these data underscore the basis for maintaining regular protocols for cleaning and disinfecting of high-touch surfaces.\nThe clinically important enteric viruses encountered in pediatric care settings include enteric adenovirus, astroviruses, caliciviruses, and rotavirus. Group A rotavirus is the most common cause of infectious diarrhea in infants and children. Transmission of this virus is primarily fecal-oral, however, the role of fecally contaminated surfaces and fomites in rotavirus transmission is unclear. During one epidemiologic investigation of enteric disease among children attending day care, rotavirus contamination was detected on 19% of inanimate objects in the center. 1148,1149 In an outbreak in a pediatric unit, secondary cases of rotavirus infection clustered in areas where children with rotaviral diarrhea were located. 1150 Astroviruses cause gastroenteritis and diarrhea in newborns and young children and can persist on fecally contaminated surfaces for several months during periods of relatively low humidity. 1151,1152 Outbreaks of small roundstructured viruses (i.e., caliciviruses ) can affect both patients and staff, with attack rates of ≥50%. 1153 Routes of person-to-person transmission include fecal-oral spread and aerosols generated from vomiting. Fecal contamination of surfaces in care settings can spread large amounts of virus to the environment. Studies that have attempted to use low-and intermediate-level disinfectants to inactivate rotavirus suspended in feces have demonstrated a protective effect of high concentrations of organic matter. 1157,1158 Intermediate-level disinfectants (e.g., alcoholic quaternary ammonium compounds, and chlorine solutions) can be effective in inactivating enteric viruses provided that a cleaning step to remove most of the organic matter precedes terminal disinfection. 1158 These findings underscore the need for proper cleaning and disinfecting procedures where contamination of environmental surfaces with body substances is likely. EPA-registered surface disinfectants with label claims for these viral agents should be used in these settings. Using disposable, protective barrier coverings may help to minimize the degree of surface contamination. 936\n\n# d. Severe Acute Respiratory Syndrome (SARS) Virus\nIn November 2002 an atypical pneumonia of unknown etiology emerged in Asia and subsequently developed into an international outbreak of respiratory illness among persons in 29 countries during the first six months of 2003. \"Severe acute respiratory syndrome\" (SARS) is a viral upper respiratory infection associated with a newly described coronavirus (SARS-associated Co-V ). SARS-CoV is an enveloped RNA virus. It is present in high titers in respiratory secretions, stool, and blood of infected persons. The modes of transmission determined from epidemiologic investigations were primarily forms of direct contact (i.e., large droplet aerosolization and person-to-person contact). Respiratory secretions were presumed to be the major source of virus in these situations; airborne transmission of virus has not been completely ruled out. Little is known about the impact of fecal-oral transmission and SARS.\nThe epidemiology of SARS-CoV infection is not completely understood, and therefore recommended infection control and prevention measures to contain the spread of SARS will evolve as new information becomes available. 1159 At present there is no indication that established strategies for cleaning (i.e., to remove the majority of bioburden) and disinfecting equipment and environmental surfaces need to be changed for the environmental infection control of SARS. In-patient rooms housing SARS patients should be cleaned and disinfected at least daily and at the time of patient transfer or discharge. More frequent cleaning and disinfection may be indicated for high-touch surfaces and following aerosolproducing procedures (e.g., intubation, bronchoscopy, and sputum production). While there are presently no disinfectant products registered by EPA specifically for inactivation of SARS-CoV, EPA-registered hospital disinfectants that are equivalent to low-and intermediate-level germicides may be used on precleaned, hard, non-porous surfaces in accordance with manufacturer's instructions for environmental surface disinfection. Monitoring adherence to guidelines established for cleaning and disinfection is an important component of environmental infection control to contain the spread of SARS.\n\n# e. Creutzfeldt-Jakob Disease (CJD) in Patient-Care Areas\nCreutzfeldt-Jakob disease (CJD) is a rare, invariably fatal, transmissible spongiform encephalopathy (TSE) that occurs worldwide with an average annual incidence of 1 case per million population. CJD is one of several TSEs affecting humans; other diseases in this group include kuru, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker syndrome. A TSE that affects a younger population (compared to the age range of CJD cases) has been described primarily in the United Kingdom since 1996. 1163 This variant form of CJD (vCJD) is clinically and neuropathologically distinguishable from classic CJD; epidemiologic and laboratory evidence suggests a causal association for bovine spongiform encephalopathy (BSE ) and vCJD. The agent associated with CJD is a prion, which is an abnormal isoform of a normal protein constituent of the central nervous system. The mechanism by which the normal form of the protein is converted to the abnormal, disease-causing prion is unknown. The tertiary conformation of the abnormal prion protein appears to confer a heightened degree of resistance to conventional methods of sterilization and disinfection. 1170,1171 Although about 90% of CJD cases occur sporadically, a limited number of cases are the result of a direct exposure to prion-containing material (usually central nervous system tissue or pituitary hormones) acquired as a result of health care (iatrogenic cases). These cases have been linked to a. pituitary hormone therapy , 1170-1174 b. transplants of either dura mater or corneas, and c. neurosurgical instruments and depth electrodes. In the cases involving instruments and depth electrodes, conventional cleaning and terminal reprocessing methods of the day failed to fully inactivate the contaminating prions and are considered inadequate by today's standards.\nPrion inactivation studies involving whole tissues and tissue homogenates have been conducted to determine the parameters of physical and chemical methods of sterilization or disinfection necessary for complete inactivation; 1170, 1186-1191 however, the application of these findings to environmental infection control in health-care settings is problematic. No studies have evaluated the effectiveness of medical instrument reprocessing in inactivating prions. Despite a consensus that abnormal prions display some extreme measure of resistance to inactivation by either physical or chemical methods, scientists disagree about the exact conditions needed for sterilization. Inactivation studies utilizing whole tissues present extraordinary challenges to any sterilizing method. 1192 Additionally, the experimental designs of these studies preclude the evaluation of surface cleaning as a part of the total approach to pathogen inactivation. 951,1192 Some researchers have recommended the use of either a 1:2 v/v dilution of sodium hypochorite (approximately 20,000 ppm), full-strength sodium hypochlorite (50,000-60,000 ppm), or 1-2 N sodium hydroxide (NaOH) for the inactivation of prions on certain surfaces (e.g., those found in the pathology laboratory). 1170,1188 Although these chemicals may be appropriate for the decontamination of laboratory, operating-room, or autopsy-room surfaces that come into contact with central nervous system tissue from a known or suspected patient, this approach is not indicated for routine or terminal cleaning of a room previously occupied by a CJD patient. Both chemicals pose hazards for the healthcare worker doing the decontamination. NaOH is caustic and should not make contact with the skin. Sodium hypochlorite solutions (i.e., chlorine bleach) can corrode metals (e.g., aluminum). MSDS information should be consulted when attempting to work with concentrated solutions of either chemical. Currently, no EPAregistered products have label claims for prion inactivation; therefore, this guidance is based on the best available evidence from the scientific literature.\nEnvironmental infection-control strategies must based on the principles of the \"chain of infection,\" regardless of the disease of concern. 13 Although CJD is transmissible, it is not highly contagious. All iatrogenic cases of CJD have been linked to a direct exposure to prion-contaminated central nervous system tissue or pituitary hormones. The six documented iatrogenic cases associated with instruments and devices involved neurosurgical instruments and devices that introduced residual contamination directly to the recipient's brain. No evidence suggests that vCJD has been transmitted iatrogenically or that either CJD or vCJD has been transmitted from environmental surfaces (e.g., housekeeping surfaces). Therefore, routine procedures are adequate for terminal cleaning and disinfection of a CJD patient's room. Additionally, in epidemiologic studies involving highly transfused patients, blood was not identified as a source for prion transmission. Routine procedures for containing, decontaminating, and disinfecting surfaces with blood spills should be adequate for proper infection control in these situations. 951,1199 Guidance for environmental infection control in ORs and autopsy areas has been published. 1197,1199 Hospitals should develop risk-assessment procedures to identify patients with known or suspected CJD in efforts to implement prion-specific infection-control measures for the OR and for instrument reprocessing. 1200 This assessment also should be conducted for older patients undergoing non-lesionous neurosurgery when such procedures are being done for diagnosis. Disposable, impermeable coverings should be used during these autopsies and neurosurgeries to minimize surface contamination. Surfaces that have become contaminated with central nervous system tissue or cerebral spinal fluid should be cleaned and decontaminated by a. removing most of the tissue or body substance with absorbent materials, b. wetting the surface with a sodium hypochlorite solution containing ≥5,000 ppm or a 1 N NaOH solution, and c. rinsing thoroughly. 951,1201 The optimum duration of contact exposure in these instances is unclear. Some researchers recommend a 1-hour contact time on the basis of tissue-inactivation studies, 1197,1198,1201 whereas other reviewers of the subject draw no conclusions from this research. 1199 Factors to consider before cleaning a potentially contaminated surface are a. the degree to which gross tissue/body substance contamination can be effectively removed and b. the ease with which the surface can be cleaned.\n\n# F. Environmental Sampling\nThis portion of Part I addresses the basic principles and methods of sampling environmental surfaces and other environmental sources for microorganisms. The applied strategies of sampling with respect to environmental infection control have been discussed in the appropriate preceding subsections.\n\n# General Principles: Microbiologic Sampling of the Environment\nBefore 1970, U.S. hospitals conducted regularly scheduled culturing of the air and environmental surfaces (e.g., floors, walls, and table tops). 1202 By 1970, CDC and the American Hospital Association (AHA) were advocating the discontinuation of routine environmental culturing because rates of healthcare-associated infection had not been associated with levels of general microbial contamination of air or environmental surfaces, and because meaningful standards for permissible levels of microbial contamination of environmental surfaces or air did not exist. 1203-1205During 1970, 25% of U.S. hospitals reduced the extent of such routine environmental culturing -a trend that has continued. 1206,1207 Random, undirected sampling (referred to as \"routine\" in previous guidelines) differs from the current practice of targeted sampling for defined purposes. 2,1204 Previous recommendations against routine sampling were not intended to discourage the use of sampling in which sample collection, culture, and interpretation are conducted in accordance with defined protocols. 2 In this guideline, targeted microbiologic sampling connotes a monitoring process that includes a. a written, defined, multidisciplinary protocol for sample collection and culturing b. analysis and interpretation of results using scientifically determined or anticipatory baseline values for comparison; and c. expected actions based on the results obtained.\nInfection control, in conjunction with laboratorians, should assess the health-care facility's capability to conduct sampling and determine when expert consultation and/or services are needed.\nMicrobiologic sampling of air, water, and inanimate surfaces (i.e., environmental sampling) is an expensive and time-consuming process that is complicated by many variables in protocol, analysis, and interpretation. It is therefore indicated for only four situations. 1208 The first is to support an investigation of an outbreak of disease or infections when environmental reservoirs or fomites are implicated epidemiologically in disease transmission. 161,1209,1210 It is important that such culturing be supported by epidemiologic data. Environmental sampling, as with all laboratory testing, should not be conducted if there is no plan for interpreting and acting on the results obtained. 11,1211,1212 Linking microorganisms from environmental samples with clinical isolates by molecular epidemiology is crucial whenever it is possible to do so.\nThe second situation for which environmental sampling may be warranted is in research. Well-designed and controlled experimental methods and approaches can provide new information about the spread of health-care associated diseases. 126, 129 A classic example is the study of environmental microbial contamination that compared health-care associated infection rates in an old hospital and a new facility before and shortly after occupancy. 947 The third indication for sampling is to monitor a potentially hazardous environmental condition, confirm the presence of a hazardous chemical or biological agent, and validate the successful abatement of the hazard. This type of sampling can be used to: a. detect bioaerosols released from the operation of health-care equipment (e.g., an ultrasonic cleaner)\nand determine the success of repairs in containing the hazard, 1213 b. detect the release of an agent of bioterrorism in an indoor environmental setting and determine its successful removal or inactivation, and c. sample for industrial hygiene or safety purposes (e.g., monitoring a \"sick building\").\nThe fourth indication is for quality assurance to evaluate the effects of a change in infection-control practice or to ensure that equipment or systems perform according to specifications and expected outcomes. Any sampling for quality-assurance purposes must follow sound sampling protocols and address confounding factors through the use of properly selected controls. Results from a single environmental sample are difficult to interpret in the absence of a frame of reference or perspective. Evaluations of a change in infection-control practice are based on the assumption that the effect will be measured over a finite period, usually of short duration. Conducting quality-assurance sampling on an extended basis, especially in the absence of an adverse outcome, is usually unjustified. A possible exception might be the use of air sampling during major construction periods to qualitatively detect breaks in environmental infection-control measures. In one study, which began as part of an investigation of an outbreak of health-care associated aspergillosis, airborne concentrations of Aspergillus spores were measured in efforts to evaluate the effectiveness of sealing hospital doors and windows during a period of construction of a nearby building. 50 Other examples of sampling for quality-assurance purposes may include commissioning newly constructed space in special care areas (i.e., ORs and units for immunosuppressed patients) or assessing a change in housekeeping practice. However, the only types of routine environmental microbiologic sampling recommended as part of a quality-assurance program are a. the biological monitoring of sterilization processes by using bacterial spores 1214 and b. the monthly culturing of water used in hemodialysis applications and for the final dialysate use dilution. Some experts also advocate periodic environmental sampling to evaluate the microbial/particulate quality for regular maintenance of the air handling system (e.g., filters) and to verify that the components of the system meet manufacturer's specifications (A. Streifel, University of Minnesota, 2000). Certain equipment in health-care settings (e.g., biological safety cabinets) may also be monitored with air flow and particulate sampling to determine performance or as part of adherence to a certification program; results can then be compared with a predetermined standard of performance. These measurements, however, usually do not require microbiologic testing.\n\n# Air Sampling\nBiological contaminants occur in the air as aerosols and may include bacteria, fungi, viruses, and pollens. 1215,1216 Aerosols are characterized as solid or liquid particles suspended in air. Talking for 5 minutes and coughing each can produce 3,000 droplet nuclei; sneezing can generate approximately 40,000 droplets which then evaporate to particles in the size range of 0.5-12 μm. 137,1217 Particles in a biological aerosol usually vary in size from <1 μm to ≥50 μm. These particles may consist of a single, unattached organism or may occur in the form of clumps composed of a number of bacteria. Clumps can also include dust and dried organic or inorganic material. Vegetative forms of bacterial cells and viruses may be present in the air in a lesser number than bacterial spores or fungal spores. Factors that determine the survival of microorganisms within a bioaerosol include a. the suspending medium, b. temperature, c. relative humidity, d. oxygen sensitivity, and e. exposure to UV or electromagnetic radiation. 1215 Many vegetative cells will not survive for lengthy periods of time in the air unless the protective cover (e.g., dried organic or inorganic matter). 1216 Pathogens that resist drying (e.g., Staphylococcus spp., Streptococcus spp., and fungal spores) can survive for long periods and can be carried considerable distances via air and still remain viable. They may also settle on surfaces and become airborne again as secondary aerosols during certain activities (e.g., sweeping and bed making). 1216,1218 Microbiologic air sampling is used as needed to determine the numbers and types of microorganisms, or particulates, in indoor air. 289 Air sampling for quality control is, however, problematic because of lack of uniform air-quality standards. Although airborne spores of Aspergillus spp. can pose a risk for neutropenic patients, the critical number (i.e., action level) of these spores above which outbreaks of aspergillosis would be expected to occur has not been defined. Health-care professionals considering the use of air sampling should keep in mind that the results represent indoor air quality at singular points in time, and these may be affected by a variety of factors, including a. indoor traffic, b. visitors entering the facility, c. temperature, d. time of day or year, e. relative humidity, f. relative concentration of particles or organisms, and g) the performance of the air-handling system components.\nTo be meaningful, air-sampling results must be compared with those obtained from other defined areas, conditions, or time periods.\nSeveral preliminary concerns must be addressed when designing a microbiologic air sampling strategy (Box 13). Because the amount of particulate material and bacteria retained in the respiratory system is largely dependent on the size of the inhaled particles, particle size should be determined when studying airborne microorganisms and their relation to respiratory infections. Particles >5 μm are efficiently trapped in the upper respiratory tract and are removed primarily by ciliary action. 1219 Particles ≤5 μm in diameter reach the lung, but the greatest retention in the alveoli is of particles 1-2 μm in diameter. \n\n# Box 13. Preliminary concerns for conducting air sampling\n- Consider the possible characteristics and conditions of the aerosol, including size range of particles, relative amount of inert material, concentration of microorganisms, and environmental factors.\n- Determine the type of sampling instruments, sampling time, and duration of the sampling program.\n- Determine the number of samples to be taken.\n- Ensure that adequate equipment and supplies are available.\n- Determine the method of assay that will ensure optimal recovery of microorganisms.\n- Select a laboratory that will provide proper microbiologic support.\n- Ensure that samples can be refrigerated if they cannot be assayed in the laboratory promptly.\nBacteria, fungi, and particulates in air can be identified and quantified with the same methods and equipment (Table 23). The basic methods include a. impingement in liquids, b. impaction on solid surfaces, c. sedimentation, d. filtration, e. centrifugation, f. electrostatic precipitation, and g. thermal precipitation. 1218 Of these, impingement in liquids, impaction on solid surfaces, and sedimentation (on settle plates) have been used for various air-sampling purposes in health-care settings. 289 Several instruments are available for sampling airborne bacteria and fungi (Box 14). Some of the samplers are self-contained units requiring only a power supply and the appropriate collecting medium, but most require additional auxiliary equipment (e.g., a vacuum pump and an airflow measuring device ). Sedimentation or depositional methods use settle plates and therefore need no special instruments or equipment. Selection of an instrument for air sampling requires a clear understanding of the type of information desired and the particular determinations that must be made (Box 14). Information may be needed regarding a. one particular organism or all organisms that may be present in the air, b. the concentration of viable particles or of viable organisms, c. the change in concentration with time, and d. the size distribution of the collected particles.\nBefore sampling begins, decisions should be made regarding whether the results are to be qualitative or quantitative. Comparing quantities of airborne microorganisms to those of outdoor air is also standard operating procedure. Infection-control professionals, hospital epidemiologists, industrial hygienists, and laboratory supervisors, as part of a multidisciplinary team, should discuss the potential need for microbial air sampling to determine if the capacity and expertise to conduct such sampling exists within the facility and when it is appropriate to enlist the services of an environmental microbiologist consultant.\n\n# Box 14. Selecting an air sampling device*\nThe following factors must be considered when choosing an air sampling instrument:\n- Viability and type of the organism to be sampled\n- Compatibility with the selected method of analysis\n- Sensitivity of particles to sampling - Assumed concentrations and particle size\n- Whether airborne clumps must be broken (i.e., total viable organism count vs. particle count)\n- Volume of air to be sampled and length of time sampler is to be continuously operated Liquid impinger and solid impactor samplers are the most practical for sampling bacteria, particles, and fungal spores, because they can sample large volumes of air in relatively short periods of time. 289 Solid impactor units are available as either \"slit\" or \"sieve\" designs. Slit impactors use a rotating disc as support for the collecting surface, which allows determinations of concentration over time. Sieve impactors commonly use stages with calibrated holes of different diameters. Some impactor-type samplers use centrifugal force to impact particles onto agar surfaces. The interior of either device must be made sterile to avoid inadvertent contamination from the sampler. Results obtained from either sampling device can be expressed as organisms or particles per unit volume of air (CFU/m 3 ).\nSampling for bacteria requires special attention, because bacteria may be present as individual organisms, as clumps, or mixed with or adhering to dust or covered with a protective coating of dried organic or inorganic substances. Reports of bacterial concentrations determined by air sampling therefore must indicate whether the results represent individual organisms or particles bearing multiple cells. Certain types of samplers (e.g., liquid impingers) will completely or partially disintegrate clumps and large particles; the sampling result will therefore reflect the total number of individual organisms present in the air.\nThe task of sizing a bioaerosol is simplified through the use of sieves or slit impactors because these samplers will separate the particles and microorganisms into size ranges as the sample is collected. These samplers must, however, be calibrated first by sampling aerosols under similar use conditions. 1225 The use of settle plates (i.e., the sedimentation or depositional method) is not recommended when sampling air for fungal spores, because single spores can remain suspended in air indefinitely. 289 Settle plates have been used mainly to sample for particulates and bacteria either in research studies or during epidemiologic investigations. 161, Results of sedimentation sampling are typically expressed as numbers of viable particles or viable bacteria per unit area per the duration of sampling time (i.e., CFU/area/time); this method can not quantify the volume of air sampled. Because the survival of microorganisms during air sampling is inversely proportional to the velocity at which the air is taken into the sampler, 1215 one advantage of using a settle plate is its reliance on gravity to bring organisms and particles into contact with its surface, thus enhancing the potential for optimal survival of collected organisms. This process, however, takes several hours to complete and may be impractical for some situations.\nAir samplers are designed to meet differing measurement requirements. Some samplers are better suited for one form of measurement than others. No one type of sampler and assay procedure can be used to collect and enumerate 100% of airborne organisms. The sampler and/or sampling method chosen should, however, have an adequate sampling rate to collect a sufficient number of particles in a reasonable time period so that a representative sample of air is obtained for biological analysis. Newer analytical techniques for assaying air samples include PCR methods and enzyme-linked immunosorbent assays (ELISAs).\n\n# Water Sampling\nA detailed discussion of the principles and practices of water sampling has been published. 945 Water sampling in health-care settings is used detect waterborne pathogens of clinical significance or to determine the quality of finished water in a facility's distribution system. Routine testing of the water in a health-care facility is usually not indicated, but sampling in support of outbreak investigations can help determine appropriate infection-control measures. Water-quality assessments in dialysis settings have been discussed in this guideline (see Water, Dialysis Water Quality and Dialysate, and Appendix C).\nHealth-care facilities that conduct water sampling should have their samples assayed in a laboratory that uses established methods and quality-assurance protocols. Water specimens are not \"static specimens\" at ambient temperature; potential changes in both numbers and types of microbial populations can occur during transport. Consequently, water samples should be sent to the testing laboratory cold (i.e., at approximately 39.2°F ) and testing should be done as soon as practical after collection (preferably within 24 hours).\nBecause most water sampling in health-care facilities involves the testing of finished water from the facility's distribution system, a reducing agent (i.e., sodium thiosulfate ) needs to be added to neutralize residual chlorine or other halogen in the collected sample. If the water contains elevated levels of heavy metals, then a chelating agent should be added to the specimen. The minimum volume of water to be collected should be sufficient to complete any and all assays indicated; 100 mL is considered a suitable minimum volume. Sterile collection equipment should always be used.\nSampling from a tap requires flushing of the water line before sample collection. If the tap is a mixing faucet, attachments (e.g., screens and aerators) must be removed, and hot and then cold water must be run through the tap before collecting the sample. 945 If the cleanliness of the tap is questionable, disinfection with 500-600 ppm sodium hypochlorite (1:100 v/v dilution of chlorine bleach) and flushing the tap should precede sample collection.\nMicroorganisms in finished or treated water often are physically damaged (\"stressed\") to the point that growth is limited when assayed under standard conditions. Such situations lead to false-negative readings and misleading assessments of water quality. Appropriate neutralization of halogens and chelation of heavy metals are crucial to the recovery of these organisms. The choice of recovery media and incubation conditions will also affect the assay. Incubation temperatures should be closer to the ambient temperature of the water rather than at 98.6°F (37°C), and recovery media should be formulated to provide appropriate concentrations of nutrients to support organisms exhibiting less than rigorous growth. 945 High-nutrient content media (e.g., blood agar and tryptic soy agar ) may actually inhibit the growth of these damaged organisms. Reduced nutrient media (e.g., diluted peptone and R2A) are preferable for recovery of these organisms. 945 Use of aerobic, heterotrophic plate counts allows both a qualitative and quantitative measurement for water quality. If bacterial counts in water are expected to be high in number (e.g., during waterborne outbreak investigations), assaying small quantities using pour plates or spread plates is appropriate. 945 Membrane filtration is used when low-count specimens are expected and larger sampling volumes are required (≥100 mL). The sample is filtered through the membrane, and the filter is applied directly faceup onto the surface of the agar plate and incubated.\nUnlike the testing of potable water supplies for coliforms (which uses standardized test and specimen collection parameters and conditions), water sampling to support epidemiologic investigations of disease outbreaks may be subjected to modifications dictated by the circumstances present in the facility. Assay methods for waterborne pathogens may also not be standardized. Therefore, control or comparison samples should be included in the experimental design. Any departure from a standard method should be fully documented and should be considered when interpreting results and developing strategies. Assay methods specific for clinically significant waterborne pathogens (e.g., Legionella spp., Aeromonas spp., Pseudomonas spp., and Acinetobacter spp.) are more complicated and costly compared with both methods used to detect coliforms and other standard indicators of water quality.\n\n# Environmental Surface Sampling\nRoutine environmental-surface sampling (e.g., surveillance cultures) in health-care settings is neither cost-effective nor warranted. 951, 1225 When indicated, surface sampling should be conducted with multidisciplinary approval in adherence to carefully considered plans of action and policy (Box 15).\n\n# Box 15. Undertaking environmental-surface sampling*\nThe following factors should be considered before engaging in environmental-surface sampling:\n- Background information from the literature and present activities (i.e., preliminary results from an epidemiologic investigation)\n- Location of surfaces to be sampled Surface sampling is used currently for research, as part of an epidemiologic investigation, or as part of a comprehensive approach for specific quality assurance purposes. As a research tool, surface sampling has been used to determine a. potential environmental reservoirs of pathogens, 564, b. survival of microorganisms on surfaces, 1232,1233 and c. the sources of the environmental contamination. 1023 Some or all of these approaches can also be used during outbreak investigations. 1232 Discussion of surface sampling of medical devices and instruments is beyond the scope of this document and is deferred to future guidelines on sterilization and disinfection issues.\nMeaningful results depend on the selection of appropriate sampling and assay techniques. 1214 The media, reagents, and equipment required for surface sampling are available from any well-equipped microbiology laboratory and laboratory supplier. For quantitative assessment of surface organisms, nonselective, nutrient-rich agar media and broth (e.g., TSA and brain-heart infusion broth with or without 5% sheep or rabbit blood supplement) are used for the recovery of aerobic bacteria. Broth media are used with membrane-filtration techniques. Further sample work-up may require the use of selective media for the isolation and enumeration of specific groups of microorganisms. Examples of selective media are MacConkey agar (MAC ), Cetrimide agar (selects for Pseudomonas aeruginosa), or Sabouraud dextrose-and malt extract agars and broths (select for fungi). Qualitative determinations of organisms from surfaces require only the use of selective or non-selective broth media.\nEffective sampling of surfaces requires moisture, either already present on the surface to be sampled or via moistened swabs, sponges, wipes, agar surfaces, or membrane filters. 1214, Dilution fluids and rinse fluids include various buffers or general purpose broth media (Table 24). If disinfectant residuals are expected on surfaces being sampled, specific neutralizer chemicals should be used in both the growth media and the dilution or rinse fluids. Lists of the neutralizers, the target disinfectant active ingredients, and the use concentrations have been published. 1214,1237 Alternatively, instead of adding neutralizing chemicals to existing culture media (or if the chemical nature of the disinfectant residuals is unknown), the use of either a. commercially available media including a variety of specific and nonspecific neutralizers or b. double-strength broth media will facilitate optimal recovery of microorganisms.\nThe inclusion of appropriate control specimens should be included to rule out both residual antimicrobial activity from surface disinfectants and potential toxicity caused by the presence of neutralizer chemicals carried over into the assay system. 1214 Several methods can be used for collecting environmental surface samples (Table 25). Specific stepbystep discussions of each of the methods have been published. 1214,1239 For best results, all methods should incorporate aseptic techniques, sterile equipment, and sterile recovery media. Sample/rinse methods are frequently chosen because of their versatility. However, these sampling methods are the most prone to errors caused by manipulation of the swab, gauze pad, or sponge. 1238 Additionally, no microbiocidal or microbiostatic agents should be present in any of these items when used for sampling. 1238 Each of the rinse methods requires effective elution of microorganisms from the item used to sample the surface. Thorough mixing of the rinse fluids after elution (e.g., via manual or mechanical mixing using a vortex mixer, shaking with or without glass beads, and ultrasonic bath) will help to remove and suspend material from the sampling device and break up clumps of organisms for a more accurate count. 1238 In some instances, the item used to sample the surface (e.g., gauze pad and sponge) may be immersed in the rinse fluids in a sterile bag and subjected to stomaching. 1238 This technique, however, is suitable only for soft or absorbent items that will not puncture the bag during the elution process.\nIf sampling is conducted as part of an epidemiologic investigation of a disease outbreak, identification of isolates to species level is mandatory, and characterization beyond the species level is preferred. 1214 When interpreting the results of the sampling, the expected degree of microbial contamination associated with the various categories of surfaces in the Spaulding classification must be considered. Environmental surfaces should be visibly clean; recognized pathogens in numbers sufficient to result in secondary transfer to other animate or inanimate surfaces should be absent from the surface being sampled. 1214 Although the interpretation of a sample with positive microbial growth is self-evident, an environmental surface sample, especially that obtained from housekeeping surfaces, that shows no growth does not represent a \"sterile\" surface. Sensitivities of the sampling and assay methods (i.e., level of detection) must be taken into account when no-growth samples are encountered. Properly collected control samples will help rule out extraneous contamination of the surface sample.\n\n# G. Laundry and Bedding\n\n# General Information\nLaundry in a health-care facility may include bed sheets and blankets, towels, personal clothing, patient apparel, uniforms, scrub suits, gowns, and drapes for surgical procedures. 1245 Although contaminated textiles and fabrics in health-care facilities can be a source of substantial numbers of pathogenic microorganisms, reports of health-care associated diseases linked to contaminated fabrics are so few in number that the overall risk of disease transmission during the laundry process likely is negligible. When the incidence of such events are evaluated in the context of the volume of items laundered in health-care settings (estimated to be 5 billion pounds annually in the United States), 1246 existing control measures (e.g., standard precautions) are effective in reducing the risk of disease transmission to patients and staff. Therefore, use of current control measures should be continued to minimize the contribution of contaminated laundry to the incidence of health-care associated infections. The control measures described in this section of the guideline are based on principles of hygiene, common sense, and consensus guidance; they pertain to laundry services utilized by health-care facilities, either inhouse or contract, rather than to laundry done in the home.\n\n# Epidemiology and General Aspects of Infection Control\nContaminated textiles and fabrics often contain high numbers of microorganisms from body substances, including blood, skin, stool, urine, vomitus, and other body tissues and fluids. When textiles are heavily contaminated with potentially infective body substances, they can contain bacterial loads of 10 6 -10 8 CFU/100 cm 2 of fabric. 1247 Disease transmission attributed to health-care laundry has involved contaminated fabrics that were handled inappropriately (i.e., the shaking of soiled linens). Bacteria (Salmonella spp., Bacillus cereus), viruses (hepatitis B virus ), fungi (Microsporum canis), and ectoparasites (scabies) presumably have been transmitted from contaminated textiles and fabrics to workers via a. direct contact or b. aerosols of contaminated lint generated from sorting and handling contaminated textiles. In these events, however, investigations could not rule out the possibility that some of these reported infections were acquired from community sources. Through a combination of soil removal, pathogen removal, and pathogen inactivation, contaminated laundry can be rendered hygienically clean. Hygienically clean laundry carries negligible risk to health-care workers and patients, provided that the clean textiles, fabric, and clothing are not inadvertently contaminated before use.\nOSHA defines contaminated laundry as \"laundry which has been soiled with blood or other potentially infectious materials or may contain sharps.\" 967 The purpose of the laundry portion of the standard is to protect the worker from exposure to potentially infectious materials during collection, handling, and sorting of contaminated textiles through the use of personal protective equipment, proper work practices, containment, labeling, hazard communication, and ergonomics.\nExperts are divided regarding the practice of transporting clothes worn at the workplace to the healthcare worker's home for laundering. Although OSHA regulations prohibit home laundering of items that are considered personal protective apparel or equipment (e.g., laboratory coats), 967 experts disagree about whether this regulation extends to uniforms and scrub suits that are not contaminated with blood or other potentially infectious material. Health-care facility policies on this matter vary and may be inconsistent with recommendations of professional organizations. 1253,1254 Uniforms without blood or body substance contamination presumably do not differ appreciably from street clothes in the degree and microbial nature of soilage. Home laundering would be expected to remove this level of soil adequately. However, if health-care facilities require the use of uniforms, they should either make provisions to launder them or provide information to the employee regarding infection control and cleaning guidelines for the item based on the tasks being performed at the facility. Health-care facilities should address the need to provide this service and should determine the frequency for laundering these items. In a recent study examining the microbial contamination of medical students' white coats, the students perceived the coats as \"clean\" as long as the garments were not visibly contaminated with body substances, even after wearing the coats for several weeks. 1255 The heaviest bacterial load was found on the sleeves and the pockets of these garments; the organisms most frequently isolated were Staphylococcus aureus, diphtheroids, and Acinetobacter spp. 1255 Presumably, the sleeves of the coat may make contact with a patient and potentially serve to transfer environmentally stable microorganisms among patients. In this study, however, surveillance was not conducted among patients to detect new infections or colonizations. The students did, however, report that they would likely replace their coats more frequently and regularly if clean coats were provided. 1255 Apart from this study, which documents the presence of pathogenic bacteria on health-care facility clothing, reports of infections attributed to either the contact with such apparel or with home laundering have been rare. 1256,1257 Laundry services for health-care facilities are provided either in-house (i.e., on-premise laundry ), co-operatives (i.e., those entities owned and operated by a group of facilities), or by off-site commercial laundries. In the latter, the textiles may be owned by the health-care facility, in which case the processor is paid for laundering only. Alternatively, the textiles may be owned by the processor who is paid for every piece laundered on a \"rental\" fee. The laundry facility in a health-care setting should be designed for efficiency in providing hygienically clean textiles, fabrics, and apparel for patients and staff. Guidelines for laundry construction and operation for health-care facilities, including nursing facilities, have been published. 120,1258 The design and engineering standards for existing facilities are those cited in the AIA edition in effect during the time of the facility's construction. 120 A laundry facility is usually partitioned into two separate areas -a \"dirty\" area for receiving and handling the soiled laundry and a \"clean\" area for processing the washed items. 1259 To minimize the potential for recontaminating cleaned laundry with aerosolized contaminated lint, areas receiving contaminated textiles should be at negative air pressure relative to the clean areas. Laundry areas should have handwashing facilities readily available to workers. Laundry workers should wear appropriate personal protective equipment (e.g., gloves and protective garments) while sorting soiled fabrics and textiles. 967 Laundry equipment should be used and maintained according to the manufacturer's instructions to prevent microbial contamination of the system. 1250,1263 Damp textiles should not be left in machines overnight. 1250\n\n# Collecting, Transporting, and Sorting Contaminated Textiles and Fabrics\nThe laundry process starts with the removal of used or contaminated textiles, fabrics, and/or clothing from the areas where such contamination occurred, including but not limited to patients' rooms, surgical/operating areas, and laboratories. Handling contaminated laundry with a minimum of agitation can help prevent the generation of potentially contaminated lint aerosols in patient-care areas. 967,1259 Sorting or rinsing contaminated laundry at the location where contamination occurred is prohibited by OSHA. 967 Contaminated textiles and fabrics are placed into bags or other appropriate containment in this location; these bags are then securely tied or otherwise closed to prevent leakage. 967 Single bags of sufficient tensile strength are adequate for containing laundry, but leak-resistant containment is needed if the laundry is wet and capable of soaking through a cloth bag. 1264 Bags containing contaminated laundry must be clearly identified with labels, color-coding, or other methods so that health-care workers handle these items safely, regardless of whether the laundry is transported within the facility or destined for transport to an off-site laundry service. 967 Typically, contaminated laundry originating in isolation areas of the hospital is segregated and handled with special practices; however, few, if any, cases of health-care associated infection have been linked to this source. 1265 Single-blinded studies have demonstrated that laundry from isolation areas is no more heavily contaminated with microorganisms than laundry from elsewhere in the hospital. 1266 Therefore, adherence to standard precautions when handling contaminated laundry in isolation areas and minimizing agitation of the contaminated items are considered sufficient to prevent the dispersal of potentially infectious aerosols. 6 Contaminated textiles and fabrics in bags can be transported by cart or chute. 1258,1262 Laundry chutes require proper design, maintenance, and use, because the piston-like action of a laundry bag traveling in the chute can propel airborne microbial contaminants throughout the facility. Laundry chutes should be maintained under negative air pressure to prevent the spread of microorganisms from floor to floor. Loose, contaminated pieces of laundry should not be tossed into chutes, and laundry bags should be closed or otherwise secured to prevent the contents from falling out into the chute. 1270 Health-care facilities should determine the point in the laundry process at which textiles and fabrics should be sorted. Sorting after washing minimizes the exposure of laundry workers to infective material in soiled fabrics, reduces airborne microbial contamination in the laundry area, and helps to prevent potential percutaneous injuries to personnel. 1271 Sorting laundry before washing protects both the machinery and fabrics from hard objects (e.g., needles, syringes, and patients' property) and reduces the potential for recontamination of clean textiles. 1272 Sorting laundry before washing also allows for customization of laundry formulas based on the mix of products in the system and types of soils encountered. Additionally, if work flow allows, increasing the amount of segregation by specific product types will usually yield the greatest amount of work efficiency during inspection, folding, and pack-making operations. 1253 Protective apparel for the workers and appropriate ventilation can minimize these exposures. 967, Gloves used for the task of sorting laundry should be of sufficient thickness to minimize sharps injuries. 967 Employee safety personnel and industrial hygienists can help to determine the appropriate glove choice.\n\n# Parameters of the Laundry Process\nFabrics, textiles, and clothing used in health-care settings are disinfected during laundering and generally rendered free of vegetative pathogens (i.e., hygienically clean), but they are not sterile. 1273 Laundering cycles consist of flush, main wash, bleaching, rinsing, and souring. 1274 Cleaned wet textiles, fabrics, and clothing are then dried, pressed as needed, and prepared (e.g., folded and packaged) for distribution back to the facility. Clean linens provided by an off-site laundry must be packaged prior to transport to prevent inadvertent contamination from dust and dirt during loading, delivery, and unloading. Functional packaging of laundry can be achieved in several ways, including a. placing clean linen in a hamper lined with a previously unused liner, which is then closed or covered b. placing clean linen in a properly cleaned cart and covering the cart with disposable material or a properly cleaned reusable textile material that can be secured to the cart; and c. wrapping individual bundles of clean textiles in plastic or other suitable material and sealing or taping the bundles.\nThe antimicrobial action of the laundering process results from a combination of mechanical, thermal, and chemical factors. 1271,1275,1276 Dilution and agitation in water remove substantial quantities of microorganisms. Soaps and detergents function to suspend soils and also exhibit some microbiocidal properties. Hot water provides an effective means of destroying microorganisms. 1277 A temperature of at least 160°F (71°C) for a minimum of 25 minutes is commonly recommended for hot-water washing. 2 Water of this temperature can be provided by steam jet or separate booster heater. 120 The use of chlorine bleach assures an extra margin of safety. 1278, 1279 A total available chlorine residual of 50-150 ppm is usually achieved during the bleach cycle. 1277 Chlorine bleach becomes activated at water temperatures of 135°F-145°F (57.2°C-62.7°C). The last of the series of rinse cycles is the addition of a mild acid (i.e., sour) to neutralize any alkalinity in the water supply, soap, or detergent. The rapid shift in pH from approximately 12 to 5 is an effective means to inactivate some microorganisms. 1247 Effective removal of residual alkali from fabrics is an important measure in reducing the risk for skin reactions among patients.\nChlorine bleach is an economical, broad-spectrum chemical germicide that enhances the effectiveness of the laundering process. Chlorine bleach is not, however, an appropriate laundry additive for all fabrics. Traditionally, bleach was not recommended for laundering flame-retardant fabrics, linens, and clothing because its use diminished the flame-retardant properties of the treated fabric. 1273 However, some modernday flame retardant fabrics can now tolerate chlorine bleach. Flame-retardant fabrics, whether topically treated or inherently flame retardant, should be thoroughly rinsed during the rinse cycles, because detergent residues are capable of supporting combustion. Chlorine alternatives (e.g., activated oxygenbased laundry detergents) provide added benefits for fabric and color safety in addition to antimicrobial activity. Studies comparing the antimicrobial potencies of chlorine bleach and oxygen-based bleach are needed. Oxygen-based bleach and detergents used in health-care settings should be registered by EPA to ensure adequate disinfection of laundry. Health-care workers should note the cleaning instructions of textiles, fabrics, drapes, and clothing to identify special laundering requirements and appropriate hygienic cleaning options. 1278 Although hot-water washing is an effective laundry disinfection method, the cost can be substantial. Laundries are typically the largest users of hot water in hospitals. They consume 50%-75% of the total hot water, 1280 representing an average of 10%-15% of the energy used by a hospital. Several studies have demonstrated that lower water temperatures of 71°F-77°F (22°C-25°C) can reduce microbial contamination when the cycling of the washer, the wash detergent, and the amount of laundry additive are carefully monitored and controlled. 1247, Low-temperature laundry cycles rely heavily on the presence of chlorine-or oxygen-activated bleach to reduce the levels of microbial contamination. The selection of hot-or cold-water laundry cycles may be dictated by state health-care facility licensing standards or by other regulation. Regardless of whether hot or cold water is used for washing, the temperatures reached in drying and especially during ironing provide additional significant microbiocidal action. 1247 Dryer temperatures and cycle times are dictated by the materials in the fabrics. Man-made fibers (i.e., polyester and polyester blends) require shorter times and lower temperatures.\nAfter washing, cleaned and dried textiles, fabrics, and clothing are pressed, folded, and packaged for transport, distribution, and storage by methods that ensure their cleanliness until use. 2 State regulations and/or accrediting standards may dictate the procedures for this activity. Clean/sterile and contaminated textiles should be transported from the laundry to the health-care facility in vehicles (e.g., trucks, vans, and carts) that allow for separation of clean/sterile and contaminated items. Clean/sterile textiles and contaminated textiles may be transported in the same vehicle, provided that the use of physical barriers and/or space separation can be verified to be effective in protecting the clean/sterile items from contamination. Clean, uncovered/unwrapped textiles stored in a clean location for short periods of time (e.g., uncovered and used within a few hours) have not been demonstrated to contribute to increased levels of health-care acquired infection. Such textiles can be stored in convenient places for use during the provision of care, provided that the textiles can be maintained dry and free from soil and body-substance contamination.\nIn the absence of microbiologic standards for laundered textiles, no rationale exists for routine microbiologic sampling of cleaned health-care textiles and fabrics. 1286 Sampling may be used as part of an outbreak investigation if epidemiologic evidence suggests that textiles, fabrics, or clothing are a suspected vehicle for disease transmission. Sampling techniques include aseptically macerating the fabric into pieces and adding these to broth media or using contact plates (RODAC plates) for direct surface sampling. 1271,1286 When evaluating the disinfecting properties of the laundering process specifically, placing pieces of fabric between two membrane filters may help to minimize the contribution of the physical removal of microorganisms. 1287 Washing machines and dryers in residential-care settings are more likely to be consumer items rather than the commercial, heavy-duty, large volume units typically found in hospitals and other institutional healthcare settings. Although all washing machines and dryers in health-care settings must be properly maintained for performance according to the manufacturer's instructions, questions have been raised\nabout the need to disinfect washers and dryers in residential-care settings. Disinfection of the tubs and tumblers of these machines is unnecessary when proper laundry procedures are followed; these procedures involve a. the physical removal of bulk solids (e.g., feces) before the wash/dry cycle and b. proper use of temperature, detergent, and laundry additives.\nInfection has not been linked to laundry procedures in residential-care facilities, even when consumer versions of detergents and laundry additives are used.\n\n# Special Laundry Situations\nSome textile items (e.g., surgical drapes and reusable gowns) must be sterilized before use and therefore require steam autoclaving after laundering. 7 Although the American Academy of Pediatrics in previous guidelines recommended autoclaving for linens in neonatal intensive care units (NICUs), studies on the microbial quality of routinely cleaned NICU linen have not identified any increased risk for infection among the neonates receiving care. 1288 Consequently, hygienically clean linens are suitable for use in this setting. 997 The use of sterile linens in burn therapy units remains unresolved.\nCoated or laminated fabrics are often used in the manufacture of PPE. When these items become contaminated with blood or other body substances, the manufacturer's instructions for decontamination and cleaning take into account the compatibility of the rubber backing with the chemical germicides or detergents used in the process. The directions for decontaminating these items should be followed as indicated; the item should be discarded when the backing develops surface cracks.\nDry cleaning, a cleaning process that utilizes organic solvents (e.g., perchloroethylene) for soil removal, is an alternative means of cleaning fabrics that might be damaged in conventional laundering and detergent washing. Several studies, however, have shown that dry cleaning alone is relatively ineffective in reducing the numbers of bacteria and viruses on contaminated linens; 1289, 1290 microbial populations are significantly reduced only when dry-cleaned articles are heat pressed. Dry cleaning should therefore not be considered a routine option for health-care facility laundry and should be reserved for those circumstances in which fabrics can not be safely cleaned with water and detergent. 1291\n\n# Surgical Gowns, Drapes, and Disposable Fabrics\nAn issue of recent concern involves the use of disposable (i.e., single use) versus reusable (i.e., multiple use) surgical attire and fabrics in health-care settings. 1292 Regardless of the material used to manufacture gowns and drapes, these items must be resistant to liquid and microbial penetration. 7, Surgical gowns and drapes must be registered with FDA to demonstrate their safety and effectiveness. Repellency and pore size of the fabric contribute to gown performance, but performance capability can be influenced by the item's design and construction. 1298,1299 Reinforced gowns (i.e., gowns with double-layered fabric) generally are more resistant to liquid strike-through. 1300,1301 Reinforced gowns may, however, be less comfortable. Guidelines for selection and use of barrier materials for surgical gowns and drapes have been published. 1302 When selecting a barrier product, repellency level and type of barrier should be compatible for the exposure expected. 967 However, data are limited regarding the association between gown or drape characteristics and risk for surgical site infections. 7,1303 Health-care facilities must ensure optimal protection of patients and health-care workers. Not all fabric items in health care lend themselves to single-use. Facilities exploring options for gowns and drapes should consider the expense of disposable items and the impact on the facility's waste-management costs once these items are discarded. Costs associated with the use of durable goods involve the fabric or textile items; staff expenses to collect, sort, clean, and package the laundry; and energy costs to operate the laundry if on-site or the costs to contract with an outside service. 1304,1305\n\n# Antimicrobial-Impregnated Articles and Consumer Items Bearing Antimicrobial Labeling\nManufacturers are increasingly incorporating antibacterial or antimicrobial chemicals into consumer and health-care items. Some consumer products bearing labels that indicate treatment with antimicrobial chemicals have included pens, cutting boards, toys, household cleaners, hand lotions, cat litter, soaps, cotton swabs, toothbrushes, and cosmetics. The \"antibacterial\" label on household cleaning products, in particular, gives consumers the impression that the products perform \"better\" than comparable products without this labeling, when in fact all household cleaners have antibacterial properties.\nIn the health-care setting, treated items may include children's pajamas, mattresses, and bed linens with label claims of antimicrobial properties. These claims require careful evaluation to determine whether they pertain to the use of antimicrobial chemicals as preservatives for the fabric or other components or whether they imply a health claim. 1306,1307 No evidence is available to suggest that use of these products will make consumers and patients healthier or prevent disease. No data support the use of these items as part of a sound infection-control strategy, and therefore, the additional expense of replacing a facility's bedding and sheets with these treated products is unwarranted.\nEPA has reaffirmed its position that manufacturers who make public health claims for articles containing antimicrobial chemicals must provide evidence to support those claims as part of the registration process. 1308 Current EPA regulations outlined in the Treated Articles Exemption of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) require manufacturers to register both the antimicrobial chemical used in or on the product and the finished product itself if a public health claim is maintained for the item. The exemption applies to the use of antimicrobial chemicals for the purpose of preserving the integrity of the product's raw material(s). The U.S. Federal Trade Commission (FTC) is evaluating manufacturer advertising of products with antimicrobial claims. 1309\n\n# Standard Mattresses, Pillows, and Air-Fluidized Beds\nStandard mattresses and pillows can become contaminated with body substances during patient care if the integrity of the covers of these items is compromised. The practice of sticking needles into the mattress should be avoided. A mattress cover is generally a fitted, protective material, the purpose of which is to prevent the mattress from becoming contaminated with body fluids and substances. A linen sheet placed on the mattress is not considered a mattress cover. Patches for tears and holes in mattress covers do not provide an impermeable surface over the mattress. Mattress covers should be replaced when torn; the mattress should be replaced if it is visibly stained. Wet mattresses, in particular, can be a substantial environmental source of microorganisms. Infections and colonizations caused by Acinetobacter spp., MRSA, and Pseudomonas aeruginosa have been described, especially among burn patients. In these reports, the removal of wet mattresses was an effective infection-control measure. Efforts were made to ensure that pads and covers were cleaned and disinfected between patients using disinfectant products compatible with mattress-cover materials to ensure that these covers remained impermeable to fluids. Pillows and their covers should be easily cleanable, preferably in a hot water laundry cycle. 1315 These should be laundered between patients or if contaminated with body substances.\nAir-fluidized beds are used for the care of patients immobilized for extended periods of time because of therapy or injury (e.g., pain, decubitus ulcers, and burns). 1316 These specialized beds consist of a base unit filled with microsphere beads fluidized by warm, dry air flowing upward from a diffuser located at the bottom of the unit. A porous, polyester filter sheet separates the patient from direct contact with the beads but allows body fluids to pass through to the beads. Moist beads aggregate into clumps which settle to the bottom where they are removed as part of routine bed maintenance.\nBecause the beads become contaminated with the patient's body substances, concerns have been raised about the potential for these beds to serve as an environmental source of pathogens. Certain pathogens (e.g., Enterococcus spp., Serratia marcescens, Staphylococcus aureus, and Streptococcus fecalis) have been recovered either from the microsphere beads or the polyester sheet after cleaning. 1317,1318 Reports of crosscontamination of patients, however, are few. 1318 Nevertheless, routine maintenance and between-patient decontamination procedures can minimize potential risks to patients. Regular removal of bead clumps, coupled with the warm, dry air of the bed, can help to minimize bacterial growth in the unit. Beads are decontaminated between patients by high heat (113°F-194°F , depending on the manufacturer's specifications) for at least 1 hour; this procedure is particularly important for the inactivation of Enterococcus spp. which are relatively resistant to heat. 1322,1323 The polyester filter sheet requires regular changing and thorough cleaning and disinfection, especially between patients. 1317,1318,1322,1323 Microbial contamination of the air space in the immediate vicinity of a properly maintained air-fluidized bed is similar to that found in air around conventional bedding, despite the air flow out of the base unit and around the patient. 1320,1324,1325 An operational air-fluidized bed can, however, interfere with proper pressure differentials, especially in negative-pressure rooms; 1326 the effect varies with the location of the bed relative to the room's configuration and supply and exhaust vent locations. Use of an air-fluidized bed in a negative-pressure room requires consultation with a facility engineer to determine appropriate placement of the bed.\nH. Animals in Health-Care Facilities\n\n# General Information\nAnimals in health-care facilities traditionally have been limited to laboratories and research areas. However, their presence in patient-care areas is now more frequent, both in acute-care and long-term care settings, prompting consideration for the potential transmission of zoonotic pathogens from animals to humans in these settings.\nAlthough dogs and cats may be commonly encountered in health-care settings, other animals (e.g., fish, birds, non-human primates, rabbits, rodents, and reptiles) also can be present as research, resident, or service animals. These animals can serve as sources of zoonotic pathogens that could potentially infect patients and health-care workers (Table 26). Animals potentially can serve as reservoirs for antibiotic-resistant microorganisms, which can be introduced to the health-care setting while the animal is present. VRE have been isolated from both farm animals and pets, 1341 and a cat in a geriatric care center was found to be colonized with MRSA. 1342 + Indicates that the pathogen associated with the infection has been isolated from animals and is considered to pose potential risk to humans.\nZoonoses can be transmitted from animals to humans either directly or indirectly via bites, scratches, aerosols, ectoparasites, accidental ingestion, or contact with contaminated soil, food, water, or unpasteurized milk. 1331,1332, Colonization and hand transferral of pathogens acquired from pets in health-care workers' homes represent potential sources and modes of transmission of zoonotic pathogens in health-care settings. An outbreak of infections caused by a yeast (Malassezia pachydermatis) among newborns was traced to transfer of the yeast from the hands of health-care workers with pet dogs at home. 1346 In addition, an outbreak of ringworm in a NICU caused by Microsporum canis was associated with a nurse and her cat, 1347 and an outbreak of Rhodococcus (Gordona) bronchialis sternal SSIs after coronary-artery bypass surgery was traced to a colonized nurse whose dogs were culture-positive for the organism. 1348 In the latter outbreak, whether the dogs were the sole source of the organism and whether other environmental reservoirs contributed to the outbreak are unknown. Nonetheless, limited data indicate that outbreaks of infectious disease have occurred as a result of contact with animals in areas housing immunocompetent patients. However, the low frequency of outbreaks may result from a. the relatively limited presence of the animals in health-care facilities and b. the immunocompetency of the patients involved in the encounters.\nFormal scientific studies to evaluate potential risks of transmission of zoonoses in health-care settings outside of the laboratory are lacking.\n\n# Animal-Assisted Activities, Animal-Assisted Therapy, and Resident Animals\nAnimal-Assisted Activities (AAA) are those programs that enhance the patients' quality of life. These programs allow patients to visit animals in either a common, central location in the facility or in individual patient rooms. A group session with the animals enhances opportunities for ambulatory patients and facility residents to interact with caregivers, family members, and volunteers. Alternatively, allowing the animals access to individual rooms provides the same opportunity to nonambulatory patients and patients for whom privacy or dignity issues are a consideration. The decision to allow this access to patients' rooms should be made on a case-by-case basis, with the consultation and consent of the attending physician and nursing staff.\nAnimal-Assisted Therapy (AAT) is a goal-directed intervention that incorporates an animal into the treatment process provided by a credentialed therapist. 1330,1331 The concept for AAT arose from the observation that some patients with pets at home recover from surgical and medical procedures more rapidly than patients without pets. 1352,1353 Contact with animals is considered beneficial for enhancing wellness in certain patient populations (e.g., children, the elderly, and extended-care hospitalized patients). 1349, However, evidence supporting this benefit is largely derived from anecdotal reports and observations of patient/animal interactions. Guidelines for establishing AAT programs are available for facilities considering this option. 1360 The incorporation of non-human primates into an AAA or AAT program is not encouraged because of concerns regarding potential disease transmission from and unpredictable behavior of these animals. 1361,1362 Animals participating in either AAA or AAT sessions should be in good health and up-to-date with recommended immunizations and prophylactic medications (e.g., heartworm prevention) as determined by a licensed veterinarian based on local needs and recommendations. Regular re-evaluation of the animal's health and behavior status is essential. 1360 Animals should be routinely screened for enteric parasites and/or have evidence of a recently completed antihelminthic regimen. 1363 They should also be free of ectoparasites (e.g., fleas and ticks) and should have no sutures, open wounds, or obvious dermatologic lesions that could be associated with bacterial, fungal, or viral infections or parasitic infestations. Incorporating young animals (i.e., those aged <1 year) into these programs is not encouraged because of issues regarding unpredictable behavior and elimination control. Additionally, health of these animals at risk. Animals should be clean and well-groomed. The visits must be supervised by persons who know the animals and their behavior. Animal handlers should be trained in these activities and receive site-specific orientation to ensure that they work efficiently with the staff in the specific healthcare environment. 1360 Additionally, animal handlers should be in good health. 1360 The most important infection-control measure to prevent potential disease transmission is strict enforcement of hand-hygiene measures (e.g., using either soap and water or an alcohol-based hand rub) for all patients, staff, and residents after handling the animals. 1355,1364 Care should also be taken to avoid direct contact with animal urine or feces. Clean-up of these substances from environmental surfaces requires gloves and the use of leak-resistant plastic bags to discard absorbent material used in the process. 2 The area must be cleaned after visits according to standard cleaning procedures.\nThe American Academy of Allergy, Asthma, and Immunology estimates that dog or cat allergies occur in approximately 15% of the population. 1365 Minimizing contact with animal saliva, dander, and/or urine helps to mitigate allergic responses. 1365-1367 Some facilities may not allow animal visitation for patients with a. underlying asthma, b. known allergies to cat or dog hair, c. respiratory allergies of unknown etiology, and d. immunosuppressive disorders.\nHair shedding can be minimized by processes that remove dead hair (e.g., grooming) and that prevent the shedding of dead hair (e.g., therapy capes for dogs). Allergens can be minimized by bathing therapy animals within 24 hours of a visit. 1333,1368 Animal therapists and handlers must take precautions to prevent animal bites. Common pathogens associated with animal bites include Capnocytophaga canimorsus, Pasteurella spp., Staphylococcus spp., and Streptococcus spp. Selecting well-behaved and well-trained animals for these programs greatly decreases the incidence of bites. Rodents, exotic species, wild/domestic animals (i.e., wolf-dog hybrids), and wild animals whose behavior is unpredictable should be excluded from AAA or AAT programs. A well-trained animal handler should be able to recognize stress in the animal and to determine when to terminate a session to minimize risk. When an animal bites a person during AAA or AAT, the animal is to be permanently removed from the program. If a bite does occur, the wound must be cleansed immediately and monitored for subsequent infection. Most infections can be treated with antibiotics, and antibiotics often are prescribed prophylactically in these situations.\nThe health-care facility's infection-control staff should participate actively in planning for and coordinating AAA and AAT sessions. Many facilities do not offer AAA or AAT programs for severely immunocompromised patients (e.g., HSCT patients and patients on corticosteroid therapy). 1339 The question of whether family pets or companion animals can visit terminally-ill HSCT patients or other severely immunosuppressed patients is best handled on a case-by-case basis, although animals should not be brought into the HSCT unit or any other unit housing severely immunosuppressed patients. An indepth discussion of this issue is presented elsewhere. 1366 Immunocompromised patients who have been discharged from a health-care facility may be at higher risk for acquiring some pet-related zoonoses. Although guidelines have been developed to minimize the risk of disease transmission to HIV-infected patients, 8 these recommendations may be applicable for patients with other immunosuppressive disorders. In addition to handwashing or hand hygiene, these recommendations include avoiding contact with a. animal feces and soiled litter box materials, b. animals with diarrhea, c. very young animals (i.e., dogs <6 months of age and cats <1 year of age), and d. exotic animals and reptiles. 8 Pets or companion animals with diarrhea should receive veterinary care to resolve their condition.\nMany health-care facilities are adopting more home-like environments for residential-care or extendedstay patients in acute-care settings, and resident animals are one element of this approach. 1369 One concept, the \"Eden Alternative,\" incorporates children, plants, and animals (e.g., dogs, cats, fish, birds, rabbits, and rodents) into the daily care setting. 1370,1371 The concept of working with resident animals has not been scientifically evaluated. Several issues beyond the benefits of therapy must be considered before embarking on such a program, including a. whether the animals will come into direct contact with patients and/or be allowed to roam freely in the facility b. how the staff will provide care for the animals; c. the management of patients' or residents' allergies, asthma, and phobias; d. precautionary measures to prevent bites and scratches; and e. measures to properly manage the disposal of animal feces and urine, thereby preventing environmental contamination by zoonotic microorganisms (e.g., Toxoplasma spp., Toxocara spp., and Ancylostoma spp.). 1372,1373 Few data document a link between health-care acquired infection rates and frequency of cleaning fish tanks or rodent cages. Skin infections caused by Mycobacterium marinum have been described among persons who have fish aquariums at home. 1374,1375 Nevertheless, immunocompromised patients should avoid direct contact with fish tanks and cages and the aerosols that these items produce. Further, fish tanks should be kept clean on a regular basis as determined by facility policy, and this task should be performed by gloved staff members who are not responsible for patient care. The use of the infectioncontrol risk assessment can help determine whether a fish tank poses a risk for patient or resident safety and health in these situations. No evidence, however, links the incidence of health-care acquired infections among immunocompetent patients or residents with the presence of a properly cleaned and maintained fish tank, even in dining areas. As a general preventive measure, resident animal programs are advised to restrict animals from a. food preparation kitchens, b. laundries, c. central sterile supply and any storage areas for clean supplies, and d. medication preparation areas.\nResident-animal programs in acute-care facilities should not allow the animals into the isolation areas, protective environments, ORs, or any area where immunocompromised patients are housed. Patients and staff routinely should wash their hands or use waterless, alcohol-based hand-hygiene products after contact with animals.\n\n# Service Animals\nAlthough this section provides an overview about service animals in health-care settings, it cannot address every situation or question that may arise (see Appendix E -Information Resources). A service animal is any animal individually trained to do work or perform tasks for the benefit of a person with a disability. 1366, 1376 A service animal is not considered a pet but rather an animal trained to provide assistance to a person because of a disability. Title III of the \"Americans with Disabilities Act\" (ADA) of 1990 mandates that persons with disabilities accompanied by service animals be allowed access with their service animals into places of public accommodation, including restaurants, public transportation, schools, and health-care facilities. 1366,1376 In health-care facilities, a person with a disability requiring a service animal may be an employee, a visitor, or a patient.\nAn overview of the subject of service animals and their presence in health-care facilities has been published. 1366 No evidence suggests that animals pose a more significant risk of transmitting infection than people; therefore, service animals should not be excluded from such areas, unless an individual patient's situation or a particular animal poses greater risk that cannot be mitigated through reasonable measures. If health-care personnel, visitors, and patients are permitted to enter care areas (e.g., inpatient rooms, some ICUs, and public areas) without taking additional precautions to prevent transmission of infectious agents (e.g., donning gloves, gowns, or masks), a clean, healthy, well-behaved service animal should be allowed access with its handler. 1366 Similarly, if immunocompromised patients are able to receive visitors without using protective garments or equipment, an exclusion of service animals from this area would not be justified. 1366 Because health-care facilities are covered by the ADA or the Rehabilitation Act, a person with a disability may be accompanied by a service animal within the facility unless the animal's presence or behavior creates a fundamental alteration in the nature of a facility's services in a particular area or a direct threat to other persons in a particular area. 1366 A \"direct threat\" is defined as a significant risk to the health or safety of others that cannot be mitigated or eliminated by modifying policies, practices, or procedures. 1376 The determination that a service animal poses a direct threat in any particular healthcare setting must be based on an individualized assessment of the service animal, the patient, and the health-care situation.\nWhen evaluating risk in such situations, health-care personnel should consider the nature of the risk (including duration and severity); the probability that injury will occur; and whether reasonable modifications of policies, practices, or procedures will mitigate the risk (J. Wodatch, U.S. Department of Justice, 2000). The person with a disability should contribute to the risk-assessment process as part of a pre-procedure health-care provider/patient conference.\nExcluding a service animal from an OR or similar special care areas (e.g., burn units, some ICUs, PE units, and any other area containing equipment critical for life support) is appropriate if these areas are considered to have \"restricted access\" with regards to the general public. General infection-control measures that dictate such limited access include a. the area is required to meet environmental criteria to minimize the risk of disease transmission, b. strict attention to hand hygiene and absence of dermatologic conditions, and c. barrier protective measures are indicated for persons in the affected space.\nNo infection-control measures regarding the use of barrier precautions could be reasonably imposed on the service animal. Excluding a service animal that becomes threatening because of a perceived danger to its handler during treatment also is appropriate; however, exclusion of such an animal must be based on the actual behavior of the particular animal, not on speculation about how the animal might behave.\nAnother issue regarding service animals is whether to permit persons with disabilities to be accompanied by their service animals during all phases of their stay in the health-care facility. Healthcare personnel should discuss all aspects of anticipatory care with the patient who uses a service animal. Health-care personnel may not exclude a service animal because health-care staff may be able to perform the same services that the service animal does (e.g., retrieving dropped items and guiding an otherwise ambulatory person to the restroom). Similarly, health-care personnel can not exclude service animals because the health-care staff perceive a lack of need for the service animal during the person's stay in the health-care facility. A person with a disability is entitled to independent access (i.e., to be accompanied by a service animal unless the animal poses a direct threat or a fundamental alteration in the nature of services); \"need\" for the animal is not a valid factor in either analysis. For some forms of care (e.g., ambulation as physical therapy following total hip replacement or knee replacement), the service animal should not be used in place of a credentialed health-care worker who directly provides therapy. However, service animals need not be restricted from being in the presence of its handler during this time; in addition, rehabilitation and discharge planning should incorporate the patient's future use of the animal. The health-care personnel and the patient with a disability should discuss both the possible need for the service animal to be separated from its handler for a period of time during non-emergency care and an alternate plan of care for the service animal in the event the patient is unable or unwilling to provide that care. This plan might include family members taking the animal out of the facility several times a day for exercise and elimination, the animal staying with relatives, or boarding off-site. Care of the service animal, however, remains the obligation of the person with the disability, not the health-care staff.\nAlthough animals potentially carry zoonotic pathogens transmissible to man, the risk is minimal with a healthy, clean, vaccinated, well-behaved, and well-trained service animal, the most common of which are dogs and cats. No reports have been published regarding infectious disease that affects humans originating in service dogs. Standard cleaning procedures are sufficient following occupation of an area by a service animal. 1366 Clean-up of spills of animal urine, feces, or other body substances can be accomplished with blood/body substance procedures outlined in the Environmental Services section of this guideline. No special bathing procedures are required prior to a service animal accompanying its handler into a health-care facility.\nProviding access to exotic animals (e.g., reptiles and non-human primates) that are used as service animals is problematic. Concerns about these animals are discussed in two published reviews. 1331,1366 Because some of these animals exhibit high-risk behaviors that may increase the potential for zoonotic disease transmission (e.g., herpes B infection), providing health-care facility access to nonhuman primates used as service animals is discouraged, especially if these animals might come into contact with the general public. 1361,1362 Health-care administrators should consult the Americans with Disabilities Act for guidance when developing policies about service animals in their facilities. 1366,1376 Requiring documentation for access of a service animal to an area generally accessible to the public would impose a burden on a person with a disability. When health-care workers are not certain that an animal is a service animal, they may ask the person who has the animal if it is a service animal required because of a disability; however, no certification or other documentation of service animal status can be required. 1377\n\n# Animals as Patients in Human Health-Care Facilities\nThe potential for direct and indirect transmission of zoonoses must be considered when rooms and equipment in human health-care facilities are used for the medical or surgical treatment or diagnosis of animals. 1378 Inquiries should be made to veterinary medical professionals to determine an appropriate facility and equipment to care for an animal.\nThe central issue associated with providing medical or surgical care to animals in human health-care facilities is whether cross-contamination occurs between the animal patient and the human health-care workers and/or human patients. The fundamental principles of infection control and aseptic practice should differ only minimally, if at all, between veterinary medicine and human medicine. Health-careassociated infections can and have occurred in both patients and workers in veterinary medical facilities when lapses in infection-control procedures are evident. Further, veterinary patients can be at risk for acquiring infection from veterinary health-care workers if proper precautions are not taken. 1385 The issue of providing care to veterinary patients in human health-care facilities can be divided into the following three areas of infection-control concerns: a. whether the room/area used for animal care can be made safe for human patients, b. whether the medical/surgical instruments used on animals can be subsequently used on human patients, and c. which disinfecting or sterilizing procedures need to be done for these purposes.\nStudies addressing these concerns are lacking. However, with respect to disinfection or sterilization in veterinary settings, only minimal evidence suggests that zoonotic microbial pathogens are unusually resistant to inactivation by chemical or physical agents (with the exception of prions). Ample evidence supports the contrary observation (i.e., that pathogens from human-and animal sources are similar in their relative instrinsic resistance to inactivation). Further, no evidence suggests that zoonotic pathogens behave differently from human pathogens with respect to ventilation. Despite this knowledge, an aesthetic and sociologic perception that animal care must remain separate from human care persists. Health-care facilities, however, are increasingly faced with requests from the veterinary medical community for access to human health-care facilities for reasons that are largely economical (e.g., costs of acquiring sophisticated diagnostic technology and complex medical instruments). If hospital guidelines allow treatment of animals, alternate veterinary resources (including veterinary hospitals, clinics, and universities) should be exhausted before using human health-care settings. Additionally, the hospital's public/media relations should be notified of the situation. The goal is to develop policies and procedures to proactively and positively discuss and disclose this activity to the general public.\nAn infection-control risk assessment (ICRA) must be undertaken to evaluate the circumstances specific to providing care to animals in a human health-care facility. Individual hospital policies and guidelines should be reviewed before any animal treatment is considered in such facilities. Animals treated in human health-care facilities should be under the direct care and supervision of a licensed veterinarian; they also should be free of known infectious diseases, ectoparasites, and other external contaminants (e.g., soil, urine, and feces). Measures should be taken to avoid treating animals with a known or suspected zoonotic disease in a human health-care setting (e.g., lambs being treated for Q fever).\nIf human health-care facilities must be used for animal treatment or diagnostics, the following general infection-control actions are suggested: a. whenever possible, the use of ORs or other rooms used for invasive procedures should be avoided b. when all other space options are exhausted and use of the aforementioned rooms is unavoidable, the procedure should be scheduled late in the day as the last procedure for that particular area such that patients are not present in the department/unit/area; c. environmental surfaces should be thoroughly cleaned and disinfected using procedures discussed in the Environmental Services portion of this guideline after the animal is removed from the care area; d. sufficient time should be allowed for ACH to help prevent allergic reactions by human patients ; e. only disposable equipment or equipment that can be thoroughly and easily cleaned, disinfected, or sterilized should be used; f. when medical or surgical instruments, especially those invasive instruments that are difficult to clean , are used on animals, these instruments should be reserved for future use only on animals; and g) standard precautions should be followed.\n\n# Research Animals in Health-Care Facilities\nThe risk of acquiring a zoonotic infection from research animals has decreased in recent years because many small laboratory animals (e.g., mice, rats, and rabbits) come from quality stock and have defined microbiologic profiles. 1392 Larger animals (e.g., nonhuman primates) are still obtained frequently from the wild and may harbor pathogens transmissible to humans. Primates, in particular, benefit from vaccinations to protect their health during the research period provided the vaccination does not interfere with the study of the particular agent. Animals serving as models for human disease studies pose some risk for transmission of infection to laboratory or health-care workers from percutaneous or mucosal exposure. Exposures can occur either through a. direct contact with an infected animal or its body substances and secretions or b. indirect contact with infectious material on equipment, instruments, surfaces, or supplies. 1392 Uncontained aerosols generated during laboratory procedures can also transmit infection.\nInfection-control measures to prevent transmission of zoonotic infections from research animals are largely derived from the following basic laboratory safety principles: a. purchasing pathogen-free animals, b. quarantining incoming animals to detect any zoonotic pathogens, c. treating infected animals or removing them from the facility, d. vaccinating animal carriers and high-risk contacts if possible, e. using specialized containment caging or facilities, and f. using protective clothing and equipment . 1392 An excellent resource for detailed discussion of these safety measures has been published. 1013 The animal research unit within a health-care facility should be engineered to provide a. adequate containment of animals and pathogens; b. daily decontamination and transport of equipment and waste; c. proper ventilation and air filtration, which prevents recirculation of the air in the unit to other areas of the facility; and d. negative air pressure in the animal rooms relative to the corridors.\nTo ensure adequate security and containment, no through traffic to other areas of the health-care facility should flow through this unit; access should be restricted to animal-care staff, researchers, environmental services, maintenance, and security personnel.\nOccupational health programs for animal-care staff, researchers, and maintenance staff should take into consideration the animals' natural pathogens and research pathogens. Components of such programs include a. prophylactic vaccines, b. TB skin testing when primates are used, c. baseline serums, and d. hearing and respiratory testing.\nWork practices, PPE, and engineering controls specific for each of the four animal biosafety levels have been published. 1013,1393 The facility's occupational or employee health clinic should be aware of the appropriate post-exposure procedures involving zoonoses and have available the appropriate postexposure biologicals and medications.\nAnimal-research-area staff should also develop standard operating procedures for a. daily animal husbandry b. pathogen containment and decontamination; c. management, cleaning, disinfecting and/or sterilizing equipment and instruments; and d. employee training for laboratory safety and safety procedures specific to animal research worksites. 1013 The federal Animal Welfare Act of 1966 and its amendments serve as the regulatory basis for ensuring animal welfare in research. 1394,1395 I. Regulated Medical Waste\n\n# Epidemiology\nNo epidemiologic evidence suggests that most of the solid-or liquid wastes from hospitals, other healthcare facilities, or clinical/research laboratories is any more infective than residential waste. Several studies have compared the microbial load and the diversity of microorganisms in residential wastes and wastes obtained from a variety of health-care settings. Although hospital wastes had a greater number of different bacterial species compared with residential waste, wastes from residences were more heavily contaminated. 1397,1398 Moreover, no epidemiologic evidence suggests that traditional wastedisposal practices of health-care facilities (whereby clinical and microbiological wastes were decontaminated on site before leaving the facility) have caused disease in either the health-care setting or the general community. 1400,1401 This statement excludes, however, sharps injuries sustained during or immediately after the delivery of patient care before the sharp is \"discarded.\" Therefore, identifying wastes for which handling and disposal precautions are indicated is largely a matter of judgment about the relative risk of disease transmission, because no reasonable standards on which to base these determinations have been developed. Aesthetic and emotional considerations (originating during the early years of the HIV epidemic) have, however, figured into the development of treatment and disposal policies, particularly for pathology and anatomy wastes and sharps. Public concerns have resulted in the promulgation of federal, state, and local rules and regulations regarding medical waste management and disposal. \n\n# Categories of Medical Waste\nPrecisely defining medical waste on the basis of quantity and type of etiologic agents present is virtually impossible. The most practical approach to medical waste management is to identify wastes that represent a sufficient potential risk of causing infection during handling and disposal and for which some precautions likely are prudent. 2 Health-care facility medical wastes targeted for handling and disposal precautions include microbiology laboratory waste (e.g., microbiologic cultures and stocks of microorganisms), pathology and anatomy waste, blood specimens from clinics and laboratories, blood products, and other body-fluid specimens. 2 Moreover, the risk of either injury or infection from certain sharp items (e.g., needles and scalpel blades) contaminated with blood also must be considered. Although any item that has had contact with blood, exudates, or secretions may be potentially infective, treating all such waste as infective is neither practical nor necessary. Federal, state, and local guidelines and regulations specify the categories of medical waste that are subject to regulation and outline the requirements associated with treatment and disposal. The categorization of these wastes has generated the term \"regulated medical waste.\" This term emphasizes the role of regulation in defining the actual material and as an alternative to \"infectious waste,\" given the lack of evidence of this type of waste's infectivity. State regulations also address the degree or amount of contamination (e.g., blood-soaked gauze) that defines the discarded item as a regulated medical waste. The EPA's Manual for Infectious Waste Management identifies and categorizes other specific types of waste generated in health-care facilities with research laboratories that also require handling precautions. 1406\n\n# Management of Regulated Medical Waste in Health-Care Facilities\nMedical wastes require careful disposal and containment before collection and consolidation for treatment. OSHA has dictated initial measures for discarding regulated medical-waste items. These measures are designed to protect the workers who generate medical wastes and who manage the wastes from point of generation to disposal. 967 A single, leak-resistant biohazard bag is usually adequate for containment of regulated medical wastes, provided the bag is sturdy and the waste can be discarded without contaminating the bag's exterior. The contamination or puncturing of the bag requires placement into a second biohazard bag. All bags should be securely closed for disposal. Puncture-resistant containers located at the point of use (e.g., sharps containers) are used as containment for discarded slides or tubes with small amounts of blood, scalpel blades, needles and syringes, and unused sterile sharps. 967 To prevent needlestick injuries, needles and other contaminated sharps should not be recapped, purposefully bent, or broken by hand. CDC has published general guidelines for handling sharps. 6,1415 Health-care facilities may need additional precautions to prevent the production of aerosols during the handling of blood-contaminated items for certain rare diseases or conditions (e.g., Lassa fever and Ebola virus infection). 203 Transporting and storing regulated medical wastes within the health-care facility prior to terminal treatment is often necessary. Both federal and state regulations address the safe transport and storage of on-and off-site regulated medical wastes. Health-care facilities are instructed to dispose medical wastes regularly to avoid accumulation. Medical wastes requiring storage should be kept in labeled, leakproof, puncture-resistant containers under conditions that minimize or prevent foul odors. The storage area should be well ventilated and be inaccessible to pests. Any facility that generates regulated medical wastes should have a regulated medical waste management plan to ensure health and environmental safety as per federal, state, and local regulations.\n\n# Treatment of Regulated Medical Waste\nRegulated medical wastes are treated or decontaminated to reduce the microbial load in or on the waste and to render the by-products safe for further handling and disposal. From a microbiologic standpoint, waste need not be rendered \"sterile\" because the treated waste will not be deposited in a sterile site. In addition, waste need not be subjected to the same reprocessing standards as are surgical instruments. Historically, treatment methods involved steam-sterilization (i.e., autoclaving), incineration, or interment (for anatomy wastes). Alternative treatment methods developed in recent years include chemical disinfection, grinding/shredding/disinfection methods, energy-based technologies (e.g., microwave or radiowave treatments), and disinfection/encapsulation methods. 1409 State medical waste regulations specify appropriate treatment methods for each category of regulated medical waste.\nOf all the categories comprising regulated medical waste, microbiologic wastes (e.g., untreated cultures, stocks, and amplified microbial populations) pose the greatest potential for infectious disease transmission, and sharps pose the greatest risk for injuries. Untreated stocks and cultures of microorganisms are subsets of the clinical laboratory or microbiologic waste stream. If the microorganism must be grown and amplified in culture to high concentration to permit work with the specimen, this item should be considered for on-site decontamination, preferably within the laboratory unit. Historically, this was accomplished effectively by either autoclaving (steam sterilization) or incineration. If steam sterilization in the health-care facility is used for waste treatment, exposure of the waste for up to 90 minutes at 250°F (121°C) in a autoclave (depending on the size of the load and type container) may be necessary to ensure an adequate decontamination cycle. After steam sterilization, the residue can be safely handled and discarded with all other nonhazardous solid waste in accordance with state solidwaste disposal regulations. On-site incineration is another treatment option for microbiologic, pathologic, and anatomic waste, provided the incinerator is engineered to burn these wastes completely and stay within EPA emissions standards. 1410 Improper incineration of waste with high moisture and low energy content (e.g., pathology waste) can lead to emission problems. State medical-waste regulatory programs identify acceptable methods for inactivating amplified stocks and cultures of microorganisms, some of which may employ technology rather than steam sterilization or incineration.\nConcerns have been raised about the ability of modern health-care facilities to inactivate microbiologic wastes on-site, given that many of these institutions have decommissioned their laboratory autoclaves. Current laboratory guidelines for working with infectious microorganisms at biosafety level (BSL) 3 recommend that all laboratory waste be decontaminated before disposal by an approved method, preferably within the laboratory. 1013 These same guidelines recommend that all materials removed from a BSL 4 laboratory (unless they are biological materials that are to remain viable) are to be decontaminated before they leave the laboratory. 1013 Recent federal regulations for laboratories that handle certain biological agents known as \"select agents\" (i.e., those that have the potential to pose a severe threat to public health and safety) require these agents (and those obtained from a clinical specimen intended for diagnostic, reference, or verification purposes) to be destroyed on-site before disposal. 1412 Although recommendations for laboratory waste disposal from BSL 1 or 2 laboratories (e.g., most health-care clinical and diagnostic laboratories) allow for these materials to be decontaminated off-site before disposal, on-site decontamination by a known effective method is preferred to reduce the potential of exposure during the handling of infectious material.\nA recent outbreak of TB among workers in a regional medical-waste treatment facility in the United States demonstrated the hazards associated with aerosolized microbiologic wastes. 1419,1420 The facility received diagnostic cultures of Mycobacterium tuberculosis from several different health-care facilities before these cultures were chemically disinfected; this facility treated this waste with a grinding/shredding process that generated aerosols from the material. 1419,1420 Several operational deficiencies facilitated the release of aerosols and exposed workers to airborne M. tuberculosis. Among the suggested control measures was that health-care facilities perform on-site decontamination of laboratory waste containing live cultures of microorganisms before release of the waste to a waste management company. 1419,1420 This measure is supported by recommendations found in the CDC/NIH guideline for laboratory workers. 1013 This outbreak demonstrates the need to avoid the use of any medical-waste treatment method or technology that can aerosolize pathogens from live cultures and stocks (especially those of airborne microorganisms) unless aerosols can be effectively contained and workers can be equipped with proper PPE. Safe laboratory practices, including those addressing waste management, have been published. 1013,1422 In an era when local, state, and federal health-care facilities and laboratories are developing bioterrorism response strategies and capabilities, the need to reinstate in-laboratory capacity to destroy cultures and stocks of microorganisms becomes a relevant issue. 1423 Recent federal regulations require health-care facility laboratories to maintain the capability of destroying discarded cultures and stocks on-site if these laboratories isolate from a clinical specimen any microorganism or toxin identified as a \"select agent\" from a clinical specimen (Table 27). 1412,1413 As an alternative, isolated cultures of select agents can be transferred to a facility registered to accept these agents in accordance with federal regulations. 1412 State medical waste regulations can, however, complicate or completely prevent this transfer if these cultures are determined to be medical waste, because most states regulate the inter-facility transfer of untreated medical wastes.\n\n# Discharging Blood, Fluids to Sanitary Sewers or Septic Tanks\nThe contents of all vessels that contain more than a few milliliters of blood remaining after laboratory procedures, suction fluids, or bulk blood can either be inactivated in accordance with state-approved treatment technologies or carefully poured down a utility sink drain or toilet. 1414 State regulations may dictate the maximum volume allowable for discharge of blood/body fluids to the sanitary sewer. No evidence indicates that bloodborne diseases have been transmitted from contact with raw or treated sewage. Many bloodborne pathogens, particularly bloodborne viruses, are not stable in the environment for long periods of time; 1425,1426 therefore, the discharge of small quantities of blood and other body fluids to the sanitary sewer is considered a safe method of disposing of these waste materials. 1414 The following factors increase the likelihood that bloodborne pathogens will be inactivated in the disposal process: a. dilution of the discharged materials with water b. inactivation of pathogens resulting from exposure to cleaning chemicals, disinfectants, and other chemicals in raw sewage; and c. effectiveness of sewage treatment in inactivating any residual bloodborne pathogens that reach the treatment facility.\nSmall amounts of blood and other body fluids should not affect the functioning of a municipal sewer system. However, large quantities of these fluids, with their high protein content, might interfere with the biological oxygen demand (BOD) of the system. Local municipal sewage treatment restrictions may dictate that an alternative method of bulk fluid disposal be selected. State regulations may dictate what quantity constitutes a small amount of blood or body fluids.\nAlthough concerns have been raised about the discharge of blood and other body fluids to a septic tank system, no evidence suggests that septic tanks have transmitted bloodborne infections. A properly functioning septic system is adequate for inactivating bloodborne pathogens. System manufacturers' instructions specify what materials may be discharged to the septic tank without jeopardizing its proper operation.\n\n# Medical Waste and CJD\nConcerns also have been raised about the need for special handling and treatment procedures for wastes generated during the care of patients with CJD or other transmissible spongiform encephalopathies (TSEs). Prions, the agents that cause TSEs, have significant resistance to inactivation by a variety of physical, chemical, or gaseous methods. 1427 No epidemiologic evidence, however, links acquisition of CJD with medical-waste disposal practices. Although handling neurologic tissue for pathologic examination and autopsy materials with care, using barrier precautions, and following specific procedures for the autopsy are prudent measures, 1197 employing extraordinary measures once the materials are discarded is unnecessary. Regulated medical wastes generated during the care of the CJD patient can be managed using the same strategies as wastes generated during the care of other patients. After decontamination, these wastes may then be disposed in a sanitary landfill or discharged to the sanitary sewer, as appropriate.\n\n# Part II. Recommendations for Environmental Infection Control in Health-Care Facilities\n\n# A. Rationale for Recommendations\nAs in previous CDC guidelines, each recommendation is categorized on the basis of existing scientific data, theoretic rationale, applicability, and possible economic benefit. The recommendations are evidence-based wherever possible. However, certain recommendations are derived from empiric infection-control or engineering principles, theoretic rationale, or from experience gained from events that cannot be readily studied (e.g., floods).\nThe HICPAC system for categorizing recommendations has been modified to include a category for engineering standards and actions required by state or federal regulations. Guidelines and standards published by the American Institute of Architects (AIA), American Society of Heating, Refrigeration, and Air-Conditioning Engineers (ASHRAE), and the Association for the Advancement in Medical Instrumentation (AAMI) form the basis of certain recommendations. These standards reflect a consensus of expert opinions and extensive consultation with agencies of the U.S. Department of Health and Human Services. Compliance with these standards is usually voluntary. However, state and federal governments often adopt these standards as regulations. For example, the standards from AIA regarding construction and design of new or renovated health-care facilities, have been adopted by reference by >40 states. Certain recommendations have two category ratings (e.g., Categories IA and IC or Categories IB and IC), indicating the recommendation is evidence-based as well as a standard or regulation.\n\n# B. Rating Categories\nRecommendations are rated according to the following categories: - - Develop and implement a maintenance schedule for ACH, pressure differentials, and filtration efficiencies using facility-specific data as part of the multidisciplinary risk assessment. Take into account the age and reliability of the system. - - Document these parameters, especially the pressure differentials. 3. Engineer humidity controls into the HVAC system and monitor the controls to ensure proper moisture removal. 120 Category IC (AIA: 7.31.D9)\n- - Locate duct humidifiers upstream from the final filters.\n- - Incorporate a water-removal mechanism into the system.\n- - Locate all duct takeoffs sufficiently down-stream from the humidifier so that moisture is completely absorbed. 4. Incorporate steam humidifiers, if possible, to reduce potential for microbial proliferation within the system, and avoid use of cool mist humidifiers. Category II 5. Ensure that air intakes and exhaust outlets are located properly in construction of new facilities and renovation of existing facilities. - - Locate exhaust outlets from contaminated areas above roof level to minimize recirculation of exhausted air. 6. Maintain air intakes and inspect filters periodically to ensure proper operation. 3,120,249,250,277 Category IC (AIA: 7.31.D8) 7. Bag dust-filled filters immediately upon removal to prevent dispersion of dust and fungal spores during transport within the facility. 106, 221 Category IB - - Seal or close the bag containing the discarded filter.\n- - Discard spent filters as regular solid waste, regardless of the area from which they were removed. 221 8. Remove bird roosts and nests near air intakes to prevent mites and fungal spores from entering the ventilation system. 3,98,119 Category IB 9. Prevent dust accumulation by cleaning air-duct grilles in accordance with facility-specific procedures and schedules when rooms are not occupied by patients. 21,120,249,250,277 Category IC, II (AIA: 7.31.D10) 10. Periodically measure output to monitor system function; clean ventilation ducts as part of routine HVAC maintenance to ensure optimum performance. 120,263,264 Category II (AIA: 7.31.D10) C. Use portable, industrial-grade HEPA filter units capable of filtration rates in the range of 300-800 ft 3 /min. to augment removal of respirable particles as needed. 219 Category II M. Whenever feasible, design and install fixed backup ventilation systems for new or renovated construction for PE rooms, AII rooms, operating rooms, and other critical care areas identified by ICRA. 120 A. Establish a multidisciplinary team that includes infection-control staff to coordinate demolition, construction, and renovation projects and consider proactive preventive measures at the inception; produce and maintain summary statements of the team's activities. 17,19,20,97,109,120,249,250, Category IB, IC (AIA: 5.1) B. Educate both the construction team and the health-care staff in immunocompromised patient-care areas regarding the airborne infection risks associated with construction projects, dispersal of fungal spores during such activities, and methods to control the dissemination of fungal spores. 3, 249, 250, 273-277, 1428-1432 Category IB C. Incorporate mandatory adherence agreements for infection control into construction contracts, with penalties for noncompliance and mechanisms to ensure timely correction of problems. 3,120,249, Category IC (AIA: 5.1) D. Establish and maintain surveillance for airborne environmental disease (e.g., aspergillosis) as appropriate during construction, renovation, repair, and demolition activities to ensure the health and safety of immunocompromised patients. 3,64,65,79 Category IB 1. Using active surveillance, monitor for airborne fungal infections in immunocompromised patients. 3,9,64,65 Category IB 2. Periodically review the facility's microbiologic, histopathologic, and postmortem data to identify additional cases. 3,9,64,65 Category IB 3. If cases of aspergillosis or other health-care associated airborne fungal infections occur, aggressively pursue the diagnosis with tissue biopsies and cultures as feasible. 3,64,65,79,249, Category IB E. Implement infection-control measures relevant to construction, renovation, maintenance, demolition, and repair. 96,97,120,276,277 Category IB, IC (AIA: 5.1, 5.2) 1. Before the project gets underway, perform an ICRA to define the scope of the project and the need for barrier measures. 96,97,120,249, - - Determine if immunocompromised patients may be at risk for exposure to fungal spores from dust generated during the project. 20, 109, 273-275, 277 - - Develop a contingency plan to prevent such exposures. 20,109,277 Category IB, IC (AIA: 5.1) 2. Implement infection-control measures for external demolition and construction activities. 50,249,283 - - Determine if the facility can operate temporarily on recirculated air; if feasible, seal off adjacent air intakes. - - If this is not possible or practical, check the low-efficiency (roughing) filter banks frequently and replace as needed to avoid buildup of particulates. - - Seal windows and reduce wherever possible other sources of outside air intrusion (e.g., open doors in stairwells and corridors), especially in PE areas. Category IB 3. Avoid damaging the underground water distribution system (i.e., buried pipes) to prevent soil and dust contamination of the water. 120,305 Category IB, IC (AIA: 5.1) 121 4. Implement infection-control measures for internal construction activities. 20,49,97,120,249, - - Construct barriers to prevent dust from construction areas from entering patient-care areas; ensure that barriers are impermeable to fungal spores and in compliance with local fire codes. 20,49,97,120,284,312,713,1431 - - Block and seal off return air vents if rigid barriers are used for containment. 120,276,277 - - Implement dust control measures on surfaces and by diverting pedestrian traffic away from work zones. 20, 49, 97, 120 - - Relocate patients whose rooms are adjacent to work zones, depending upon their immune status, the scope of the project, the potential for generation of dust or water aerosols, and the methods used to control these aerosols. 49,120,281 120,249, ~ Category IB h. Clean work zones and their entrances daily by\n- wet-wiping tools and tool carts before their removal from the work zone;\n- placing mats with tacky surfaces inside the entrance; and\n- covering debris and securing this covering before removing debris from the work zone. 120,249, ~ Category IB i. In patient-care areas, for major repairs that include removal of ceiling tiles and disruption of the space above the false ceiling, use plastic sheets or prefabricated plastic units to contain dust; use a negative pressure system within this enclosure to remove dust; and either pass air through an industrial grade, portable HEPA filter capable of filtration rates ranging from 300-800 ft 3 /min., or exhaust air directly to the outside. 49,276,277,281,309 - - properly constructing windows, doors, and intake and exhaust ports;\n- - maintaining ceilings that are smooth and free of fissures, open joints, and crevices;\n- - sealing walls above and below the ceiling, and\n- - monitoring for leakage and making necessary repairs. 3,111,120,317,318 Category IB, IC (AIA: 7.2.D3) 3. Ventilate the room to maintain ≥12 ACH. 3,9,120,241,317,318 Category IC (AIA: 7.2.D) 4. Locate air supply and exhaust grilles so that clean, filtered air enters from one side of the room, flows across the patient's bed, and exits from the opposite side of the room. 3,120,317,318 Category IC (AIA: 7.31.D1) 5. Maintain positive room air pressure (≥2.5 Pa ) in relation to the corridor. 3,35,120,317,318 Category IB, IC (AIA: Table 7.2) 6. Maintain airflow patterns and monitor these on a daily basis by using permanently installed visual means of detecting airflow in new or renovated construction, or using other visual methods (e.g., flutter strips, or smoke tubes) in existing PE units. Document the monitoring results. 120,273 Category IC (AIA: 7.2.D6) 7. Install self-closing devices on all room exit doors in protective environments. 120 3. Place smallpox patients in negative pressure rooms at the onset of their illness, preferably using a room with an anteroom if available. 6 Category II D. No recommendation is offered regarding negative pressure or isolation rooms for patients with Pneumocystis carinii pneumonia. 126,131,132 Unresolved issue E. Maintain back-up ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for AII rooms and take immediate steps to restore the fixed ventilation system function. 4,120,278 Category IC (AIA: 5.1)\n\n# C.V. Infection-Control and Ventilation Requirements for Operating Rooms\nA. Implement environmental infection-control and ventilation measures for operating rooms. 1. Maintain positive-pressure ventilation with respect to corridors and adjacent areas. 7,120,356 Category IB, IC (AIA: Table 7.2) 2. Maintain ≥15 ACH, of which ≥3 ACH should be fresh air. 120,357,358 Category IC (AIA: Table 7.2) 3. Filter all recirculated and fresh air through the appropriate filters, providing 90% efficiency (dust-spot testing) at a minimum. 120,362 Category IC (AIA: Table 7.3) 4. In rooms not engineered for horizontal laminar airflow, introduce air at the ceiling and exhaust air near the floor. 120,357,359 B.1) because extubation is a coughproducing procedure. 4,358 Category IB C. Use portable, industrial-grade HEPA filters temporarily for supplemental air cleaning during intubation and extubation for infectious TB patients who require surgery. 4,219,358 Category II 1. Position the units appropriately so that all room air passes through the filter; obtain engineering consultation to determine the appropriate placement of the unit. 4 Category II 2. Switch the portable unit off during the surgical procedure. Category II 3. Provide fresh air as per ventilation standards for operating rooms; portable units do not meet the requirements for the number of fresh ACH. 120,215,219 Category II D. If possible, schedule infectious TB patients as the last surgical cases of the day to maximize the time available for removal of airborne contamination. Category II E. No recommendation is offered for performing orthopedic implant operations in rooms supplied with laminar airflow. 362,364 Unresolved issue F. Maintain backup ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for operating rooms, and take immediate steps to restore the fixed ventilation system function. 68,120,278,372 Category IB, IC (AIA: 5.1)\n\n# C.VI. Other Potential Infectious Aerosol Hazards in Health-Care Facilities\nA. In settings where surgical lasers are used, wear appropriate personal protective equipment, including N95 or N100 respirators, to minimize exposure to laser plumes. 347, 378, 389 Category IC (OSHA; 29 CFR 1910.134,139) B. Use central wall suction units with in-line filters to evacuate minimal laser plumes. 378,382,386,389 Category II C. Use a mechanical smoke evacuation system with a high-efficiency filter to manage the generation of large amounts of laser plume, when ablating tissue infected with human papilloma virus (HPV) or performing procedures on a patient with extrapulmonary TB. 4,382, Category II\n\n# D. Recommendations-Water\n\n# D.I. Controlling the Spread of Waterborne Microoganisms\nA. Practice hand hygiene to prevent the hand transfer of waterborne pathogens, and use barrier precautions (e.g., gloves) as defined by other guidelines. 6,464,577,586,592,1364 - - Flush each outlet until chlorine odor is detected.\n- - Maintain the elevated chlorine concentration in the system for ≥2 hrs (but ≤24 hrs). 4. Use a very thorough flushing of the water system instead of chlorination if a highly chlorineresistant microorganism (e.g., Cryptosporidium spp.) is suspected as the water contaminant. Category II F. Flush and restart equipment and fixtures according to manufacturers' instructions. Category II G. Change the pretreatment filter and disinfect the dialysis water system with an EPA-registered product to prevent colonization of the reverse osmosis membrane and downstream microbial contamination. 721 Category II H. Run water softeners through a regeneration cycle to restore their capacity and function. Category II I. If the facility has a water-holding reservoir or water-storage tank, consult the facility engineer or local health department to determine whether this equipment needs to be drained, disinfected with an EPA-registered product, and refilled. Category II J. Implement facility management procedures to manage a sewage system failure or flooding (e.g., arranging with other health-care facilities for temporary transfer of patients or provision of services), and establish communications with the local municipal water utility and the local health department to ensure that advisories are received in a timely manner upon release. 713 These recommendations refer to the spraying or fogging of chemicals (e.g., formaldehyde, phenolbased agents, or quaternary ammonium compounds) as a way to decontaminate environmental surfaces or disinfect the air in patient rooms. The recommendation against fogging was based on studies in the 1970's that reported a lack of microbicidal efficacy (e.g., use of quaternary ammonium compounds in mist applications) but also adverse effects on healthcare workers and others in facilities where these methods were utilized. Furthermore, some of these chemicals are not EPA-registered for use in fogging-type applications. The 2003 recommendations still apply; however, CDC does not yet make a recommendation regarding these newer technologies. This issue will be revisited as additional evidence becomes available.\nG. Avoid large-surface cleaning methods that produce mists or aerosols or disperse dust in patient-care areas. 9,20,109,272\n\n# H.II. Animal-Assisted Activities, Animal-Assisted Therapy, and Resident Animal Programs\nA. Avoid selection of nonhuman primates and reptiles in animal-assisted activities, animal-assisted therapy, or resident animal programs. 1360-1362 Category IB B. Enroll animals that are fully vaccinated for zoonotic diseases and that are healthy, clean, wellgroomed, and negative for enteric parasites or otherwise have completed recent antihelminthic treatment under the regular care of a veterinarian. 1349, 1360 Category II C. Enroll animals that are trained with the assistance or under the direction of individuals who are experienced in this field. 1360 Category II D. Ensure that animals are handled by persons trained in providing activities or therapies safely, and who know the animals' health status and behavior traits. 1349,1360 Category II E. Take prompt action when an incident of biting or scratching by an animal occurs during an animalassisted activity or therapy. 1. Remove the animal permanently from these programs. 1360 Category II 2. Report the incident promptly to appropriate authorities (e.g., infection-control staff, animal program coordinator, or local animal control). 1360 Category II 3. Promptly clean and treat scratches, bites, or other accidental breaks in the skin. Category II F. Perform an ICRA and work actively with the animal handler prior to conducting an animal-assisted activity or therapy to determine if the session should be held in a public area of the facility or in individual patient rooms. 1349,1360 Category II G. Take precautions to mitigate allergic responses to animals. Category II 1. Minimize shedding of animal dander by bathing animals <24 hours before a visit. 1360 Category II 2. Groom animals to remove loose hair before a visit, or using a therapy animal cape. 1358 Category II H. Use routine cleaning protocols for housekeeping surfaces after therapy sessions. Category II I. Restrict resident animals, including fish in fish tanks, from access to or placement in patient-care areas, food preparation areas, dining areas, laundry, central sterile supply areas, sterile and clean supply storage areas, medication preparation areas, operating rooms, isolation areas, and PE areas. Category II J. Establish a facility policy for regular cleaning of fish tanks, rodent cages, bird cages, and any other animal dwellings and assign this cleaning task to a nonpatient-care staff member; avoid splashing tank water or contaminating environmental surfaces with animal bedding. Category II\n\n# H.III. Protective Measures for Immunocompromised Patients\nA. Advise patients to avoid contact with animal feces and body fluids such as saliva, urine, or solid litter box material. 8 Category II B. Promptly clean and treat scratches, bites, or other wounds that break the skin. 8 Category II C. Advise patients to avoid direct or indirect contact with reptiles. 1340 Category IB D. Conduct a case-by-case assessment to determine if animal-assisted activities or animal-assisted therapy programs are appropriate for immunocompromised patients. 1349 Category II E. No recommendation is offered regarding permitting pet visits to terminally ill immunosuppressed patients outside their PE units. Unresolved issue\n\n# H.IV. Service Animals\nEdit : An - indicates recommendations that were renumbered for clarity. The renumbering does not constitute change to the intent of the recommendations.\nA. Avoid providing access to nonhuman primates and reptiles as service animals. 1340, 1362 Category IB B. Allow service animals access to the facility in accordance with the Americans with Disabilities Act of 1990, unless the presence of the animal creates a direct threat to other persons or a fundamental alteration in the nature of services. 1366,1376 Category IC (U.S. Department of Justice: 28 CFR § 36.302) C. When a decision must be made regarding a service animal's access to any particular area of the health-care facility, evaluate the service animal, the patient, and the health-care situation on a caseby-case basis to determine whether significant risk of harm exists and whether reasonable modifications in policies and procedures will mitigate this risk. 1376 Category IC (Justice: 28 CFR § 36.208 and App.B) D. If a patient must be separated from his or her service animal while in the health-care facility\n- - ascertain from the person what arrangements have been made for supervision or care of the animal during this period of separation; and - - make appropriate arrangements to address the patient's needs in the absence of the service animal. Category II\n\n# H.V. Animals as Patients in Human Health-Care Facilities\nA. Develop health-care facility policies to address the treatment of animals in human healthcare facilities.\n1. Use the multidisciplinary team approach to policy development, including public media relations in order to disclose and discuss these activities. Category II 2. Exhaust all veterinary facility, equipment, and instrument options before undertaking the procedure. Category II 3. Ensure that the care of the animal is supervised by a licensed veterinarian. Category II B. When animals are treated in human health-care facilities, avoid treating animals in operating rooms or other patient-care areas where invasive procedures are performed (e.g., cardiac catheterization laboratories, or invasive nuclear medicine areas). Category II C. Schedule the animal procedure for the last case of the day for the area, at a time when human patients are not scheduled to be in the vicinity. Category II D. Adhere strictly to standard precautions. Category II E. Clean and disinfect environmental surfaces thoroughly using an EPA-registered product in the room after the animal is removed. Category II F. Allow sufficient ACH to clean the air and help remove airborne dander, microorganisms, and allergens [Appendix B,\n\n# Part III. References\nNote: The bold item in parentheses indicated the citation number or the location of this reference listed in the MMWR version of this guideline.\nmicrobiological agents they work with. There are four biosafety levels based on the hazards associated with the various microbiological agents. BOD5: the amount of dissolved oxygen consumed in five days by biological processes breaking down organic matter. Bonneting: a floor cleaning method for either carpeted or hard surface floors that uses a circular motion of a large fibrous disc to lift and remove soil and dust from the surface. Capped spur: a pipe leading from the water recirculating system to an outlet that has been closed off (\"capped\"). A capped spur cannot be flushed, and it might not be noticed unless the surrounding wall is removed. CFU/m 3 : colony forming units per cubic meter (of air). Chlamydospores: thick-walled, typically spherical or ovoid resting spores asexually produced by certain types of fungi from cells of the somatic hyphae. Chloramines: compounds containing nitrogen, hydrogen, and chlorine. These are formed by the reaction between hypochlorous acid (HOCl) and ammonia (NH3) and/or organic amines in water. The formation of chloramines in drinking water treatment extends the disinfecting power of chlorine. The term is also referred to as Combined Available Chlorine.\nCleaning: the removal of visible soil and organic contamination from a device or surface, using either the physical action of scrubbing with a surfactant or detergent and water, or an energy-based process (e.g., ultrasonic cleaners) with appropriate chemical agents. Coagulation-flocculation: coagulation is the clumping of particles that results in the settling of impurities. It may be induced by coagulants (e.g., lime, alum, and iron salts). Flocculation in water and wastewater treatment is the agglomeration or clustering of colloidal and finely-divided suspended matter after coagulation by gentle stirring by either mechanical or hydraulic means, such that they can be separated from water or sewage. Commissioning (a room): testing a system or device to ensure that it meets the pre-use specifications as indicated by the manufacturer or predetermined standard, or air sampling in a room to establish a preoccupancy baseline standard of microbial or particulate contamination. The term is also referred to as benchmarking at 77°F (25°C).\nCompletely packaged: functionally packaged, as for laundry.\nConidia: asexual spores of fungi borne externally.\nConidiophores: specialized hyphae that bear conidia in fungi. Conditioned space: that part of a building that is heated or cooled, or both, for the comfort of the occupants. Contaminant: an unwanted airborne constituent that may reduce the acceptibility of air. Convection: the transfer of heat or other atmospheric properties within the atmosphere or in the airspace of an enclosure by the circulation of currents from one region to another, especially by such motion directed upward.\nCooling tower: a structure engineered to receive accumulated heat from ventilation systems and equipment and transfer this heat to water, which then releases the stored heat to the atmosphere through evaporative cooling.\nCritical item (medical instrument): a medical instrument or device that contacts normally sterile areas of the body or enters the vascular system. There is a high risk of infection from such devices if they are microbiologically contaminated prior to use. These devices must be sterilized before use. Dead legs: areas in the water system where water stagnates. A dead leg is a pipe or spur, leading from the water recirculating system to an outlet that is used infrequently, resulting in inadequate flow of water from the recirculating system to the outlet. This inadequate flow reduces the perfusion of heat or chlorine into this part of the water distribution system, thereby adversely affecting the disinfection of the water system in that area. Deionization: removal of ions from water by exchange with other ions associated with fixed charges on a resin bed. Cations are usually removed and H + ions are exchanged; OHions are exchanged for anions. Detritis: particulate matter produced by or remaining after the wearing away or disintegration of a substance or tissue. Dew point: the temperature at which a gas or vapor condenses to form a liquid; the point at which moisture begins to condense out of the air. At dew point, air is cooled to the point where it is at 100% relative humidity or saturation.\nDialysate: the aqueous electrolyte solution, usually containing dextrose, used to make a concentration gradient between the solution and blood in the hemodialyzer (dialyzer). Dialyzer: a device that consists of two compartments (blood and dialysate) separated by a semipermeable membrane. A dialyzer is usually referred to as an artificial kidney. Diffuser: the grille plate that disperses the air stream coming into the conditioned air space. Direct transmission: involves direct body surface-to-body surface contact and physical transfer of microorganisms between a susceptible host and an infected/colonized person, or exposure to cloud of infectious particles within 3 feet of the source; the aerosolized particles are >5 μm in size. Disability: as defined by the Americans with Disabilities Act, a disability is any physical or mental impairment that substantially limits one or more major life activities, including but not limited to walking, talking, seeing, breathing, hearing, or caring for oneself. Disinfection: a generally less lethal process of microbial inactivation (compared to sterilization) that eliminates virtually all recognized pathogenic microorganisms but not necessarily all microbial forms (e.g., bacterial spores). Drain pans: pans that collect water within the HVAC system and remove it from the system. Condensation results when air and steam come together. Drift: circulating water lost from the cooling tower in the form as liquid droplets entrained in the exhaust air stream (i.e., exhaust aerosols from a cooling tower). Drift eliminators: an assembly of baffles or labyrinth passages through which the air passes prior to its exit from the cooling tower. The purpose of a drift eliminator is to remove entrained water droplets from the exhaust air. Droplets: particles of moisture, such as are generated when a person coughs or sneezes, or when water is converted to a fine mist by a device such as an aerator or shower head. These particles may contain infectious microorganisms. Intermediate in size between drops and droplet nuclei, these particles tend to quickly settle out from the air so that any risk of disease transmission is generally limited to persons in close proximity to the droplet source. Droplet nuclei: sufficiently small particles (1-5 μm in diameter) that can remain airborne indefinitely and cause infection when a susceptible person is exposed at or beyond 3 feet of the source of these particles.\nDual duct system: an HVAC system that consists of parallel ducts that produce a cold air stream in one and a hot air stream in the other.\nDust: an air suspension of particles (aerosol) of any solid material, usually with particle sizes ≤100 μm in diameter.\nDust-spot test: a procedure that uses atmospheric air or a defined dust to measure a filter's ability to remove particles. A photometer is used to measure air samples on either side of the filter, and the difference is expressed as a percentage of particles removed. Effective leakage area: the area through which air can enter or leave the room. This does not include supply, return, or exhaust ducts. The smaller the effective leakage area, the better isolated the room. Endotoxin: the lipopolysaccharides of gram-negative bacteria, the toxic character of which resides in the lipid portion. Endotoxins generally produce pyrogenic reactions in persons exposed to these bacterial components.\nEnveloped virus: a virus whose outer surface is derived from a membrane of the host cell (either nuclear or the cell's outer membrane) during the budding phase of the maturation process. This membrane-derived material contains lipid, a component that makes these viruses sensitive to the action of chemical germicides. Evaporative condenser: a wet-type, heat-rejection unit that produces large volumes of aerosols during the process of removing heat from conditioned space air. Exhaust air: air removed from a space and not reused therein. Exposure: the condition of being subjected to something (e.g., infectious agents) that could have a harmful effect.\nFastidious: having complex nutritional requirements for growth, as in microorganisms.\nFill: that portion of a cooling tower which makes up its primary heat transfer surface. Fill is alternatively known as \"packing.\" Finished water: treated, or potable water. Fixed room-air HEPA recirculation systems: nonmobile devices or systems that remove airborne contaminants by recirculating air through a HEPA filter. These may be built into the room and permanently\n\n# Air Sampling for Aerosols Containing Legionellae\nAir sampling is an insensitive means of detecting Legionella pneumophila, and is of limited practical value in environmental sampling for this pathogen. In certain instances, however, it can be used to a. demonstrate the presence of legionellae in aerosol droplets associated with suspected bacterial reservoirs b. define the role of certain devices in disease transmission; and c. quantitate and determine the size of the droplets containing legionellae. 1436 Stringent controls and calibration are necessary when sampling is used to determine particle size and numbers of viable bacteria. 1437 Samplers should be placed in locations where human exposure to aerosols is anticipated, and investigators should wear a NIOSH-approved respirator (e.g., N95 respirator) if sampling involves exposure to potentially infectious aerosols.\nMethods used to sample air for legionellae include impingement in liquid, impaction on solid medium, and sedimentation using settle plates. 1436 The Chemical Corps.-type all-glass impingers (AGI) with the stem 30 mm from the bottom of the flask have been used successfully to sample for legionellae. 1436 Because of the velocity at which air samples are collected, clumps tend to become fragmented, leading to a more accurate count of bacteria present in the air. The disadvantages of this method are a. the velocity of collection tends to destroy some vegetative cells b. the method does not differentiate particle sizes; and c. AGIs are easily broken in the field.\nYeast extract broth (0.25%) is the recommended liquid medium for AGI sampling of legionellae; 1437 standard methods for water samples can be used to culture these samples.\nAndersen samplers are viable particle samplers in which particles pass through jet orifices of decreasing size in cascade fashion until they impact on an agar surface. 1218 The agar plates are then removed and incubated. The stage distribution of the legionellae should indicate the extent to which the bacteria would have penetrated the respiratory system. The advantages of this sampling method are a. the equipment is more durable during use b. the sampler can cetermine the number and size of droplets containing legionellae; c. the agar plates can be placed directly in an incubator with no further manipulations; and d. both selective and nonselective BCYE agar can be used. If the samples must be shipped to a laboratory, they should be packed and shipped without refrigeration as soon as possible.\n\n# Calculation of Air Sampling Results\nAssuming that each colony on the agar plate is the growth from a single bacteria-carrying particle, the contamination of the air being sampled is determined from the number of colonies counted. The airborne microorganisms may be reported in terms of the number per cubic foot of air sampled. The following formulas can be applied to convert colony counts to organisms per cubic foot of air sampled. 1218 For solid agar impactor samplers: C / (R H P) = N where N = number of organisms collected per cubic foot of air sampled C = total plate count R = airflow rate in cubic feet per minute P = duration of sampling period in minutes For liquid impingers: (C H V) / (Q H P H R) = N where C = total number of colonies from all aliquots plated V = final volume in mL of collecting media Q = total number of mL plated P, R, and N are defined as above 3. To satisfy exhaust needs, replacement air from outside is necessary. Table B.3 does not attempt to describe specific amounts of outside air to be supplied to individual spaces except for certain areas such as those listed. Distribution of the outside air, added to the system to balance required exhaust, shall be as required by good engineering practice.\n4. Number of air changes may be reduced when the room is unoccupied if provisions are made to ensure that the number of air changes indicated is reestablished any time the space is being utilized. Adjustments shall include provisions so that the direction of air movement shall remain the same when the number of air changes is reduced. Areas not indicated as having continuous directional control may have ventilation systems shut down when space is unoccupied and ventilation is not otherwise needed.\n5. Air from areas with contamination and/or odor problems shall be exhausted to the outside and not recirculated to other areas. Note that individual circumstances may require special consideration for air exhaust to outside.\n6. Because of cleaning difficulty and potential for buildup of contamination, recirculating room units shall not be used in areas marked \"No.\" Isolation rooms may be ventilated by reheat induction units in which only the primary air supplied from a central system passes through the reheat unit. Gravitytype heating or cooling units such as radiators or convectors shall not be used in special care areas.\n7. The ranges listed are the minimum and maximum limits where control is specifically needed. See A8.31.D in the AIA guideline (reference 120) for additional information.\n8. Where temperature ranges are indicated, the systems shall be capable of maintaining the rooms at any point within the range. A single figure indicates a heating or cooling capacity of at least the indicated temperature. This is usually applicable where residents may be undressed and require a warmer environment. Nothing in these guidelines shall be construed as precluding the use of temperatures lower than those noted when the residents' comfort and medical conditions make lower temperatures desirable. Unoccupied areas such as storage rooms shall have temperatures appropriate for the function intended.\n9. See A8.31.D1 in the AIA guideline (reference 120).\n10. Food preparation facilities shall have ventilation systems whose air supply mechanisms are interfaced appropriately with exhaust hood controls or relief vents so that exfiltration or infiltration to or from exit corridors does not compromise the exit corridor restrictions of NFPA 90A, the pressure requirements of NFPA 96, or the maximum defined in the table. The number of air changes may be reduced or varied to any extent required for odor control when the space is not in use. heterotrophic plate count would suggest a greater rate and extent of biofilm formation in a health-care facility water system. The water supplied to the facility should also contain <1 coliform bacteria/100 mL. Coliform bacteria are organisms whose presence in the distribution system could indicate fecal contamination. It has been shown that coliform bacteria can colonize biofilms within drinking water systems. Intermittant contamination of a water system with these organisms could lead to colonization of the system.\nWater samples can be collected from throughout the health-care facility system, including both hot and cold water sources; samples should be cultured by standard methods. 945 If heterotrophic plate counts in samples from the facility water system are higher than those from samples collected at the point of water entry to the building, it can be concluded that the facility water quality has diminished. If biofilms are detected in the facility water system and determined by an epidemiologic and environmental investigation to be a reservoir for health-care associated pathogens, the municipal water supplier could be contacted with a request to provide higher chlorine residuals in the distribution system, or the health-care facility could consider installing a supplemental chlorination system.\nSample collection sites for biofilm in health-care facilities include a. hot water tanks b. shower heads; and c. faucet aerators, especially in immunocompromised patient-care areas.\nSwabs should be placed into tubes containing phosphate buffered water, pH 7.2 or phosphate buffered saline, shipped to the laboratory under refrigeration and processed within 24 hrs. of collection. Samples are suspended by vortexing with sterile glass beads and plated onto a nonselective medium (e.g., Plate Count Agar or R2A medium) and selective media (e.g., media for Legionella spp. isolation) after serial dilution. If the plate counts are elevated above levels in the water (i.e. comparing the plate count per square centimeter of swabbed surface to the plate count per milliliter of water), then biofilm formation can be suspected. In the case of an outbreak, it would be advisable to isolate organisms from these plates to determine whether the suspect organisms are present in the biofilm or water samples and compare them to the organisms isolated from patient specimens.\n\n# Water and Dialysate Sampling Strategies in Dialysis\nIn order to detect the low, total viable heterotrophic plate counts outlined by the current AAMI standards for water and dialysate in dialysis settings, it is necessary to use standard quantitative culture techniques with appropriate sensitivity levels. 792,832,833 The membrane filter technique is particularly suited for this application because it permits large volumes of water to be assayed. 792,834 Since the membrane filter technique may not be readily available in clinical laboratories, the spread plate assay can be used as an alternative. 834 If the spread plate assay is used, however, the standard prohibits the use of a calibrated loop when applying sample to the plate. 792 The prohibition is based on the low sensitivity of the calibrated loop. A standard calibrated loop transfers 0.001 mL of sample to the culture medium, so that the minimum sensitivity of the assay is 1,000 CFU/mL. This level of sensitivity is unacceptable when the maximum allowable limit for microorganisms is 200 CFU/mL. Therefore, when the spread plate method is used, a pipette must be used to place 0.1-0.5 mL of water on the culture medium.\nThe current AAMI standard specifically prohibits the use of nutrient-rich media (e.g., blood agar, and chocolate agar) in dialysis water and dialysate assays because these culture media are too rich for growth of the naturally occurring organisms found in water. 792 Debate continues within AAMI, however, as to the most appropriate culture medium and incubation conditions to be used. The original clinical observations on which the microbiological requirements of this standard were based used Standard Methods Agar (SMA), a medium containing relatively few nutrients. 666 The use of tryptic soy agar (TSA), a general purpose medium for isolating and cultivating microorganisms was recommended in later versions of the standard because it was thought to be more appropriate for culturing bicarbonate-containing dialysate. 788,789,835 Moreover, culturing systems based on TSA are readily available from commercial sources. Several studies, however, have shown that the use of nutrient-poor media, such as R2A, results in an increased recovery of bacteria from water. 1451,1452 The original standard also specified incubation for 48 hours at 95°F-98.6°F (35°C-37°C) before enumeration of bacterial colonies. Extending the culturing time up to 168 hours, or 7 days and using incubation temperatures of 73.4°F-82.4°F (23°C-28°C) have also been shown to increase the recovery of bacteria. 1451,1452 Other investigators, however, have not found such clear cut differences between culturing techniques. 835,1453 After considerable discussion, the AAMI Committee has not reached a consensus regarding changes in the assay technique, and the use of TSA or its equivalent for 48 hours at 95°F-98.6°F (35°C-37°C) remains the recommended method. It should be recognized, however, that these culturing conditions may underestimate the bacterial burden in the water and fail to identify the presence of some organisms. Specifically, the recommended method may not detect the presence of various NTM that have been associated with several outbreaks of infection in dialysis units. 31,32 In these instances, however, the high numbers of mycobacteria in the water were related to the total heterotrophic plate counts, each of which was significantly greater than that allowable by the AAMI standard. Additionally, the recommended method will not detect fungi and yeast, which have been shown to contaminate water used for hemodialysis applications. 1454 Biofilm on the surface of the pipes may hide viable bacterial colonies, even though no viable colonies are detected in the water using sensitive culturing techniques. 1455 Many disinfection processes remove biofilm poorly, and a rapid increase in the level of bacteria in the water following disinfection may indicate significant biofilm formation. Therefore, although the results of microbiological surveillance obtained using the test methods outlined above may be useful in guiding disinfection schedules and in demonstrating compliance with AAMI standards, they should not be taken as an indication of the absolute microbiological purity of the water. 792 Endotoxin can be tested by one of two types of assays a. a kinetic test method or b. a gel-clot assay.\nEndotoxin units are assayed by the Limulus Amebocyte Lysate (LAL) method. Because endotoxins differ in their activity on a mass basis, their activity is referred to a standard Escherichia coli endotoxin. The current standard (EC-6) is prepared from E. coli O113:H10. The relationship between mass of endotoxin and its activity varies with both the lot of LAL and the lot of control standard endotoxin used. Since standards for endotoxin were harmonized in 1983 with the introduction of EC-5, the relationship between mass and activity of endotoxin has been approximately 5-10 EU/ng. Studies to harmonize standards have led to the measurement of endotoxin units (EU) where 5 EU is equivalent to 1 ng E. coli O55:B5 endotoxin. 1456 In summary, water used to prepare dialysate and to reprocess hemodialyzers should not contain a total microbial count >200 CFU/mL as determined by assay on TSA agar for 48 hrs. at 96.8°F (36°C), and ≤2 endotoxin units (EU) per mL. The dialysate at the end of a dialysis treatment should not contain >2,000 CFU/mL. 31, 32, 668, 789, 792\n\n# Water Sampling Strategies and Culture Techniques for Detecting Legionellae\nLegionella spp. are ubiquitous and can be isolated from 20%-40% of freshwater environments, including man-made water systems. 1457,1458 In health-care facilities, where legionellae in potable water rarely result in disease among immunocompromised patients, courses of remedial action are unclear.\nScheduled microbiologic monitoring for legionellae remains controversial because the presence of legionellae is not necessarily evidence of a potential for causing disease. 1459 CDC recommends aggressive disinfection measures for cleaning and maintaining devices known to transmit legionellae, but does not recommend regularly scheduled microbiologic assays for the bacteria. 396 However, scheduled monitoring of potable water within a hospital might be considered in certain settings where persons are highly susceptible to illness and mortality from Legionella infection (e.g., hematopoietic stem cell transplantation units and solid organ transplant units). 9 Also, after an outbreak of legionellosis, health officials agree monitoring is necessary to identify the source and to evaluate the efficacy of biocides or other prevention measures.\nExamination of water samples is the most efficient microbiologic method for identifying sources of legionellae and is an integral part of an epidemiologic investigation into health-care associated Legionnaires disease. Because of the diversity of plumbing and HVAC systems in health-care facilities, the number and types of sites to be tested must be determined before collection of water samples. One environmental sampling protocol that addresses sampling site selection in hospitals might serve as a prototype for sampling in other institutions. 1209 Any water source that might be aerosolized should be considered a potential source for transmission of legionellae. The bacteria are rarely found in municipal water supplies and tend to colonize plumbing systems and point-of-use devices. To colonize, legionellae usually require a temperature range of 77°F-108°F (25°C-42.2°C) and are most commonly located in hot water systems. 1460 Legionellae do not survive drying. Therefore, air-conditioning equipment condensate, which frequently evaporates, is not a likely source. 1461 Water samples and swabs from point-of-use devices or system surfaces should be collected when sampling for legionellae (Box C.1). 1437 Swabs of system surfaces allow sampling of biofilms, which frequently contain legionellae. When culturing faucet aerators and shower heads, swabs of surface areas should be collected first; water samples are collected after aerators or shower heads are removed from their pipes. Collection and culture techniques are outlined (Box C.2). Swabs can be streaked directly onto buffered charcoal yeast extract agar (BCYE) plates if the pates are available at the collection site. If the swabs and water samples must be transported back to a laboratory for processing, immersing individual swabs in sample water minimizes drying during transit. Place swabs and water samples in insulated coolers to protect specimens from temperature extremes.\nBox C.1. Potential sampling sites for Legionella spp. in health-care facilities*\n- Potable water systems incoming water main, water softener unit, holding tanks, cisterns, water heater tanks (at the inflows and outflows)\n- Potable water outlets, especially those in or near patient rooms faucets or taps, showers\n- Cooling towers and evaporative condensers makeup water (e.g., added to replace water lost because of evaporation, drift, or leakage), basin (i.e., area under the tower for collection of cooled water), sump (i.e., section of basin from which cooled water returns to heat source), heat sources (e.g., chillers)\n- Humidfiers (e.g., nebullizers) bubblers for oxygen, water used for respiratory therapy equipment 2. Collect culture swabs of internal surfaces of faucets, aerators, and shower heads in a sterile, screw-top container (e.g., 50 mL plastic centrifuge tube). Submerge each swab in 5-10 mL of sample water taken from the same device from which the sample was obtained. 3. Transport samples and process in a laboratory proficient at culturing water specimens for Legionella spp. as soon as possible after collection. (Samples may be transported at room temperature but must be protected from temperature extremes. Samples not processed within 24 hours of collection should be refrigerated.) 4. Test samples for the presence of Legionella spp. by using semiselective culture media using procedures specific to the cultivation and detection of Legionella spp.\n- Detection of Legionella spp. antigen by the direct fluorescent antibody technique is not suitable for environmental samples. o Use of polymerase chain reaction for identification of Legionella spp. is not recommended until more data regading the sensitivity and specificity of this procedure are available.\n\n# Procedure for Cleaning Cooling Towers and Related Equipment I. Perform these steps prior to chemical disinfection and mechanical cleaning.\nA. Provide protective equipment to workers who perform the disinfection, to prevent their exposure to chemicals used for disinfection and aerosolized water containing Legionella spp. Protective equipment may include full-length protective clothing, boots, gloves, goggles, and a full-or halfface mask that combines a HEPA filter and chemical cartridges to protect against airborne chlorine levels of up to 10 mg/L. B. Shut off cooling tower.\n1. Shut off the heat source, if possible. 2. Shut off fans, if present, on the cooling tower/evaporative condenser (CT/EC).\n3. Shut off the system blowdown (i.e., purge) valve. 4. Shut off the automated blowdown controller, if present, and set the system controller to manual. 5. Keep make-up water valves open. 6. Close building air-intake vents within at least 30 meters of the CT/EC until after the cleaning procedure is complete. 7. Continue operating pumps for water circulation through the CT/EC.\n\n# II. Perform these chemical disinfection procedures.\nA. Add fast-release, chlorine-containing disinfectant in pellet, granular, or liquid form, and follow safety instructions on the product label. Use EPA-registered products, if available. Examples of disinfectants include sodium hypochlorite (NaOCl) or calcium hypochlorite (Ca2), calculated to achieve initial free residual chlorine (FRC) of 50 mg/L: either a. Monitor the FRC by using an FRC-measuring device with the DPD method (e.g., a swimmingpool test kit), and measure the pH with a pH meter every 15 minutes for 2 hours. Add chlorine as needed to maintain the FRC at ≥10 mg/L. Because the biocidal effect of chlorine is reduced at a higher pH, adjust the pH to 7.5-8.0. The pH may be lowered by using any acid (e.g., nuriatic acid or sulfuric acid used for maintenance of swimming pools) that is compatible with the treatment chemicals. E. Two hours after adding disinfectant and dispersant or after the FRC level is stable at ≥10 mg/L, monitor at 2-hour intervals and maintain the FRC at ≥10 mg/L for 24 hours. F. After the FRC level has been maintained at ≥10 mg/L for 24 hours, drain the system. CT/EC water may be drained safely into the sanitary sewer. Municipal water and sewerage authorities should be contacted regarding local regulations. If a sanitary sewer is not available, consult local or state authorities (e.g., a department of natural resources or environmental protection) regarding disposal of water. If necessary, the drain-off may be dechlorinated by dissipation or chemical neutralization with sodium bisulfite.\n- - sharps . 2 Category II B. Consult federal, state, and local regulations to determine if other waste items are considered regulated medical wastes. 967,1407,1408\n\n# I.II. Disposal Plan for Regulated Medical Wastes\nA. Develop a plan for the collection, handling, predisposal treatment, and terminal disposal of regulated medical wastes. 967\n\n# I.III. Handling, Transporting, and Storing Regulated Medical Wastes\nA. Inform personnel involved in the handling and disposal of potentially infective waste of the possible health and safety hazards; ensure that they are trained in appropriate handling and disposal methods. 967 Category IC (OSHA: 29 CFR 1910.1030 § g.2.i) B. Manage the handling and disposal of regulated medical wastes generated in isolation areas by using the same methods as for regulated medical wastes from other patient-care areas. 2 Category II C. Use proper sharps disposal strategies. 967 Category IC (OSHA: 29 CFR 191029 CFR .1030.iii.A)\n1. Use a sharps container capable of maintaining its impermeability after waste treatment to avoid subsequent physical injuries during final disposal. 967 Category IC (OSHA: 29 CFR 191029 CFR .1030.iii.A) 2. Place disposable syringes with needles, including sterile sharps that are being discarded, scalpel blades, and other sharp items into puncture-resistant containers located as close as practical to the point of use. 967 Category IC (OSHA: 29 CFR 191029 CFR .1030.iii.A) 3. Do not bend, recap, or break used syringe needles before discarding them into a container. 6,967,1415 Category IC (OSHA: 29 CFR 1910.1030 § d.2.vii and § d.2.vii.A) D. Store regulated medical wastes awaiting treatment in a properly ventilated area that is inaccessible to vertebrate pests; use waste containers that prevent the development of noxious odors. Category IC (States; AHJ) E. If treatment options are not available at the site where the medical waste is generated, transport regulated medical wastes in closed, impervious containers to the on-site treatment location or to another facility for treatment as appropriate. Category IC (States; AHJ)\n\n# I.IV. Treatment and Disposal of Regulated Medical Wastes\nA. Treat regulated medical wastes by using a method (e.g., steam sterilization, incineration, interment, or an alternative treatment technology) approved by the appropriate authority having jurisdiction (AHJ) (e.g., states, Indian Health Service , Veterans Affairs ) before disposal in a sanitary landfill. Category IC (States, AHJ) B. Follow precautions for treating microbiological wastes (e.g., amplified cultures and stocks of microorganisms). 1013 Category IC (DHHS: BMBL) 1. Biosafety level 4 laboratories must inactivate microbiological wastes in the laboratory by using an approved inactivation method (e.g., autoclaving) before transport to and disposal in a sanitary landfill. 1013 Category IC (DHHS: BMBL) 2. Biosafety level 3 laboratories must inactivate microbiological wastes in the laboratory by using an approved inactivation method (e.g., autoclaving) or incinerate them at the facility before transport to and disposal in a sanitary landfill. 1013 Category IC (DHHS: BMBL) C. Biosafety levels 1 and 2 laboratories should develop strategies to inactivate amplified microbial cultures and stocks onsite by using an approved inactivation method (e.g., autoclaving) instead of packaging and shipping untreated wastes to an offsite facility for treatment and disposal. 1013, Category II\n\n# Part IV. Appendices Appendix A. Glossary of Terms\nAcceptable indoor air quality: air in which there are no known contaminants at harmful concentrations as determined by knowledgeble authorities and with which a substantial majority (≥80%) of the people exposed do not express dissatisfaction. ACGIH: American Conference of Governmental Industrial Hygienists. Action level: the concentration of a contaminant at which steps should be taken to interrupt the trend toward higher, unacceptable levels. Aerosol: particles of respirable size generated by both humans and environmental sources and that have the capability of remaining viable and airborne for extended periods in the indoor environment. AIA: American Institute of Architects, a professional group responsible for publishing the Guidelines for Design and Construction of Hospitals and Healthcare Facilities, a consensus document for design and construction of health-care facilities endorsed by the U.S. Department of Health and Human Services, healthcare professionals, and professional organizations.\n\n# Air changes per hour (ACH):\nthe ratio of the volume of air flowing through a space in a certain period of time (the airflow rate) to the volume of that space (the room volume). This ratio is expressed as the number of air changes per hour (ACH).\nAir mixing: the degree to which air supplied to a room mixes with the air already in the room, usually expressed as a mixing factor. This factor varies from 1 (for perfect mixing) to 10 (for poor mixing). It is used as a multiplier to determine the actual airflow required (i.e., the recommended ACH multiplied by the mixing factor equals the actual ACH required). Airborne transmission: a means of spreading infection when airborne droplet nuclei (small particle residue of evaporated droplets ≤5 μm in size containing microorganisms that remain suspended in air for long periods of time) are inhaled by the susceptible host. Air-cleaning system: a device or combination of devices applied to reduce the concentration of airborne contaminants (e.g., microorganisms, dusts, fumes, aerosols, other particulate matter, and gases).\nAir conditioning: the process of treating air to meet the requirements of a conditioned space by controlling its temperature, humidity, cleanliness, and distribution. Allogeneic: non-twin, non-self. The term refers to transplanted tissue from a donor closely matched to a recipient but not related to that person. Ambient air: the air surrounding an object. Anemometer: a flow meter which measures the wind force and velocity of air. An anemometer is often used as a means of determining the volume of air being drawn into an air sampler. Anteroom: a small room leading from a corridor into an isolation room. This room can act as an airlock, preventing the escape of contaminants from the isolation room into the corridor. ASHE: American Society for Healthcare Engineering, an association affiliated with the American Hospital Association. ASHRAE: American Society of Heating, Refrigerating, and Air-Conditioning Engineers Inc.\n\n# Autologous self:\nThe term refers to transplanted tissue whose source is the same as the recipient, or an identical twin. Automated cycler: a machine used during peritoneal dialysis which pumps fluid into and out of the patient while he/she sleeps. Biochemical oxygen demand (BOD): a measure of the amount of oxygen removed from aquatic environments by aerobic microorganisms for their metabolic requirements. Measurement of BOD is used to determine the level of organic pollution of a stream or lake. The greater the BOD, the greater the degree of water pollution. The term is also referred to as Biological Oxygen Demand (BOD). Biological oxygen demand (BOD): an indirect measure of the concentration of biologically degradable material present in organic wastes (pertaining to water quality). It usually reflects the amount of oxygen consumed in five days by biological processes breaking down organic waste (BOD5). Biosafety level: a combination of microbiological practices, laboratory facilities, and safety equipment determined to be sufficient to reduce or prevent occupational exposures of laboratory personnel to the Intermediate-level disinfection: a disinfection process that inactivates vegetative bacteria, most fungi, mycobacteria, and most viruses (particularly the enveloped viruses), but does not inactivate bacterial spores. Isoform: a possible configuration (tertiary structure) of a protein molecule. With respect to prion proteins, the molecules with large amounts of α-conformation are the normal isoform of that particular protein, whereas those prions with large amounts of β-sheet conformation are the proteins associated with the development of spongiform encephalopathy (e.g., Creutzfeldt-Jakob disease ). Laminar flow: HEPA-filtered air that is blown into a room at a rate of 90 ± 10 feet/min in a unidirectional pattern with 100 ACH-400 ACH. Large enveloped virus: viruses whose particle diameter is >50 nm and whose outer surface is covered by a lipid-containing structure derived from the membranes of the host cells. Examples of large enveloped viruses include influenza viruses, herpes simplex viruses, and poxviruses. Laser plume: the transfer of electromagnetic energy into tissues which results in a release of particles, gases, and tissue debris. Lipid-containing viruses: viruses whose particle contains lipid components. The term is generally synonymous with enveloped viruses whose outer surface is derived from host cell membranes. Lipidcontaining viruses are sensitive to the inactivating effects of liquid chemical germicides. Lithotriptors: instruments used for crushing caliculi (i.e., calcified stones, and sand) in the bladder or kidneys.\nLow efficiency filter: the prefilter with a particle-removal efficiency of approximately 30% through which incoming air first passes. See also Prefilter. Low-level disinfection: a disinfection process that will inactivate most vegetative bacteria, some fungi, and some viruses, but cannot be relied upon to inactivate resistant microorganisms (e.g., mycobacteria or bacterial spores). Makeup air: outdoor air supplied to the ventilation system to replace exhaust air. Makeup water: a cold water supply source for a cooling tower.\nManometer: a device that measures the pressure of liquids and gases. A manometer is used to verify air filter performance by measuring pressure differentials on either side of the filter. Membrane filtration: an assay method suitable for recovery and enumeration of microorganisms from liquid samples. This method is used when sample volume is large and anticipated microbial contamination levels are low. Mesophilic: that which favors a moderate temperature. For mesophilic bacteria, a temperature range of 68°F-131°F (20°C-55°C) is favorable for their growth and proliferation.\nMixing box: the site where the cold and hot air streams mix in the HVAC system, usually situated close to the air outlet for the room.\nMixing faucet: a faucet that mixes hot and cold water to produce water at a desired temperature. MMAD: Mass Median Aerodynamic Diameter. This is the unit used by ACGIH to describe the size of particles when particulate air sampling is conducted. Moniliaceous: hyaline or brightly colored. This is a laboratory term for the distinctive characteristics of certain opportunistic fungi in culture (e.g., Aspergillus spp. and Fusarium spp.). Monochloramine: the result of the reaction between chlorine and ammonia that contains only one chlorine atom. Monochloramine is used by municipal water systems as a water treatment. Natural ventilation: the movement of outdoor air into a space through intentionally provided openings (i.e., windows, doors, or nonpowered ventilators). Negative pressure: air pressure differential between two adjacent airspaces such that air flow is directed into the room relative to the corridor ventilation (i.e., room air is prevented from flowing out of the room and into adjacent areas). Neutropenia: a medical condition in which the patient's concentration of neutrophils is substantially less than that in the normal range. Severe neutropenia occurs when the concentration is <1,000 polymorphonuclear cells/μL for 2 weeks or <100 polymorphonuclear cells /mL for 1 week, particularly for hematopoietic stem cell transplant (HSCT) recipients. Noncritical devices: medical devices or surfaces that come into contact with only intact skin. The risk of infection from use of these devices is low.\nNon-enveloped virus: a virus whose particle is not covered by a structure derived from a membrane of the host cell. Non-enveloped viruses have little or no lipid compounds in their biochemical composition, a characteristic that is significant to their inherent resistance to the action of chemical germicides. Nosocomial: an occurrence, usually an infection, that is acquired in a hospital as a result of medical care. NTM: nontuberculous mycobacteria. These organisms are also known as atypical mycobacteria, or as \"Mycobacteria other than tuberculosis\" (MOTT). This descriptive term refers to any of the fast-or slowgrowing Mycobacterium spp. found in primarily in natural or man-made waters, but it excludes Mycobacterium tuberculosis and its variants. Nuisance dust: generally innocuous dust, not recognized as the direct cause of serious pathological conditions. Oocysts: a cyst in which sporozoites are formed; a reproductive aspect of the life cycle of a number of parasitic agents (e.g., Cryptosporidium spp., and Cyclospora spp.).\nOutdoor air: air taken from the external atmosphere and, therefore, not previously circulated through the ventilation system. Parallel streamlines: a unidirectional airflow pattern achieved in a laminar flow setting, characterized by little or no mixing of air.\nParticulate matter (particles): a state of matter in which solid or liquid substances exist in the form of aggregated molecules or particles. Airborne particulate matter is typically in the size range of 0.01-100 μm diameter.\nPasteurization: a disinfecting method for liquids during which the liquids are heated to 140°F (60°C) for a short time (≥30 mins.) to significantly reduce the numbers of pathogenic or spoilage microorganisms.\nPlinth: a treatment table or a piece of equipment used to reposition the patient for treatment.\nPortable room-air HEPA recirculation units: free-standing portable devices that remove airborne contaminants by recirculating air through a HEPA filter.\nPositive pressure: air pressure differential between two adjacent air spaces such that air flow is directed from the room relative to the corridor ventilation (i.e., air from corridors and adjacent areas is prevented from entering the room). Potable (drinking) water: water that is fit to drink. The microbiological quality of this water as defined by EPA microbiological standards from the Surface Water Treatment Rule: a. Giardia lamblia: 99.9% killed/inactivated b. viruses: 99.9% inactivated; c. Legionella spp.: no limit, but if Giardia and viruses are inactivated, Legionella will also be controlled; d. heterotrophic plate count : ≤500 CFU/mL; and e. >5% of water samples total coliform-positive in a month. PPE: Personal Protective Equipment. ppm: parts per million. The term is a measure of concentration in solution. Chlorine bleaches (undiluted) that are available in the U.S. (5.25%-6.15% sodium hypochlorite) contain approximately 50,000-61,500 parts per million of free and available chlorine. Prefilter: the first filter for incoming fresh air in a HVAC system. This filter is approximately 30% efficient in removing particles from the air. See also Low-Efficiency Filter. Prion: a class of agent associated with the transmission of diseases knowns as transmissible spongiform encephalopathies (TSEs). Prions are considered to consist of protein only, and the abnormal isoform of this protein is thought to be the agent that causes diseases such as Creutzfeldt-Jakob disease (CJD), kuru, scrapie, bovine spongiform encephalopathy (BSE), and the human version of BSE which is variant CJD (vCJD). Product water: water produced by a water treatment system or individual component of that system. Protective environment: a special care area, usually in a hospital, designed to prevent transmission of opportunistic airborne pathogens to severely immunosuppressed patients. Pseudoepidemic (pseudo-outbreak): a cluster of positive microbiologic cultures in the absence of clinical disease. A pseudoepidemic usually results from contamination of the laboratory apparatus and process used to recover microorganisms. Pyrogenic: an endotoxin burden such that a patient would receive ≥5 endotoxin units (EU) per kilogram of body weight per hour, thereby causing a febrile response. In dialysis this usually refers to water or dialysate having endotoxin concentrations of ≥5 EU/mL.\nRank order: a strategy for assessing overall indoor air quality and filter performance by comparing airborne particle counts from lowest to highest (i.e., from the best filtered air spaces to those with the least filtration). RAPD: a method of genotyping microorganisms by randomly amplified polymorphic DNA. This is one version of the polymerase chain reaction method. Recirculated air: air removed from the conditioned space and intended for reuse as supply air.\nRelative humidity: the ratio of the amount of water vapor in the atmosphere to the amount necessary for saturation at the same temperature. Relative humidity is expressed in terms of percent and measures the percentage of saturation. At 100% relative humidity, the air is saturated. The relative humidity decreases when the temperature is increased without changing the amount of moisture in the air. Reprocessing (of medical instruments): the procedures or steps taken to make a medical instrument safe for use on the next patient. Reprocessing encompasses both cleaning and the final or terminal step (i.e., sterilization or disinfection) which is determined by the intended use of the instrument according to the Spaulding classification.\nResiduals: the presence and concentration of a chemical in media (e.g., water) or on a surface after the chemical has been added.\nReservoir: a nonclinical source of infection.\nRespirable particles: those particles that penetrate into and are deposited in the nonciliated portion of the lung. Particles >10 μm in diameter are not respirable.\nReturn air: air removed from a space to be then recirculated.\nReverse osmosis (RO): an advanced method of water or wastewater treatment that relies on a semipermeable membrane to separate waters from pollutants. An external force is used to reverse the normal osmotic process resulting in the solvent moving from a solution of higher concentration to one of lower concentration.\nRiser: water piping that connects the circulating water supply line, from the level of the base of the tower or supply header, to the tower's distribution system. RODAC: Replicate Organism Direct Agar Contact. This term refers to a nutrient agar plate whose convex agar surface is directly pressed onto an environmental surface for the purpose of microbiologic sampling of that surface. Room-air HEPA recirculation systems and units: devices (either fixed or portable) that remove airborne contaminants by recirculating air through a HEPA filter. Routine sampling: environmental sampling conducted without a specific, intended purpose and with no action plan dependent on the results obtained.\nSanitizer: an agent that reduces microbial contamination to safe levels as judged by public health standards or requirements. Saprophytic: a naturally-occurring microbial contaminant. Sedimentation: the act or process of depositing sediment from suspension in water. The term also refers to the process whereby solids settle out of wastewater by gravity during treatment. Semicritical devices: medical devices that come into contact with mucous membranes or non-intact skin. Service animal: any animal individually trained to do work or perform tasks for the benefit of a person with a disability. Shedding: the generation and dispersion of particles and spores by sources within the patient area, through activities such as patient movement and airflow over surfaces. Single-pass ventilation: ventilation in which 100% of the air supplied to an area is exhausted to the outside. Small, non-enveloped viruses: viruses whose particle diameter is <50 nm and whose outer surface is the protein of the particle itself and not that of host cell membrane components. Examples of small, nonenveloped viruses are polioviruses and hepatitis A virus. Spaulding Classification: the categorization of inanimate medical device surfaces in the medical environment as proposed in 1972 by Dr. Earle Spaulding. Surfaces are divided into three general categories, based on the theoretical risk of infection if the surfaces are contaminated at time of use. The categories are \"critical,\" \"semicritical,\" and \"noncritical.\" Specific humidity: the mass of water vapor per unit mass of moist air. It is expressed as grains of water per pound of dry air, or pounds of water per pound of dry air. The specific humidity changes as moisture is added or removed. However, temperature changes do not change the specific humidity unless the air is cooled below the dew point.\nSplatter: visible drops of liquid or body fluid that are expelled forcibly into the air and settle out quickly, as distinguished from particles of an aerosol which remain airborne indefinitely. Steady state: the usual state of an area. Sterilization: the use of a physical or chemical procedure to destroy all microbial life, including large numbers of highly-resistant bacterial endospores. Stop valve: a valve that regulates the flow of fluid through a pipe. The term may also refer to a faucet. Substitution fluid: fluid that is used for fluid management of patients receiving hemodiafiltration. This fluid can be prepared on-line at the machine through a series of ultrafilters or with the use of sterile peritoneal dialysis fluid. Supply air: air that is delivered to the conditioned space and used for ventilation, heating, cooling, humidification, or dehumidification.\nTensile strength: the resistance of a material to a force tending to tear it apart, measured as the maximum tension the material can withstand without tearing. Ultrafilter: a membrane filter with a pore size in the range of 0.001-0.05 μm, the performance of which is usually rated in terms of a nominal molecular weight cut-off (defined as the smallest molecular weight species for which the filter membrance has more than 90% rejection).\nUltrafiltered dialysate: the process by which dialysate is passed through a filter having a molecular weight cut-off of approximately 1 kilodalton for the purpose of removing bacteria and endotoxin from the bath. Ultraviolet germicidal irradiation (UVGI): the use of ultraviolet radiation to kill or inactivate microorganisms.\nUltraviolet germicidal irradiation lamps: lamps that kill or inactivate microorganisms by emitting ultraviolet germicidal radiation, predominantly at a wavelength of 254 nm. UVGI lamps can be used in ceiling or wall fixtures or within air ducts of ventilation systems.\nVapor pressure: the pressure exerted by free molecules at the surface of a solid or liquid. Vapor pressure is a function of temperature, increasing as the temperature rises.\nVegetative bacteria: bacteria that are actively growing and metabolizing, as opposed to a bacterial state of quiescence that is achieved when certain bacteria (gram-positive bacilli) convert to spores when the environment can no longer support active growth. Vehicle: any object, person, surface, fomite, or media that may carry and transfer infectious microorganisms from one site to another.\nVentilation: the process of supplying and removing air by natural or mechanical means to and from any space. Such air may or may not be conditioned. Ventilation air: that portion of the supply air consisting of outdoor air plus any recirculated air that has been treated for the purpose of maintaining acceptable indoor air quality. Ventilation, dilution: an engineering control technique to dilute and remove airborne contaminants by the flow of air into and out of an area. Air that contains droplet nuclei is removed and replaced by contaminantfree air. If the flow is sufficient, droplet nuclei become dispersed, and their concentration in the air is diminished. Ventilation, local exhaust: ventilation used to capture and removed airborne contaminants by enclosing the contaminant source (the patient) or by placing an exhaust hood close to the contaminant source. v/v: volume to volume. This term is an expression of concentration of a percentage solution when the principle component is added as a liquid to the diluent. w/v: weight to volume. This term is an expression of concentration of a percentage solution when the principle component is added as a solid to the diluent.\nWeight-arrestance: a measure of filter efficiency, used primarily when describing the performance of lowand medium-efficiency filters. The measurement of weight-arrestance is performed by feeding a standardized synthetic dust to the filter and weighing the fraction of the dust removed. Q / V = ACH ¶ Values apply to an empty room with no aerosol-generating source. With a person present and generating aerosol, this table would not apply. Other equations are available that include a constant generating source. However, certain diseases (e.g., infectious tuberculosis) are not likely to be aerosolized at a constant rate. The times given assume perfect mixing of the air within the space (i.e., mixing factor = 1). However, perfect mixing usually does not occur. Removal times will be longer in rooms or areas with imperfect mixing or air stagnation. 213 Caution should be exercised in using this table in such situations. For booths or other local ventilation enclosures, manufacturers' instructions should be consulted.\n\n# Appendix B. Air 1. Airborne Contaminant Removal\n\n# Ventilation Specifications for Health-Care Facilities\nThe following tables from the AIA Guidelines for Design and Construction of Hospitals and Health-Care Facilities, 2001 are reprinted with permission of the American Institute of Architects and the publisher (The Facilities Guidelines Institute). 120 Note: This table is Table 7 20. Food preparation centers shall have ventilation systems whose air supply mechanisms are interfaced appropriately with exhaust hood controls or relief vents so that exfiltration or infiltration to or from exit corridors does not compromise the exit corridor restrictions of NFPA 90A, the pressure requirements of NFPA 96, or the maximum defined in the table. The number of air changes may be reduced or varied to any extent required for odor control when the space is not in use. See Section 7.31.D1.p in the AIA guideline (reference 120).\n\n# Appendix I:\nA7. Recirculating devices with HEPA filters may have potential uses in existing facilities as interim, supplemental environmental controls to meet requirements for the control of airborne infectious agents. Limitations in design must be recognized. The design of either portable or fixed systems should prevent stagnation and short circuiting of airflow. The supply and exhaust locations should direct clean air to areas where health-care workers are likely to work, across the infectious source, and then to the exhaust, so that the healthcare worker is not in position between the infectious source and the exhaust location. The design of such systems should also allow for easy access for scheduled preventative maintenance and cleaning.\nA11. The verification of airflow direction can include a simple visual method such as smoke trail, ball-in-tube, or flutterstrip. These devices will require a minimum differential air pressure to indicate airflow direction. Notes:\n1. The ventilation rates in this table cover ventilation for comfort, as well as for asepsis and odor control in areas of nursing facilities that directly affect resident care and are determined based on nursing facilities being predominantly \"No Smoking\" facilities. Where smoking may be allowed, ventilation rates will need adjustment. Areas where specific ventilation rates are not given in the table shall be ventilated in accordance with ASHRAE Standard 62, Ventilation for Acceptable Indoor Air Quality, and ASHRAE Handbook -HVAC Applications. OSHA standards and/or NIOSH criteria require special ventilation requirements for employee health and safety within nursing facilities.\n2. Design of the ventilation system shall, insofar as possible, provide that air movement is from clean to less clean areas. However, continuous compliance may be impractical with full utilization of some forms of variable air volume and load shedding systems that may be used for energy conservation.\nAreas that do require positive and continuous control are noted with \"Out\" or \"In\" to indicate the required direction of air movement in relation to the space named. Rate of air movement may, of course, be varied as needed within the limits required for positive control. Where indication of air movement direction is enclosed in parentheses, continuous directional control is required only when the specialized equipment or device is in use or where room use may otherwise compromise the intent of movement from clean to less clean. Air movement for rooms with dashes and nonpatient areas may vary as necessary to satisfy the requirements of those spaces. Additional adjustments may be needed when space is unused or unoccupied and air systems are deenergized or reduced.\n\n# Appendix C. Water 1. Biofilms\nMicroorganisms have a tendency to associate with and stick to surfaces. These adherent organisms can initiate and develop biofilms, which are comprised of cells embedded in a matrix of extracellularly produced polymers and associated abiotic particles. 1438 It is inevitable that biofilms will form in most water systems. In the health-care facility environment, biofilms may be found in the potable water supply piping, hot water tanks, air conditioning cooling towers, or in sinks, sink traps, aerators, or shower heads. Biofilms, especially in water systems, are not present as a continuous slime or film, but are more often scanty and heterogeneous in nature. 1439 Biofilms may form under stagnant as well as flowing conditions, so storage tanks, in addition to water system piping, may be vulnerable to the development of biofilm, especially if water temperatures are low enough to allow the growth of thermophilic bacteria (e.g., Legionella spp.). Favorable conditions for biofilm formation are present if these structures and equipment are not cleaned for extended periods of time. 1440 Algae, protozoa, and fungi may be present in biofilms, but the predominant microorganisms of water system biofilms are gram-negative bacteria. Although most of these organisms will not normally pose a problem for healthy individuals, certain biofilm bacteria (e.g., Pseudomonas aeruginosa, Klebsiella spp., Pantoea agglomerans, and Enterobacter cloacae) all may be agents for opportunistic infections for immunocompromised individuals. 1441,1442 These biofilm organisms may easily contaminate indwelling medical devices or intravenous (IV) fluids, and they could be transferred on the hands of health-care workers. Biofilms may potentially provide an environment for the survival of pathogenic organisms, such as Legionella pneumophila and E. coli O157:H7. Although the association of biofilms and medical devices provides a plausible explanation for a variety of health-care associated infections, it is not clear how the presence of biofilms in the water system may influence the rates of health-care-associated waterborne infection.\nOrganisms within biofilms behave quite differently than their planktonic (i.e., free floating) counterparts.\nResearch has shown that biofilm-associated organisms are more resistant to antibiotics and disinfectants than are planktonic organisms, either because the cells are protected by the polymer matrix, or because they are physiologically different. Nevertheless, municipal water utilities attempt to maintain a chlorine residual in the distribution system to discourage microbiological growth. Though chlorine in its various forms is a proven disinfectant, it has been shown to be less effective against biofilm bacteria. 1448 Higher levels of chlorine for longer contact times are necessary to eliminate biofilms.\nRoutine sampling of health-care facility water systems for biofilms is not warranted. If an epidemiologic investigation points to the water supply system as a possible source of infection, then water sampling for biofilm organisms should be considered so that prevention and control strategies can be developed. An established biofilm is is difficult to remove totally in existing piping. Strategies to remediate biofilms in a water system would include flushing the system piping, hot water tank, dead legs, and those areas of the facility's water system subject to low or intermittent flow. The benefits of this treatment would include a. elimination of corrosion deposits and sludge from the bottom of hot water tanks, b. removal of biofilms from shower heads and sink aerators, and c. circulation of fresh water containing elevated chlorine residuals into the health-care facility water system.\nThe general strategy for evaluating water system biofilm depends on a comparision of the bacteriological quality of the incoming municipal water and that of water sampled from within facility's distribution system. Heterotrophic plate counts and coliform counts, both of which are routinely run by the municipal water utility, will at least provide in indication of the potential for biofilm formation. Heterotrophic plate count levels in potable water should be 500 CFU/mL would indicate a general decrease in water quality. A direct correlation between heterotrophic plate count and biofilm levels has been demonstrated. 1450 Therefore, an increase in G. Refill the system with water and repeat the procedure outline in steps 2-7 in I-B above.\n\n# III. Perform mechanical cleaning.\nA. After water from the second chemical disinfection has been drained, shut down the CT/EC. B. Inspect all water-contact areas for sediment, sludge, and scale. Using brushes and/or a lowpressure water hose, thoroughly clean all CT/EC water-contact areas, including the basin, sump, fill, spray nozzles, and fittings. Replace components as needed. C. If possible, clean CT/EC water-contact areas within the chillers.\n\n# IV. Perform these procedures after mechanical cleaning.\nA. Fill the system with water and add chlorine to achieve an FRC level of 10 mg/L. B. Circulate the water for 1 hour, then open the blowdown valve and flush the entire system until the water is free of turbidity. C. Drain the system. D. Open any air-intake vents that were closed before cleaning. E. Fill the system with water. The CT/EC may be put back into service using an effective watertreatment program.\n\n# Maintenance Procedures Used to Decrease Survival and Multiplications of Legionella spp. in Potable-Water Distribution Systems\nWherever allowable by state code, provide water at ≥124°F (≥51°C) at all points in the heated water system, including the taps. This requires that water in calorifiers (e.g., water heaters) be maintained at ≥140°F (≥60°C). In the United Kingdom, where maintenance of water temperatures at ≥122°F (≥50°C) in hospitals has been mandated, installation of blending or mixing valves at or near taps to reduce the water temperature to ≤109.4°F (≤63°C) has been recommended in certain settings to reduce the risk for scald injury to patients, visitors, and health care workers. 726 However, Legionella spp. can multiply even in short segments of pipe containing water at this temperature. Increasing the flow rate from the hot-watercirculation system may help lessen the likelihood of water stagnation and cooling. 711,1465 Insulation of plumbing to ensure delivery of cold (<68°F ) water to water heaters (and to cold-water outlets) may diminish the opportunity for bacterial multiplication. 456 Both dead legs and capped spurs within the plumbing system provide areas of stagnation and cooling to <122°F (<50°C) regardless of the circulating water temperature; these segments may need to be removed to prevent colonization. 704 Rubber fittings within plumbing systems have been associated with persistent colonization, and replacement of these fittings may be required for Legionella spp. eradication. 1467 Continuous chlorination to maintain concentrations of free residual chlorine at 1-2 mg/L (1-2 ppm) at the tap is an alternative option for treatment. This requires the placement of flow-adjusted, continuous injectors of chlorine throughout the water distribution system. Adverse effects of continuous chlorination can include accelerated corrosion of plumbing (resulting in system leaks) and production of potentially carcinogenic trihalomethanes. However, when levels of free residual chlorine are below 3 mg/L (3 ppm), trihalomethane levels are kept below the maximum safety level recommended by the EPA. 727, 1468, 1469 228\n\n# Appendix D. Insects and Microorganisms\nFormat Change : The format of this section was changed to improve readability and accessibility. The content is unchanged.\n\n# Appendix E. Information Resources\nThe following sources of information may be helpful to the reader. Some of these are available at no charge, while others are available for purchase from the publisher.\n\n# Air and Water\n\n# Appendix F. Areas of Future Research Air\n- Standardize the methodology and interpretation of microbiologic air sampling (e.g., determine action levels or minimum infectious dose for aspergillosis, and evaluate the significance of airborne bacteria and fungi in the surgical field and the impact on postoperative SSI). - Develop new molecular typing methods to better define the epidemiology of health-care associated outbreaks of aspergillosis and to associate isolates recovered from both clinical and environmental sources. - Develop new methods for the diagnosis of aspergillosis that can lead reliably to early recognition of infection. - Assess the value of laminar flow technology for surgeries other than for joint replacement surgery.\n- Determine if particulate sampling can be routinely performed in lieu of microbiologic sampling for purposes such as determining air quality of clean environments (e.g., operating rooms, HSCT units).\n\n# Water\n- Evaluate new methods of water treatment, both in the facility and at the water utility (e.g., ozone, chlorine dioxide, copper/silver/monochloramine) and perform cost-benefit analyses of treatment in preventing health-care associated legionellosis. - Evaluate the role of biofilms in overall water quality and determine the impact of water treatments for the control of biofilm in distribution systems. - Determine if the use of ultrapure fluids in dialysis is feasible and warranted, and determine the action level for the final bath. - Develop quality assurance protocols and validated methods for sampling filtered rinse water used with AERs and determine acceptable microbiologic quality of AER rinse water.\n\n# Environmental Services\n- Evaluate the innate resistance of microorganisms to the action of chemical germicides, and determine what, if any, linkage there may be between antibiotic resistance and resistance to disinfectants.\n\n# Laundry and Bedding\n- Evaluate the microbial inactivation capabilities of new laundry detergents, bleach substitutes, other laundry additives, and new laundry technologies.\n\n# Animals in Health-Care Facilities\n- Conduct surveillance to monitor incidence of infections among patients in facilities that use animal programs, and conduct investigations to determine new infection control strategies to prevent these infections. - Evaluate the epidemiologic impact of performing procedures on animals (e.g., surgery or imaging) in human health-care facilities.\n\n# Regulated Medical Waste\n- Determine the efficiency of current medical waste treatment technologies to inactivate emerging pathogens that may be present in medical waste (e.g., SARS-coV). - Explore options to enable health-care facilities to reinstate the capacity to inactivate microbiological cultures and stocks on-site."},"raw_text":{"kind":"string","value":"Although the environment serves as a reservoir for a variety of microorganisms, it is rarely implicated in disease transmission except in the immunocompromised population. Inadvertent exposures to environmental opportunistic pathogens (e.g., Aspergillus spp. and Legionella spp.) or airborne pathogens (e.g., Mycobacterium tuberculosis and varicella-zoster virus) may result in infections with significant morbidity and/or mortality. Lack of adherence to established standards and guidance (e.g., water quality in dialysis, proper ventilation for specialized care areas such as operating rooms, and proper use of disinfectants) can result in adverse patient outcomes in health-care facilities.The objective is to develop an environmental infection-control guideline that reviews and reaffirms strategies for the prevention of environmentally-mediated infections, particularly among health-care workers and immunocompromised patients. The recommendations are evidence-based whenever possible.The contributors to this guideline reviewed predominantly English-language articles identified from MEDLINE literature searches, bibliographies from published articles, and infection-control textbooks.Articles dealing with outbreaks of infection due to environmental opportunistic microorganisms and epidemiological-or laboratory experimental studies were reviewed. Current editions of guidelines and standards from organizations (i.e.# Outcome Measures:\nInfections caused by the microorganisms described in this guideline are rare events, and the effect of these recommendations on infection rates in a facility may not be readily measurable. Therefore, the following steps to measure performance are suggested to evaluate these recommendations:\n1. Document whether infection-control personnel are actively involved in all phases of a healthcare facility's demolition, construction, and renovation. Activities should include performing a risk assessment of the necessary types of construction barriers, and daily monitoring and documenting of the presence of negative airflow within the construction zone or renovation area.\n2. Monitor and document daily the negative airflow in airborne infection isolation rooms (AII) and positive airflow in protective environment rooms (PE), especially when patients are in these rooms.\n3. Perform assays at least once a month by using standard quantitative methods for endotoxin in water used to reprocess hemodialyzers, and for heterotrophic, mesophilic bacteria in water used to prepare dialysate and for hemodialyzer reprocessing. \n# Executive Summary\nThe Guidelines for Environmental Infection Control in Health-Care Facilities is a compilation of recommendations for the prevention and control of infectious diseases that are associated with healthcare environments. This document a. revises multiple sections from previous editions of the Centers for Disease Control and Prevention [CDC] document titled Guideline for Handwashing and Hospital Environmental Control; 1, 2 b. incorporates discussions of air and water environmental concerns from CDC's Guideline for the Prevention of Nosocomial Pneumonia; 3 c. consolidates relevant environmental infection-control measures from other CDC guidelines; [4][5][6][7][8][9] and d. includes two topics not addressed in previous CDC guidelines -infection-control concerns related to animals in health-care facilities and water quality in hemodialysis settings.\nPart I of this report, Background Information: Environmental Infection Control in Health-Care Facilities, provides a comprehensive review of the scientific literature. Attention is given to engineering and infectioncontrol concerns during construction, demolition, renovation, and repairs of health-care facilities. Use of an infection-control risk assessment is strongly supported before the start of these or any other activities expected to generate dust or water aerosols. Also reviewed in Part I are infection-control measures used to recover from catastrophic events (e.g., flooding, sewage spills, loss of electricity and ventilation, and disruption of the water supply) and the limited effects of environmental surfaces, laundry, plants, animals, medical wastes, cloth furnishings, and carpeting on disease transmission in healthcare facilities.\nPart II of this guideline, Recommendations for Environmental Infection Control in Health-Care Facilities, outlines environmental infection control in health-care facilities, describing measures for preventing infections associated with air, water, and other elements of the environment. These recommendations represent the views of different divisions within CDC's National Center for Infectious Diseases (NCID) (e.g., the Division of Healthcare Quality Promotion [DHQP] and the Division of Bacterial and Mycotic Diseases [DBMD]) and the consensus of the Healthcare Infection Control Practices Advisory Committee (HICPAC), a 12-member group that advises CDC on concerns related to the surveillance, prevention, and control of health-care associated infections, primarily in U.S. healthcare facilities.10 In 1999, HICPAC's infection-control focus was expanded from acute-care hospitals to all venues where health care is provided (e.g., outpatient surgical centers, urgent care centers, clinics, outpatient dialysis centers, physicians' offices, and skilled nursing facilities). The topics addressed in this guideline are applicable to the majority of health-care venues in the United States. This document is intended for use primarily by infection-control professionals (ICPs), epidemiologists, employee health and safety personnel, information system specialists, administrators, engineers, facility managers, environmental service professionals, and architects for health-care facilities.\nKey recommendations include a. infection-control impact of ventilation system and water system performance; b. establishment of a multidisciplinary team to conduct infection-control risk assessment; c. use of dust-control procedures and barriers during construction, repair, renovation, or demolition; d. environmental infection-control measures for special care areas with patients at high risk; e. use of airborne particle sampling to monitor the effectiveness of air filtration and dust-control measures; f. procedures to prevent airborne contamination in operating rooms when infectious tuberculosis [TB] patients require surgery g. guidance regarding appropriate indications for routine culturing of water as part of a comprehensive control program for legionellae; h. guidance for recovering from water system disruptions, water leaks, and natural disasters [e.g., flooding]; i. infection-control concepts for equipment that uses water from main lines [e.g., water systems for hemodialysis, ice machines, hydrotherapy equipment, dental unit water lines, and automated endoscope reprocessors]); j. environmental surface cleaning and disinfection strategies with respect to antibiotic-resistant microorganisms; k. infection-control procedures for health-care laundry; l. use of animals in health care for activities and therapy; m. managing the presence of service animals in health-care facilities; n. infection-control strategies for when animals receive treatment in human health-care facilities; and o. a call to reinstate the practice of inactivating amplified cultures and stocks of microorganisms on-site during medical waste treatment.\nWhenever possible, the recommendations in Part II are based on data from well-designed scientific studies. However, certain of these studies were conducted by using narrowly defined patient populations or for specific health-care settings (e.g., hospitals versus long-term care facilities), making generalization of findings potentially problematic. Construction standards for hospitals or other healthcare facilities may not apply to residential home-care units. Similarly, infection-control measures indicated for immunosuppressed patient care are usually not necessary in those facilities where such patients are not present. Other recommendations were derived from knowledge gained during infectious disease investigations in health-care facilities, where successful termination of the outbreak was often the result of multiple interventions, the majority of which cannot be independently and rigorously evaluated. This is especially true for construction situations involving air or water.\nOther recommendations are derived from empiric engineering concepts and may reflect an industry standard rather than an evidence-based conclusion. Where recommendations refer to guidance from the American Institute of Architects (AIA), (AIA guidance has been superseded by the Facilities Guidelines Institute [FGI]) the statements reflect standards intended for new construction or renovation. Existing structures and engineered systems are expected to be in continued compliance with the standards in effect at the time of construction or renovation. Also, in the absence of scientific confirmation, certain infectioncontrol recommendations that cannot be rigorously evaluated are based on a strong theoretical rationale and suggestive evidence. Finally, certain recommendations are derived from existing federal regulations.\nThe references and the appendices comprise Parts III and IV of this document, respectively.\nInfections caused by the microorganisms described in these guidelines are rare events, and the effect of these recommendations on infection rates in a facility may not be readily measurable. Therefore, the following steps to measure performance are suggested to evaluate these recommendations (Box 1):\nBox 1. Environmental infection control: performance measures 1. Document whether infection-control personnel are actively involved in all phases of a health-care facility's demolition, construction, and renovation. Activities should include performing a risk assessment of the necessary types of construction barriers, and daily monitoring and documenting of the presence of negative airflow within the construction zone or renovation area.\n2. Monitor and document daily the negative airflow in airborne infection isolation (AII) rooms and positive airflow in protective environment (PE) rooms, especially when patients are in these rooms.\n3. Perform assays at least once a month by using standard quantitative methods for endotoxin in water used to reprocess hemodialyzers, and for heterotrophic and mesophilic bacteria in water used to prepare dialysate and for hemodialyzer reprocessing.\n4. Evaluate possible environmental sources (e.g., water, laboratory solutions, or reagents) of specimen contamination when nontuberculous mycobacteria (NTM) of unlikely clinical importance are isolated from clinical cultures. If environmental contamination is found, eliminate the probable mechanisms.\n5. Document policies to identify and respond to water damage. Such policies should result in either repair and drying of wet structural or porous materials within 72 hours, or removal of the wet material if drying is unlikely with 72 hours.\nTopics outside the scope of this document include a. noninfectious adverse events (e.g., sick building syndrome); b. environmental concerns in the home; c. home health care; d. bioterrorism; and e. healthcare-associated foodborne illness.\nThis document includes only limited discussion of handwashing/hand hygiene; standard precautions; and infection-control measures used to prevent instrument or equipment contamination during patient care (e.g., preventing waterborne contamination of nebulizers or ventilator humidifiers).\nThese topics are mentioned only if they are important in minimizing the transfer of pathogens to and from persons or equipment and the environment. Although the document discusses principles of cleaning and disinfection as they are applied to maintenance of environmental surfaces, the full discussion of sterilization and disinfection of medical instruments and direct patient-care devices is deferred for inclusion in the \n# Part I. Background Information: Environmental Infection Control in Health-Care Facilities\n\n# A. Introduction\nThe health-care environment contains a diverse population of microorganisms, but only a few are significant pathogens for susceptible humans. Microorganisms are present in great numbers in moist, organic environments, but some also can persist under dry conditions. Although pathogenic microorganisms can be detected in air and water and on fomites, assessing their role in causing infection and disease is difficult. 11 Only a few reports clearly delineate a \"cause and effect\" with respect to the environment and in particular, housekeeping surfaces.\nEight criteria are used to evaluate the strength of evidence for an environmental source or means of transmission of infectious agents (Box 2). 11,12 Applying these criteria to disease investigations allows scientists to assess the contribution of the environment to disease transmission. An example of this application is the identification of a pathogen (e.g., vancomycin-resistant enterococci [VRE]) on an environmental surface during an outbreak. The presence of the pathogen does not establish its causal role; its transmission from source to host could be through indirect means (e.g., via hand transferral). 11 The surface, therefore, would be considered one of a number of potential reservoirs for the pathogen, but not the \"de facto\" source of exposure. An understanding of how infection occurs after exposure, based on the principles of the \"chain of infection,\" is also important in evaluating the contribution of the environment to health-care associated disease. 13 All of the components of the \"chain\" must be operational for infection to occur (Box 3).\nBox 2. Eight criteria for evaluating the strength of evidence for environmental sources of infection*+\n1. The organism can survive after inoculation onto the fomite.\n2. The organism can be cultured from in-use fomites.\n3. The organism can proliferate in or on the fomite.\n4. Some measure of acquisition of infection cannot be explained by other recognized modes of transmission.\n5. Retrospective case-control studies show an association between exposure to the fomite and infection.\n# 6.\nProspective case-control studies may be possible when more than one similar type of fomite is in use. 7. Prospective studies allocating exposure to the fomite to a subset of patients show an association between exposure and infection. The presence of the susceptible host is one of these components that underscores the importance of the health-care environment and opportunistic pathogens on fomites and in air and water. As a result of advances in medical technology and therapies (e.g., cytotoxic chemotherapy and transplantation medicine), more patients are becoming immunocompromised in the course of treatment and are therefore at increased risk for acquiring health-care associated opportunistic infections. Trends in health-care delivery (e.g., early discharge of patients from acute care facilities) also are changing the distribution of patient populations and increasing the number of immunocompromised persons in nonacute-care hospitals. According to the American Hospital Association (AHA), in 1998, the number of hospitals in the United States totaled 6,021; these hospitals had a total of 1,013,000 beds, 14 representing a 5.5% decrease in the number of acute-care facilities and a 10.2% decrease in the number of beds over the 5year period 1994-1998. 14 In addition, the total average daily number of patients receiving care in U.S. acute-care hospitals in 1998 was 662,000 (65.4%) -36.5% less than the 1978 average of 1,042,000. 14 As the number of acute-care hospitals declines, the length of stay in these facilities is concurrently decreasing, particularly for immunocompetent patients. Those patients remaining in acute-care facilities are likely to be those requiring extensive medical interventions who therefore at high risk for opportunistic infection. The growing population of severely immunocompromised patients is at odds with demands on the health-care industry to remain viable in the marketplace; to incorporate modern equipment, new diagnostic procedures, and new treatments; and to construct new facilities. Increasing numbers of health-care facilities are likely to be faced with construction in the near future as hospitals consolidate to reduce costs, defer care to ambulatory centers and satellite clinics, and try to create more \"home-like\" acute-care settings. In 1998, approximately 75% of health-care associated construction projects focused on renovation of existing outpatient facilities or the building of such facilities; 15 the number of projects associated with outpatient health care rose by 17% from 1998 through 1999. 16 An aging population is also creating increasing demand for assisted-living facilities and skilled nursing centers. Construction of assisted-living facilities in 1998 increased 49% from the previous year, with 138 projects completed at a cost of $703 million. 16 Overall, from 1998 to 1999, health-care associated construction costs increased by 28.5%, from $11.56 billion to $14.86 billion. 16 Environmental disturbances associated with construction activities near health-care facilities pose airborne and waterborne disease threats risks for the substantial number of patients who are at risk for health-care associated opportunistic infections. The increasing age of hospitals and other health-care facilities is also generating ongoing need for repair and remediation work (e.g., installing wiring for new information systems, removing old sinks, and repairing elevator shafts) that can introduce or increase contamination of the air and water in patient-care environments. Aging equipment, deferred maintenance, and natural disasters provide additional mechanisms for the entry of environmental pathogens into highrisk patient-care areas.\nArchitects, engineers, construction contractors, environmental health scientists, and industrial hygienists historically have directed the design and function of hospitals' physical plants. Increasingly, however, because of the growth in the number of susceptible patients and the increase in construction projects, the involvement of hospital epidemiologists and infection-control professionals is required. These experts help make plans for building, maintaining, and renovating health-care facilities to ensure that the adverse impact of the environment on the incidence of health-care associated infections is minimal. The following are examples of adverse outcomes that could have been prevented had such experts been involved in the planning process: transmission of infections caused by Mycobacterium tuberculosis, varicella-zoster virus (VZV), and measles (i.e., rubeola) facilitated by inappropriate air-handling systems in health-care facilities; 6 disease outbreaks caused by Aspergillus spp., [17][18][19] Mucoraceae, 20 and Penicillium spp. associated with the absence of environmental controls during periods of health-care facility-associated construction; 21 infections and/or colonizations of patients and staff with vancomycin-resistant Enterococcus faecium [VRE] and Clostridium difficile acquired indirectly from contact with organisms present on environmental surfaces in health-care facilities; [22][23][24][25] and outbreaks and pseudoepidemics of legionellae, 26,27 Pseudomonas aeruginosa, 28-30 and the nontuberculous mycobacteria (NTM) 31,32 linked to water and aqueous solutions used in health-care facilities.\nThe purpose of this guideline is to provide useful information for both health-care professionals and engineers in efforts to provide a safe environment in which quality health care may be provided to patients. The recommendations herein provide guidance to minimize the risk for and prevent transmission of pathogens in the indoor environment.\n# B. Key Terms Used in this Guideline\nAlthough Appendix A provides definitions for terms discussed in Part I, several terms that pertain to specific patient-care areas and patients who are at risk for health-care associated opportunistic infections are presented here. Specific engineering parameters for these care areas are discussed more fully in the text. Airborne Infection Isolation (AII) refers to the isolation of patients infected with organisms spread via airborne droplet nuclei <5 μm in diameter. This isolation area receives numerous air changes per hour (ACH) (≥12 ACH for new construction as of 2001; ≥6 ACH for construction before 2001), and is under negative pressure, such that the direction of the airflow is from the outside adjacent space (e.g., corridor) into the room. The air in an AII room is preferably exhausted to the outside, but may be recirculated provided that the return air is filtered through a high efficiency particulate air (HEPA) filter. The use of personal respiratory protection is also indicated for persons entering these rooms.\nProtective Environment (PE) is a specialized patient-care area, usually in a hospital, with a positive airflow relative to the corridor (i.e., air flows from the room to the outside adjacent space). The combination of HEPA filtration, high numbers of air changes per hour (≥12 ACH), and minimal leakage of air into the room creates an environment that can safely accommodate patients who have undergone allogeneic hematopoietic stem cell transplant (HSCT).\nImmunocompromised patients are those patients whose immune mechanisms are deficient because of immunologic disorders (e.g., human immunodeficiency virus [HIV] infection, congenital immune deficiency syndrome, chronic diseases [such as diabetes, cancer, emphysema, and cardiac failure]) or immunosuppressive therapy (e.g., radiation, cytotoxic chemotherapy, anti-rejection medication, and steroids). Immunocompromised patients who are identified as high-risk patients have the greatest risk of infection caused by airborne or waterborne microorganisms. Patients in this subset include those who are severely neutropenic for prolonged periods of time (i.e., an absolute neutrophil count [ANC] of ≤500 cells/mL), allogeneic HSCT patients, and those who have received intensive chemotherapy (e.g., childhood acute myelogenous leukemia patients).\n# C. Air 1. Modes of Transmission of Airborne Diseases\nA variety of airborne infections in susceptible hosts can result from exposures to clinically significant microorganisms released into the air when environmental reservoirs (i.e., soil, water, dust, and decaying organic matter) are disturbed. Once these materials are brought indoors into a health-care facility by any of a number of vehicles (e.g., people, air currents, water, construction materials, and equipment), the attendant microorganisms can proliferate in various indoor ecological niches and, if subsequently disbursed into the air, serve as a source for airborne health-care associated infections.\nRespiratory infections can be acquired from exposure to pathogens contained either in droplets or droplet nuclei. Exposure to microorganisms in droplets (e.g., through aerosolized oral and nasal secretions from infected patients 33 ) constitutes a form of direct contact transmission. When droplets are produced during a sneeze or cough, a cloud of infectious particles >5 μm in size is expelled, resulting in the potential exposure of susceptible persons within 3 feet of the source person. 6 Examples of pathogens spread in this manner are influenza virus, rhinoviruses, adenoviruses, and respiratory syncytial virus (RSV). Because these agents primarily are transmitted directly and because the droplets tend to fall out of the air quickly, measures to control air flow in a health-care facility (e.g., use of negative pressure rooms) generally are not indicated for preventing the spread of diseases caused by these agents. Strategies to control the spread of these diseases are outlined in another guideline. 3 The spread of airborne infectious diseases via droplet nuclei is a form of indirect transmission. 34 Droplet nuclei are the residuals of droplets that, when suspended in air, subsequently dry and produce particles ranging in size from 1-5 μm. These particles can a. contain potentially viable microorganisms, b. be protected by a coat of dry secretions, c. remain suspended indefinitely in air, and d. be transported over long distances.\nThe microorganisms in droplet nuclei persist in favorable conditions (e.g., a dry, cool atmosphere with little or no direct exposure to sunlight or other sources of radiation). Pathogenic microorganisms that can be spread via droplet nuclei include Mycobacterium tuberculosis, VZV, measles virus (i.e., rubeola), and smallpox virus (i.e., variola major). 6 Several environmental pathogens have life-cycle forms that are similar in size to droplet nuclei and may exhibit similar behavior in the air. The spores of Aspergillus fumigatus have a diameter of 2-3.5 μm, with a settling velocity estimated at 0.03 cm/second (or about 1 meter/hour) in still air. With this enhanced buoyancy, the spores, which resist desiccation, can remain airborne indefinitely in air currents and travel far from their source. 35\n# Airborne Infectious Diseases in Health-Care Facilities a. Aspergillosis and Other Fungal Diseases\nAspergillosis is caused by molds belonging to the genus Aspergillus. Aspergillus spp. are prototype health-care acquired pathogens associated with dusty or moist environmental conditions. Clinical and epidemiologic aspects of aspergillosis (Table 1) are discussed extensively in another guideline. 3 Format Change [November 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged.\n# Table 1. Clinical and epidemiologic characteristics of aspergillosis\n\n# Modes of transmission\nAirborne transmission of fungal spores; direct inhalation; direct inoculation from environmental sources (rare)\nand equipment can become contaminated with Aspergillus spp. spores and serve as sources of infection if stored in such areas. 57 Most cases of aspergillosis are caused by Aspergillus fumigatus, a thermotolerant/thermophilic fungus capable of growing over a temperature range from 53.6°F-127.4°F (12°C-53°C); optimal growth occurs at approximately 104°F (40°C), a temperature inhibitory to most other saprophytic fungi. 99 It can use cellulose or sugars as carbon sources; because its respiratory process requires an ample supply of carbon, decomposing organic matter is an ideal substrate. (For AIA guidance on Aspergillus spp. see Table 2.)\nOther opportunistic fungi that have been occasionally linked with health-care associated infections are members of the order Mucorales (e.g., Rhizopus spp.) and miscellaneous moniliaceous molds (e.g., Fusarium spp. and Penicillium spp.) (Table 2). Many of these fungi can proliferate in moist environments (e.g., water-damaged wood and building materials). Some fungi (e.g., Fusarium spp. and Pseudoallescheria spp.) also can be airborne pathogens. 100 As with aspergillosis, a major risk factor for disease caused by any of these pathogens is the host's severe immunosuppression from either underlying disease or immunosuppressive therapy. 101,102 Format Change [November 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged.\n# Table 2. Environmental fungal pathogens: entry into and contamination of the healthcare facility\nFungal pathogen Implicated environmental vehicle Aspergillus spp.\n• Improperly functioning ventilation systems 20,46,47,97,98,103,104 • Air filters+ 17,18,[105][106][107] Pigeons, their droppings and roosts are associated with spread of Aspergillus, Cryptococcus, and Histoplasma spp. There have been at least three outbreaks linked to contamination of the filtering systems from bird droppings 98,103,104 Pigeon mites may gain access into a health-care facility through the ventilation system. 119 • Air filter frames 17,18 • Window air conditioners 96 • Backflow of contaminated air 107\n• Air exhaust contamination+ 104 • False ceilings 48,57,97,108 • Fibrous insulation and perforated metal ceilings 66 • Acoustic ceiling tiles, plasterboard 18,109 • Fireproofing material 48,49 • Damp wood building materials 49 • Opening doors to construction site 110 \n# • Construction 69\n• Open windows 20,108,111 105 • Topical anesthetic 117 Acremonium spp.\n• Air filters 105 Cladosporium spp.\n• Air filters 105 \n# Sporothrix\n• Construction (pseudoepidemic) 118 + The American Institute of Architects (AIA) standards stipulate that for new or renovated construction o exhaust outlets are to be placed >25 feet from air intake systems, o the bottom of outdoor air intakes for HVAC systems should be 6 feet above ground or 3 feet above roof level, and o exhaust outlets from contaminated areas are situated above the roof level and arranged to minimize the recirculation of exhausted air back into the building. 120 Infections due Cryptococcus neoformans, Histoplasma capsulatum, or Coccidioides immitis can occur in health-care settings if nearby ground is disturbed and a malfunction of the facility's air-intake components allows these pathogens to enter the ventilation system. C. neoformans is a yeast usually 4-8 μm in size. However, viable particles of <2 μm diameter (and thus permissive to alveolar deposition) have been found in soil contaminated with bird droppings, particularly from pigeons. 98,103,104,121 H. capsulatum, with the infectious microconidia ranging in size from 2-5 μm, is endemic in the soil of the central river valleys of the United States. Substantial numbers of these infectious particles have been associated with chicken coops and the roosts of blackbirds. 98,103,104,122 Several outbreaks of histoplasmosis have been associated with disruption of the environment; construction activities in an endemic area may be a potential risk factor for health-care acquired airborne infection. 123,124 C. immitis, with arthrospores of 3-5 μm diameter, has similar potential, especially in the endemic southwestern United States and during seasons of drought followed by heavy rainfall. After the 1994 earthquake centered near Northridge, California, the incidence of coccidioidomycosis in the surrounding area exceeded the historical norm. 125 Emerging evidence suggests that Pneumocystis carinii, now classified as a fungus, may be spread via airborne, person-to-person transmission. 126 Controlled studies in animals first demonstrated that P. carinii could be spread through the air. 127 More recent studies in health-care settings have detected nucleic acids of P. carinii in air samples from areas frequented or occupied by P. carinii-infected patients but not in control areas that are not occupied by these patients. 128,129 Clusters of cases have been identified among immunocompromised patients who had contact with a source patient and with each other. Recent studies have examined the presence of P. carinii DNA in oropharyngeal washings and the nares of infected patients, their direct contacts, and persons with no direct contact. 130,131 Molecular analysis of the DNA by polymerase chain reaction (PCR) provides evidence for airborne transmission of P. carinii from infected patients to direct contacts, but immunocompetent contacts tend to become transiently colonized rather than infected. 131 The role of colonized persons in the spread of P. carinii pneumonia (PCP) remains to be determined. At present, specific modifications to ventilation systems to control spread of PCP in a health-care facility are not indicated. Current recommendations outline isolation procedures to minimize or eliminate contact of immunocompromised patients not on PCP prophylaxis with PCP-infected patients. 6,132 \n# b. Tuberculosis and Other Bacterial Diseases\nThe bacterium most commonly associated with airborne transmission is Mycobacterium tuberculosis. A comprehensive review of the microbiology and epidemiology of M. tuberculosis and guidelines for tuberculosis (TB) infection control have been published. 4,133,134 A summary of the clinical and epidemiologic information from these materials is provided in this guideline (Table 3).\nFormat Change [November 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged. \n# Factors affecting severity and outcomes\n• Concentration of droplet nuclei in air, duration of exposure • Age at infection • Immunosuppression due to therapy or disease, underlying chronic medical conditions, history of malignancies or lesions or the lungs Occurrence • Worldwide; incidence in the United States is 56 cases/100,000 population (2001) 136 Mortality rate • 930 deaths in the United States (1999) 136 Chemoprophylaxis / treatment • Treatment of latent infection includes isoniazid (INH) or rifampin (RIF) 4,134,[137][138][139] • Directly observed therapy (DOT) for active cases as indicated: INH, RIF, pyrazinamide (PZA), ethambutol (EMB), streptomycin (SM) in various combinations determined by prevalent levels of specific resistance 4,134,[137][138][139] • Consult therapy guidelines for specific treatment indications 139 * Material in this table is compiled from references 4, 133-141.\nM. tuberculosis is carried by droplet nuclei generated when persons (primarily adults and adolescents) who have pulmonary or laryngeal TB sneeze, cough, speak, or sing; 139 normal air currents can keep these particles airborne for prolonged periods and spread them throughout a room or building. 142 However, transmission of TB has occurred from mycobacteria aerosolized during provision of care (e.g., wound/lesion care or during handling of infectious peritoneal dialysis fluid) for extrapulmonary TB patients. 135,140 Gram-positive cocci (i.e., Staphylococcus aureus, group A beta-hemolytic streptococci), also important health-care associated pathogens, are resistant to inactivation by drying and can persist in the environment and on environmental surfaces for extended periods. These organisms can be shed from heavily colonized persons and discharged into the air. Airborne dispersal of S. aureus is directly associated with the concentration of the bacterium in the anterior nares. 143 Approximately 10% of healthy carriers will disseminate S. aureus into the air, and some persons become more effective disseminators of S. aureus than others. [144][145][146][147][148] The dispersal of S. aureus into air can be exacerbated by concurrent viral upper respiratory infection, thereby turning a carrier into a \"cloud shedder.\" 149 Outbreaks of surgical site infections (SSIs) caused by group A beta-hemolytic streptococci have been traced to airborne transmission from colonized operating-room personnel to patients. [150][151][152][153] In these situations, the strain causing the outbreak was recovered from the air in the operating room 150,151,154 or on settle plates in a room in which the carrier exercised. [151][152][153] S. aureus and group A streptococci have not been linked to airborne transmission outside of operating rooms, burn units, and neonatal nurseries. 155,156 Transmission of these agents occurs primarily via contact and droplets.\nOther gram-positive bacteria linked to airborne transmission include Bacillus spp. which are capable of sporulation as environmental conditions become less favorable to support their growth. Outbreaks and pseudo-outbreaks have been attributed to Bacillus cereus in maternity, pediatric, intensive care, and bronchoscopy units; many of these episodes were secondary to environmental contamination. [157][158][159][160] Gram-negative bacteria rarely are associated with episodes of airborne transmission because they generally require moist environments for persistence and growth. The main exception is Acinetobacter spp., which can withstand the inactivating effects of drying. In one epidemiologic investigation of bloodstream infections among pediatric patients, identical Acinetobacter spp. were cultured from the patients, air, and room air conditioners in a nursery. 161 Aerosols generated from showers and faucets may potentially contain legionellae and other gram-negative waterborne bacteria (e.g., Pseudomonas aeruginosa). Exposure to these organisms is through direct inhalation. However, because water is the source of the organisms and exposure occurs in the vicinity of the aerosol, the discussion of the diseases associated with such aerosols and the prevention measures used to curtail their spread is discussed in another section of the Guideline (see Part I: Water).\n# c. Airborne Viral Diseases\nSome human viruses are transmitted from person to person via droplet aerosols, but very few viruses are consistently airborne in transmission (i.e., are routinely suspended in an infective state in air and capable of spreading great distances), and health-care associated outbreaks of airborne viral disease are limited to a few agents. Consequently, infection-control measures used to prevent spread of these viral diseases in health-care facilities primarily involve patient isolation, vaccination of susceptible persons, and antiviral therapy as appropriate rather than measures to control air flow or quality. 6 Infections caused by VZV frequently are described in health-care facilities. Health-care associated airborne outbreaks of VZV infections from patients with primary infection and disseminated zoster have been documented; patients with localized zoster have, on rare occasions, also served as source patients for outbreaks in health-care facilities. [162][163][164][165][166] VZV infection can be prevented by vaccination, although patients who develop a rash within 6 weeks of receiving varicella vaccine or who develop breakthrough varicella following exposure should be considered contagious. 167 Viruses whose major mode of transmission is via droplet contact rarely have caused clusters of infections in group settings through airborne routes. The factors facilitating airborne distribution of these viruses in an infective state are unknown, but a presumed requirement is a source patient in the early stage of infection who is shedding large numbers of viral particles into the air. Airborne transmission of measles has been documented in health-care facilities. [168][169][170][171] In addition, institutional outbreaks of influenza virus infections have occurred predominantly in nursing homes, [172][173][174][175][176] and less frequently in medical and neonatal intensive care units, chronic-care areas, HSCT units, and pediatric wards. [177][178][179][180] Some evidence supports airborne transmission of influenza viruses by droplet nuclei, 181,182 and case clusters in pediatric wards suggest that droplet nuclei may play a role in transmitting certain respiratory pathogens (e.g., adenoviruses and respiratory syncytial virus [RSV]). 177,183,184 Some evidence also supports airborne transmission of enteric viruses. An outbreak of a Norwalk-like virus infection involving more than 600 staff personnel over a 3-week period was investigated in a Toronto, Ontario hospital in 1985; common sources (e.g., food and water) were ruled out during the investigation, leaving airborne spread as the most likely mode of transmission. 185 Smallpox virus, a potential agent of bioterrorism, is spread predominantly via direct contact with infectious droplets, but it also can be associated with airborne transmission. 186,187 A German hospital study from 1970 documented the ability of this virus to spread over considerable distances and cause infection at low doses in a well-vaccinated population; factors potentially facilitating transmission in this situation included a patient with cough and an extensive rash, indoor air with low relative humidity, and faulty ventilation patterns resulting from hospital design (e.g., open windows). 188 Smallpox patients with extensive rash are more likely to have lesions present on mucous membranes and therefore have greater potential to disseminate virus into the air. 188 In addition to the smallpox transmission in Germany, two cases of laboratory-acquired smallpox virus infection in the United Kingdom in 1978 also were thought to be caused by airborne transmission. 189 Ebola Virus Disease Update [August 2014]: The recommendations in this guideline for Ebola has been superseded by these CDC documents:\n• Infection Prevention and Control Recommendations for Hospitalized Patients with Known or Suspected Ebola Virus Disease in U.S. Hospitals (https://www.cdc.gov/vhf/ebola/healthcareus/hospitals/infection-control.html) • Interim Guidance for Environmental Infection Control in Hospitals for Ebola Virus (https://www.cdc.gov/vhf/ebola/healthcare-us/cleaning/hospitals.html) See CDC's Ebola Virus Disease website (https://www.cdc.gov/vhf/ebola/index.html) for current information on how Ebola virus is transmitted.\nAirborne transmission may play a role in the natural spread of hantaviruses and certain hemorrhagic fever viruses (e.g., Ebola, Marburg, and Lassa), but evidence for airborne spread of these agents in health-care facilities is inconclusive. 190 Although hantaviruses can be transmitted when aerosolized from rodent excreta, 191,192 person-to-person spread of hantavirus infection from source patients has not occurred in healthcare facilities. [193][194][195] Nevertheless, health-care workers are advised to contain potentially infectious aerosols and wear National Institute of Occupational Safety and Health (NIOSH) approved respiratory protection when working with this agent in laboratories or autopsy suites. 196 Lassa virus transmission via aerosols has been demonstrated in the laboratory and incriminated in health-care associated infections in Africa, [197][198][199] but airborne spread of this agent in hospitals in developed nations likely is inefficient. 200,201 Yellow fever is considered to be a viral hemorrhagic fever agent with high aerosol infectivity potential, but health-care associated transmission of this virus has not been described. 202 Viral hemorrhagic fever diseases primarily occur after direct exposure to infected blood and body fluids, and the use of standard and droplet precautions prevents transmission early in the course of these illnesses. 203,204 However, whether these viruses can persist in droplet nuclei that might remain after droplet production from coughs or vomiting in the latter stages of illness is unknown. 205 Although the use of a negative-pressure room is not required during the early stages of illness, its use might be prudent at the time of hospitalization to avoid the need for subsequent patient transfer. Current CDC guidelines recommend negative-pressure rooms with anterooms for patients with hemorrhagic fever and use of HEPA respirators by persons entering these rooms when the patient has prominent cough, vomiting, diarrhea, or hemorrhage. 6,203 Face shields or goggles will help to prevent mucous-membrane exposure to potentially-aerosolized infectious material in these situations. If an anteroom is not available, portable, industrial-grade high efficiency particulate air (HEPA) filter units can be used to provide the equivalent of additional air changes per hour (ACH). \n# Mycobacterium tuberculosis+\nMeasles (rubeola) virus [168][169][170] Varicella-zoster virus [162][163][164][165][166] Occasional reports in health-care facilities (atypical) Acremonium spp. 105,206 Fusarium spp. 102 Pseudoallescheria boydii 100 Scedosporium spp. 116 Sporothrix cyanescens ¶ 118 Acinetobacter spp. 161 Bacillus spp. ¶ 160,207 Brucella spp.** [208][209][210][211] Staphylococcus aureus 148,156 Group A Streptococcus 151 Smallpox virus (variola) § 188,189 Influenza viruses 181,182 Respiratory syncytial virus 183 Adenoviruses 184 Norwalk-like virus 185 No reports in health-care facilities; known to be airborne outside.\nCoccidioides immitis 125 Cryptococcus spp. 121 Histoplasma capsulatum 124 Coxiella burnetii (Q fever) 212 Hantaviruses 193,195 Lassa virus 205 Marburg virus 205 Ebola virus † 205 Crimean-Congo virus 205 Under investigation Pneumocystis carinii 131 n/a n/a * This list excludes microorganisms transmitted from aerosols derived from water. \n# Heating, Ventilation, and Air Conditioning Systems in Health-Care Facilities\n\n# a. Basic Components and Operations\nHeating, ventilation, and air conditioning (HVAC) systems in health-care facilities are designed to maintain the indoor air temperature and humidity at comfortable levels for staff, patients, and visitors control odors; remove contaminated air; facilitate air-handling requirements to protect susceptible staff and patients from airborne health-care associated pathogens; and minimize the risk for transmission of airborne pathogens from infected patients. 35,120 An HVAC system includes an outside air inlet or intake; filters; humidity modification mechanisms (i.e., humidity control in summer, humidification in winter); heating and cooling equipment; fans; ductwork; air exhaust or out-takes; and registers, diffusers, or grilles for proper distribution of the air (Figure 1). 213,214 Decreased performance of healthcare facility HVAC systems, filter inefficiencies, improper installation, and poor maintenance can contribute to the spread of health-care associated airborne infections.\nThe American Institute of Architects (AIA) has published guidelines for the design and construction of new health-care facilities and for renovation of existing facilities. These AIA guidelines address indoor air-quality standards (e.g., ventilation rates, temperature levels, humidity levels, pressure relationships, and minimum air changes per hour [ACH]) specific to each zone or area in health-care facilities (e.g., operating rooms, laboratories, diagnostic areas, patient-care areas, and support departments). 120 ). More than 40 state agencies that license health-care facilities have either incorporated or adopted by reference these guidelines into their state standards. JCAHO, through its surveys, ensures that facilities are in compliance with the ventilation guidelines of this standard for new construction and renovation.\n# Figure 1. Diagram of a ventilation system*\nOutdoor air and recirculated air pass through air cleaners (e.g., filter banks) designed to reduce the concentration of airborne contaminants. Air is conditioned for temperature and humidity before it enters the occupied space as supply air. Infiltration is air leakage inward through cracks and interstitial spaces of walls, floors, and ceilings. Exfiltration is air leakage outward through these same cracks and spaces. Return air is largely exhausted from the system, but a portion is recirculated with fresh, incoming air.\n* Used with permission of the publisher of reference 214 (ASHRAE)\nEngineering controls to contain or prevent the spread of airborne contaminants center on local exhaust ventilation [i.e., source control], general ventilation, and air cleaning. 4 General ventilation encompasses dilution and removal of contaminants via well-mixed air distribution of filtered air, directing contaminants toward exhaust registers and grilles via uniform, non-mixed airflow patterns, pressurization of individual spaces relative to all other spaces, and pressurization of buildings relative to the outdoors and other attached buildings.\nA centralized HVAC system operates as follows. Outdoor air enters the system, where low-efficiency or \"roughing\" filters remove large particulate matter and many microorganisms. The air enters the distribution system for conditioning to appropriate temperature and humidity levels, passes through an additional bank of filters for further cleaning, and is delivered to each zone of the building. After the conditioned air is distributed to the designated space, it is withdrawn through a return duct system and delivered back to the HVAC unit. A portion of this \"return air\" is exhausted to the outside while the remainder is mixed with outdoor air for dilution and filtered for removal of contaminants. 215 Air from toilet rooms or other soiled areas is usually exhausted directly to the atmosphere through a separate duct exhaust system. Air from rooms housing tuberculosis patients is exhausted to the outside if possible, or passed through a HEPA filter before recirculation. Ultraviolet germicidal irradiation (UVGI) can be used as an adjunct air-cleaning measure, but it cannot replace HEPA filtration. 15 b. Filtration i. Filter Types and Methods of Filtration Filtration, the physical removal of particulates from air, is the first step in achieving acceptable indoor air quality. Filtration is the primary means of cleaning the air. Five methods of filtration can be used (Table 5). During filtration, outdoor air passes through two filter beds or banks (with efficiencies of 20%-40% and ≥90%, respectively) for effective removal of particles 1-5 μm in diameter. 35,120 The low-to-medium efficiency filters in the first bank have low resistance to airflow, but this feature allows some small particulates to pass onto heating and air conditioning coils and into the indoor environment. 35 Incoming air is mixed with recirculated air and reconditioned for temperature and humidity before being filtered by the second bank of filters. The performance of filters with ≤90% efficiency is measured using either the dust-spot test or the weight-arrestance test. 35,216 The second filter bank usually consists of high-efficiency filters. This filtration system is adequate for most patient-care areas in ambulatory-care facilities and hospitals, including the operating room environment and areas providing central services. 120 Nursing facilities use 90% dust-spot efficient filters as the second bank of filters, 120 whereas a HEPA filter bank may be indicated for special-care areas of hospitals. HEPA filters are at least 99.97% efficient for removing particles ≥0.3 μm in diameter. (As a reference, Aspergillus spores are 2.5-3.0 μm in diameter.) Examples of care areas where HEPA filters are used include PE rooms and those operating rooms designated for orthopedic implant procedures. 35 Maintenance costs associated with HEPA filters are high compared with other types of filters, but use of in-line disposable prefilters can increase the life of a HEPA filter by approximately 25%. Alternatively, if a disposable prefilter is followed by a filter that is 90% efficient, the life of the HEPA filter can be extended ninefold. This concept, called progressive filtration, allows HEPA filters in special care areas to be used for 10 years. 213 Although progressive filtering will extend the mechanical ability of the HEPA filter, these filters may absorb chemicals in the environment and later desorb those chemicals, thereby necessitating a more frequent replacement program. HEPA filter efficiency is monitored with the dioctylphthalate (DOP) particle test using particles that are 0.3 μm in diameter. 218 HEPA filters are usually framed with metal, although some older versions have wood frames. A metal frame has no advantage over a properly fitted wood frame with respect to performance, but wood can compromise the air quality if it becomes and remains wet, allowing the growth of fungi and bacteria. Hospitals are therefore advised to phase out water-damaged or spent wood-framed filter units and replace them with metal-framed HEPA filters.\nHEPA filters are usually fixed into the HVAC system; however, portable, industrial grade HEPA units are available that can filter air at the rate of 300-800 ft 3 /min. Portable HEPA filters are used to a. temporarily recirculate air in rooms with no general ventilation, b. augment systems that cannot provide adequate airflow, and c. provide increased effectiveness in airflow. 4 Portable HEPA units are useful engineering controls that help clean the air when the central HVAC system is undergoing repairs 219 but these units do not satisfy fresh-air requirements. 214 The effectiveness of the portable unit for particle removal is dependent on a. the configuration of the room, b. the furniture and persons in the room, c. the placement of the units relative to the contents and layout of the room, and d. the location of the supply and exhaust registers or grilles.\nIf portable, industrial-grade units are used, they should be capable of recirculating all or nearly all of the room air through the HEPA filter, and the unit should be designed to achieve the equivalent of ≥12 ACH. 4 (An average room has approximately 1,600 ft 3 of airspace.) The hospital engineering department should be contacted to provide ACH information in the event that a portable HEPA filter unit is necessary to augment the existing fixed HVAC system for air cleaning.\nii. Filter Maintenance Efficiency of the filtration system is dependent on the density of the filters, which can create a drop in pressure unless compensated by stronger and more efficient fans, thus maintaining air flow. For optimal performance, filters require monitoring and replacement in accordance with the manufacturer's recommendations and standard preventive maintenance practices. 220 Upon removal, spent filters can be bagged and discarded with the routine solid waste, regardless of their patient-care area location. 221 Excess accumulation of dust and particulates increases filter efficiency, requiring more pressure to push the air through. The pressure differential across filters is measured by use of manometers or other gauges. A pressure reading that exceeds specifications indicates the need to change the filter. Filters also require regular inspection for other potential causes of decreased performance. Gaps in and around filter banks and heavy soil and debris upstream of poorly maintained filters have been implicated in health-care associated outbreaks of aspergillosis, especially when accompanied by construction activities at the facility. 17,18,106,222 \n# c. Ultraviolet Germicidal Irradiation (UVGI)\nAs a supplemental air-cleaning measure, UVGI is effective in reducing the transmission of airborne bacterial and viral infections in hospitals, military housing, and classrooms, but it has only a minimal inactivating effect on fungal spores. [223][224][225][226][227][228] UVGI is also used in air handling units to prevent or limit the growth of vegetative bacteria and fungi. Most commercially available UV lamps used for germicidal purposes are low-pressure mercury vapor lamps that emit radiant energy predominantly at a wave-length of 253.7 nm. 229,230 Two systems of UVGI have been used in health-care settings -duct irradiation and upper-room air irradiation. In duct irradiation systems, UV lamps are placed inside ducts that remove air from rooms to disinfect the air before it is recirculated. When properly designed, installed, and maintained, high levels of UVGI can be attained in the ducts with little or no exposure of persons in the rooms. 231,232 In upper-room air irradiation, UV lamps are either suspended from the ceiling or mounted on the wall. 4 Upper air UVGI units have two basic designs: a. a \"pan\" fixture with UVGI unshielded above the unit to direct the irradiation upward and b. a fixture with a series of parallel plates to columnize the irradiation outward while preventing the light from getting to the eyes of the room's occupants.\nThe germicidal effect is dependent on air mixing via convection between the room's irradiated upper zone and the lower patient-care zones. 233,234 Bacterial inactivation studies using BCG mycobacteria and Serratia marcescens have estimated the effect of UVGI as equivalent to 10 ACH-39 ACH. 235,236 Another study, however, suggests that UVGI may result in fewer equivalent ACH in the patient-care zone, especially if the mixing of air between zones is insufficient. 234 The use of fans or HVAC systems to generate air movement may increase the effectiveness of UVGI if airborne microorganisms are exposed to the light energy for a sufficient length of time. 233,235,[237][238][239] The optimal relationship between ventilation and UVGI is not known.\nBecause the clinical effectiveness of UV systems may vary, UVGI is not recommended for air management prior to air recirculation from airborne isolation rooms. It is also not recommended as a substitute for HEPA filtration, local exhaust of air to the outside, or negative pressure. 4 The use of UV lamps and HEPA filtration in a single unit offers only minimal infection-control benefits over those provided by the use of a HEPA filter alone. 240 Duct systems with UVGI are not recommended as a substitute for HEPA filters if the air from isolation rooms must be recirculated to other areas of the facility. 4 Regular maintenance of UVGI systems is crucial and usually consists of keeping the bulbs free of dust and replacing old bulbs as necessary. Safety issues associated with the use of UVGI systems are described in other guidelines. 4\n# d. Conditioned Air in Occupied Spaces\nTemperature and humidity are two essential components of conditioned air. After outside air passes through a low-or medium-efficiency filter, the air undergoes conditioning for temperature and humidity control before it passes through high-efficiency or HEPA filtration.\ni. Temperature HVAC systems in health-care facilities are often single-duct or dual-duct systems. 35,241 A single-duct system distributes cooled air (55°F [12.8°C]) throughout the building and uses thermostatically controlled reheat boxes located in the terminal ductwork to warm the air for individual or multiple rooms. The dual-duct system consists of parallel ducts, one with a cold air stream and the other with a hot air stream. A mixing box in each room or group of rooms mixes the two air streams to achieve the desired temperature. Temperature standards are given as either a single temperature or a range, depending on the specific health-care zone. Cool temperature standards (68°F-73°F [20°C-23°C]) usually are associated with operating rooms, clean workrooms, and endoscopy suites. 120 A warmer temperature (75°F [24°C]) is needed in areas requiring greater degrees of patient comfort. Most other zones use a temperature range of 70°F-75°F (21°C-24°C). 120 Temperatures outside of these ranges may be needed occasionally in limited areas depending on individual circumstances during patient care (e.g., cooler temperatures in operating rooms during specialized operations).\nii. Humidity Four measures of humidity are used to quantify different physical properties of the mixture of water vapor and air. The most common of these is relative humidity, which is the ratio of the amount of water vapor in the air to the amount of water vapor air can hold at that temperature. 242 The other measures of humidity are specific humidity, dew point, and vapor pressure. 242 Relative humidity measures the percentage of saturation. At 100% relative humidity, the air is saturated. For most areas within health-care facilities, the designated comfort range is 30%-60% relative humidity. 120,214 Relative humidity levels >60%, in addition to being perceived as uncomfortable, promote fungal growth. 243 Humidity levels can be manipulated by either of two mechanisms. 244 In a water-wash unit, water is sprayed and drops are taken up by the filtered air; additional heating or cooling of this air sets the humidity levels. The second mechanism is by means of water vapor created from steam and added to filtered air in humidifying boxes. Reservoir-type humidifiers are not allowed in health-care facilities as per AIA guidelines and many state codes. 120 Cool-mist humidifiers should be avoided, because they can disseminate aerosols containing allergens and microorganisms. 245 Additionally, the small, personal-use versions of this equipment can be difficult to clean.\n# iii. Ventilation\nThe control of air pollutants (e.g., microorganisms, dust, chemicals, and smoke) at the source is the most effective way to maintain clean air. The second most effective means of controlling indoor air pollution is through ventilation. Ventilation rates are voluntary unless a state or local government specifies a standard in health-care licensing or health department requirements. These standards typically apply to only the design of a facility, rather than its operation. 220,246 Health-care facilities without specific ventilation standards should follow the AIA guideline specific to the year in which the building was 120, 214, 241 built or the ANSI/ASHRAE Standard 62, Ventilation for Acceptable Indoor Air Quality.\nVentilation guidelines are defined in terms of air volume per minute per occupant and are based on the assumption that occupants and their activities are responsible for most of the contaminants in the conditioned space. 215 Most ventilation rates for health-care facilities are expressed as room ACH. Peak efficiency for particle removal in the air space occurs between 12 ACH-15 ACH. 35,247,248 Ventilation rates vary among the different patient-care areas of a health-care facility (Appendix B). 120 Health-care facilities generally use recirculated air. 35,120,241,249,250 Fans create sufficient positive pressure to force air through the building duct work and adequate negative pressure to evacuate air from the conditioned space into the return duct work and/or exhaust, thereby completing the circuit in a sealed system (Figure 1). However, because gaseous contaminants tend to accumulate as the air recirculates, a percentage of the recirculated air is exhausted to the outside and replaced by fresh outdoor air. In hospitals, the delivery of filtered air to an occupied space is an engineered system design issue, the full discussion of which is beyond the scope of this document.\nHospitals with areas not served by central HVAC systems often use through-the-wall or fan coil air conditioning units as the sole source of room ventilation. AIA guidelines for newly installed systems stipulate that through-the-wall fan-coil units be equipped with permanent (i.e., cleanable) or replaceable filters with a minimum efficiency of 68% weight arrestance. 120 These units may be used only as recirculating units; all outdoor air requirements must be met by a separate central air handling system with proper filtration, with a minimum of two outside air changes in general patient rooms (D. Erickson, ASHE, 2000). 120 If a patient room is equipped with an individual through-the-wall fan coil unit, the room should not be used as either AII or as PE. 120 These requirements, although directed to new HVAC installations also are appropriate for existing settings. Non-central air-handling systems are prone to problems associated with excess condensation accumulating in drip pans and improper filter maintenance; health-care facilities should clean or replace the filters in these units on a regular basis while the patient is out of the room.\nLaminar airflow ventilation systems are designed to move air in a single pass, usually through a bank of HEPA filters either along a wall or in the ceiling, in a one-way direction through a clean zone with parallel streamlines. Laminar airflow can be directed vertically or horizontally; the unidirectional system optimizes airflow and minimizes air turbulence. 63,241 Delivery of air at a rate of 0.5 meters per second (90 ± 20 ft/min) helps to minimize opportunities for microorganism proliferation. 63,251,252 Laminar airflow systems have been used in PE to help reduce the risk for health-care associated airborne infections (e.g., aspergillosis) in high-risk patients. 63,93,253,254 However, data that demonstrate a survival benefit for patients in PE with laminar airflow are lacking. Given the high cost of installation and apparent lack of benefit, the value of laminar airflow in this setting is questionable. 9,37 Few data support the use of laminar airflow systems elsewhere in a hospital. 255 iv. Pressurization Positive and negative pressures refer to a pressure differential between two adjacent air spaces (e.g., rooms and hallways). Air flows away from areas or rooms with positive pressure (pressurized), while air flows into areas with negative pressure (depressurized). AII rooms are set at negative pressure to prevent airborne microorganisms in the room from entering hallways and corridors. PE rooms housing severely neutropenic patients are set at positive pressure to keep airborne pathogens in adjacent spaces or corridors from coming into and contaminating the airspace occupied by such high-risk patients. Selfclosing doors are mandatory for both of these areas to help maintain the correct pressure differential. 4,6,120 Older health-care facilities may have variable pressure rooms (i.e., rooms in which the ventilation can be manually switched between positive and negative pressure). These rooms are no longer permitted in the construction of new facilities or in renovated areas of the facility, 120 and their use in existing facilities has been discouraged because of difficulties in assuring the proper pressure differential, especially for the negative pressure setting, and because of the potential for error associated with switching the pressure differentials for the room. Continued use of existing variable pressure rooms depends on a partnership between engineering and infection control. Both positive-and negativepressure rooms should be maintained according to specific engineering specifications (Table 6). Health-care professionals (e.g., infection control, hospital epidemiologists) must perform a risk assessment to determine the appropriate number of AII rooms (negative pressure) and/or PE rooms (positive pressure) to serve the patient population. The AIA guidelines require a certain number of AII rooms as a minimum, and it is important to refer to the edition under which the building was built for appropriate guidance. 120 In large health-care facilities with central HVAC systems, sealed windows help to ensure the efficient operation of the system, especially with respect to creating and maintaining pressure differentials. Sealing the windows in PE areas helps minimize the risk of airborne contamination from the outside. One outbreak of aspergillosis among immunosuppressed patients in a hospital was attributed in part to an open window in the unit during a time when both construction and a fire happened nearby; sealing the window prevented further entry of fungal spores into the unit from the outside air. 111 Additionally, all emergency exits (e.g., fire escapes and emergency doors) in PE wards should be kept closed (except during emergencies) and equipped with alarms.\n# e. Infection Control Impact of HVAC System Maintenance and Repair\nA failure or malfunction of any component of the HVAC system may subject patients and staff to discomfort and exposure to airborne contaminants. Only limited information is available from formal studies on the infection-control implications of a complete air-handling system failure or shutdown for maintenance. Most experience has been derived from infectious disease outbreaks and adverse outcomes among high-risk patients when HVAC systems are poorly maintained. (See Table 7 for potential ventilation hazards, consequences, and correction measures.)\nAIA guidelines prohibit U.S. hospitals and surgical centers from shutting down their HVAC systems for purposes other than required maintenance, filter changes, and construction. 120 Airflow can be reduced; however, sufficient supply, return, and exhaust must be provided to maintain required pressure relationships when the space is not occupied. Maintaining these relationships can be accomplished with special drives on the air-handling units (i.e., a variable air ventilation [VAV] system).\nMicroorganisms proliferate in environments wherever air, dust, and water are present, and air-handling systems can be ideal environments for microbial growth. 35 Properly engineered HVAC systems require routine maintenance and monitoring to provide acceptable indoor air quality efficiently and to minimize conditions that favor the proliferation of health-care associated pathogens. 35,249 Performance monitoring of the system includes determining pressure differentials across filters, regular inspection of system filters, DOP testing of HEPA filters, testing of low-or medium efficiency filters, and manometer tests for positive-and negative-pressure areas in accordance with nationally recognized standards, guidelines, and manufacturers' recommendations. The use of hand-held, calibrated equipment that can provide a numerical reading on a daily basis is preferred for engineering purposes (A.Streifel, University of Minnesota, 2000). 256 Several methods that provide a visual, qualitative measure of pressure differentials (i.e., airflow direction) include smoke-tube tests or placing flutter strips, ping-pong balls, or tissue in the air stream.\nPreventive filter and duct maintenance (e.g., cleaning ductwork vents, replacing filters as needed, and properly disposing spent filters into plastic bags immediately upon removal) is important to prevent potential exposures of patients and staff during HVAC system shut-down. The frequency of filter inspection and the parameters of this inspection are established by each facility to meet their unique needs. Ductwork in older health-care facilities may have insulation on the interior surfaces that can trap contaminants. This insulation material tends to break down over time to be discharged from the HVAC system. Additionally, a malfunction of the air-intake system can overburden the filtering system and permit aerosolization of fungal pathogens. Keeping the intakes free from bird droppings, especially those from pigeons, helps to minimize the concentration of fungal spores entering from the outside. 98 Accumulation of dust and moisture within HVAC systems increases the risk for spread of health-careassociated environmental fungi and bacteria. Clusters of infections caused by Aspergillus spp., P. aeruginosa, S. aureus, and Acinetobacter spp. have been linked to poorly maintained and/or malfunctioning air conditioning systems. 68,161,257,258 Efforts to limit excess humidity and moisture in the infrastructure and on air-stream surfaces in the HVAC system can minimize the proliferation and dispersion of fungal spores and waterborne bacteria throughout indoor air. [259][260][261][262] Within the HVAC system, water is present in water-wash units, humidifying boxes, or cooling units. The dual-duct system may also create conditions of high humidity and excess moisture that favor fungal growth in drain pans as well as in fibrous insulation material that becomes damp as a result of the humid air passing over the hot stream and condensing.\nIf moisture is present in the HVAC system, periods of stagnation should be avoided. Bursts of organisms can be released upon system start-up, increasing the risk of airborne infection. 206 Proper engineering of the HVAC system is critical to preventing dispersal of airborne organisms. In one hospital, endophthalmitis caused by Acremonium kiliense infection following cataract extraction in an ambulatory surgical center was traced to aerosols derived from the humidifier water in the ventilation system. 206 The organism proliferated because the ventilation system was turned off routinely when the center was not in operation; the air was filtered before humidification, but not afterwards.\nMost health-care facilities have contingency plans in case of disruption of HVAC services. These plans include back-up power generators that maintain the ventilation system in high-risk areas (e.g., operating rooms, intensive-care units, negative-and positive-pressure rooms, transplantation units, and oncology units). Alternative generators are required to engage within 10 seconds of a loss of main power. If the ventilation system is out of service, rendering indoor air stagnant, sufficient time must be allowed to clean the air and re-establish the appropriate number of ACH once the HVAC system begins to function again.\nAir filters may also need to be changed, because reactivation of the system can dislodge substantial amounts of dust and create a transient burst of fungal spores.\nDuct cleaning in health-care facilities has benefits in terms of system performance, but its usefulness for infection control has not been conclusively determined. Duct cleaning typically involves using specialized tools to dislodge dirt and a high-powered vacuum cleaner to clean out debris. 263 Some duct-cleaning services also apply chemical biocides or sealants to the inside surfaces of ducts to minimize fungal growth and prevent the release of particulate matter. The U.S. Environmental Protection Agency (EPA), however, has concerns with the use of sanitizers and/or disinfectants to treat the surfaces of ductwork, because the label indications for most of these products may not specifically include the use of the product in HVAC systems. 264 Further, EPA has not evaluated the potency of disinfectants in such applications, nor has the agency examined the potential attendant health and safety risks. The EPA recommends that companies use only those chemical biocides that are registered for use in HVAC systems. 264 Although infrequent cleaning of the exhaust ducts in AII areas has been documented as a cause of diminishing negative pressure and a decrease in the air exchange rates, 214 no data indicate that duct cleaning, beyond what is recommended for optimal performance, improves indoor air quality or reduces the risk of infection. Exhaust return systems should be cleaned as part of routine system maintenance. Duct cleaning has not been shown to prevent any health problems, 265 and EPA studies indicate that airborne particulate levels do not increase as a result of dirty air ducts, nor do they diminish after cleaning, presumably because much of the dirt inside air ducts adheres to duct surfaces and does not enter the conditioned space. 265 Additional research is needed to determine if air-duct contamination can significantly increase the airborne infection risk in general areas of health-care facilities.\n# Construction, Renovation, Remediation, Repair, and Demolition\n\n# a. General Information\nEnvironmental disturbances caused by construction and/or renovation and repair activities (e.g., disruption of the above-ceiling area, running cables through the ceiling, and structural repairs) in and near health-care facilities markedly increase the airborne Aspergillus spp. spore counts in the indoor air of such facilities, thereby increasing the risk for health-care associated aspergillosis among high-risk patients.\nAlthough one case of health-care associated aspergillosis is often difficult to link to a specific environmental exposure, the occurrence of temporarily clustered cases increase the likelihood that an environmental source within the facility may be identified and corrected. Construction, renovation, repair, and demolition activities in health-care facilities require substantial planning and coordination to minimize the risk for airborne infection both during projects and after their completion. Several organizations and experts have endorsed a multi-disciplinary team approach (Box 4) to coordinate the various stages of construction activities (e.g., project inception, project implementation, final walk-through, and completion). 120,249,250,[273][274][275][276] Environmental services, employee health, engineering, and infection control must be represented in construction planning and design meetings should be convened with architects and design engineers. The number of members and disciplines represented is a function of the complexity of a project. Smaller, less complex projects and maintenance may require a minimal number of members beyond the core representation from engineering, infection control, environmental services, and the directors of the specialized departments.\n# Box 4. Suggested members and functions of a multi-disciplinary coordination team for construction, renovation, repair, and demolition projects\n\n# Members\n• Infection-control personnel, including hospital epidemiologists • Laboratory personnel • Facility administrators or their designated representatives, facility managers • Director of engineering • Risk-management personnel • Directors of specialized programs (e.g., transplantation, oncology and ICU [intensive care unit] programs) • Employee safety personnel, industrial hygienists, and regulatory affairs personnel • Environmental services personnel Information systems personnel • Construction administrators or their designated representatives • Architects, design engineers, project managers, and contractors\n# Functions and responsibilities\n\n# •\nCoordinate members' input in developing a comprehensive project management plan.\n# •\nConduct a risk assessment of the project to determine potential hazards to susceptible patients.\n# •\nPrevent unnecessary exposures of patients, visitors, and staff to infectious agents.\n# •\nOversee all infection-control aspects of construction activities.\n# •\nEstablish site-specific infection-control protocols for specialized areas.\n# •\nProvide education about the infection-control impact of construction to staff and construction workers.\n# •\nEnsure compliance with technical standards, contract provisions, and regulations.\n# •\nEstablish a mechanism to address and correct problems quickly.\n# •\nDevelop contingency plans for emergency response to power failures, water supply disruptions, and fires.\n# •\nProvide a water-damage management plan (including drying protocols) for handling water intrusion from floods, leaks, and condensation.\n# •\nDevelop a plan for structural maintenance.\nEducation of maintenance and construction workers, health-care staff caring for high-risk patients, and persons responsible for controlling indoor air quality heightens awareness that minimizing dust and moisture intrusion from construction sites into high-risk patient-care areas helps to maintain a safe environment. 120,250,271,[275][276][277][278] Visual and printed educational materials should be provided in the language spoken by the workers. Staff and construction workers also need to be aware of the potentially catastrophic consequences of dust and moisture intrusion when an HVAC system or water system fails during construction or repair; action plans to deal quickly with these emergencies should be developed in advance and kept on file. Incorporation of specific standards into construction contracts may help to prevent departures from recommended practices as projects progress. Establishing specific lines of communication is important to address problems (e.g., dust control, indoor air quality, noise levels, and vibrations), resolve complaints, and keep projects moving toward completion. Health-care facility staff should develop a mechanism to monitor worker adherence to infection-control guidelines on a daily basis in and around the construction site for the duration of the project.\n# b. Preliminary Considerations\nThe three major topics to consider before initiating any construction or repair activity are as follows: a. design and function of the new structure or area, b. assessment of environmental risks for airborne disease and opportunities for prevention, and c. measures to contain dust and moisture during construction or repairs.\nA checklist of design and function considerations can help to ensure that a planned structure or area can be easily serviced and maintained for environmental infection control (Box 5) . 17,250,273,[275][276][277] Specifications for the construction, renovation, remodeling, and maintenance of health-care facilities are outlined in the AIA document, Guidelines for Design and Construction of Hospitals and Health Care Facilities. 120,275 Box 5. Construction design and function considerations for environmental infection control Proactive strategies can help prevent environmentally mediated airborne infections in health-care facilities during demolition, construction, and renovation. The potential presence of dust and moisture and their contribution to health-care associated infections must be critically evaluated early in the planning of any demolition, construction, renovation, and repairs. 120,250,251,273,274,[276][277][278][279] Consideration must extend beyond dust generated by major projects to include dust that can become airborne if disturbed during routine maintenance and minor renovation activities (e.g., exposure of ceiling spaces for inspection; installation of conduits, cable, or sprinkler systems; rewiring; and structural repairs or replacement). 273,276,277 Other projects that can compromise indoor air quality include construction and repair jobs that inadvertently allow substantial amounts of raw, unfiltered outdoor air to enter the facility (e.g., repair of elevators and elevator shafts) and activities that dampen any structure, area, or item made of porous materials or characterized by cracks and crevices (e.g., sink cabinets in need of repair, carpets, ceilings, floors, walls, vinyl wall coverings, upholstery, drapes, and countertops). 18,273,277 Molds grow and proliferate on these surfaces when they become and remain wet. 21,120,250,266,270,272,280 Scrubbable materials are preferred for use in patient-care areas.\nContainment measures for dust and/or moisture control are dictated by the location of the construction site. Outdoor demolition and construction require actions to keep dust and moisture out of the facility (e.g., sealing windows and vents and keeping doors closed or sealed). Containment of dust and moisture generated from construction inside a facility requires barrier structures (either pre-fabricated or constructed of more durable materials as needed) and engineering controls to clean the air in and around the construction or repair site.\n# c. Infection-Control Risk Assessment\nAn infection-control risk assessment (ICRA) conducted before initiating repairs, demolition, construction, or renovation activities can identify potential exposures of susceptible patients to dust and moisture and determine the need for dust and moisture containment measures. This assessment centers on the type and extent of the construction or repairs in the work area but may also need to include adjacent patient-care areas, supply storage, and areas on levels above and below the proposed project. An example of designing an ICRA as a matrix, the policy for performing an ICRA and implementing its results, and a sample permit form that streamlines the communication process are available. 281 Knowledge of the air flow patterns and pressure differentials helps minimize or eliminate the inadvertent dispersion of dust that could contaminate air space, patient-care items, and surfaces. 57,282,283 A recent aspergillosis outbreak among oncology patients was attributed to depressurization of the building housing the HSCT unit while construction was underway in an adjacent building. Pressure readings in the affected building (including 12 of 25 HSCT-patient rooms) ranged from 0.1 Pa-5.8 Pa. Unfiltered outdoor air flowed into the building through doors and windows, exposing patients in the HSCT unit to fungal spores. 283 During long-term projects, providing temporary essential services (e.g., toilet facilities) and conveniences (e.g., vending machines) to construction workers within the site will help to minimize traffic in and out of the area. The type of barrier systems necessary for the scope of the project must be defined. 12,120,250,279,284 Depending on the location and extent of the construction, patients may need to be relocated to other areas in the facility not affected by construction dust. 51,285 Such relocation might be especially prudent when construction takes place within units housing immunocompromised patients (e.g., severely neutropenic patients and patients on corticosteroid therapy). Advance assessment of high-risk locations and planning for the possible transport of patients to other departments can minimize delays and waiting time in hallways. 51 Although hospitals have provided immunocompromised patients with some form of respiratory protection for use outside their rooms, the issue is complex and remains unresolved until more research can be done. Previous guidance on this issue has been inconsistent. 9 Protective respirators (i.e., N95) were well tolerated by patients when used to prevent further cases of construction-related aspergillosis in a recent outbreak. 283 The routine use of the N95 respirator by patients, however, has not been evaluated for preventing exposure to fungal spores during periods of non-construction. Although health-care workers who would be using the N95 respirator for personal respiratory protect must be fittested, there is no indication that either patients or visitors should undergo fit-testing.\nSurveillance activities should augment preventive strategies during construction projects. 3,4,20,110,286,287 By determining baseline levels of health-care acquired airborne and waterborne infections, infectioncontrol staff can monitor changes in infection rates and patterns during and immediately after construction, renovations, or repairs. 3\n# d. Air Sampling\nAir sampling in health-care facilities may be conducted both during periods of construction and on a periodic basis to determine indoor air quality, efficacy of dust-control measures, or air-handling system performance via parametric monitoring. Parametric monitoring consists of measuring the physical periodic assessment of the system (e.g., air flow direction and pressure, ACH, and filter efficiency) can give assurance of proper ventilation, especially for special care areas and operating rooms. 288 Air sampling is used to detect aerosols (i.e., particles or microorganisms). Particulate sampling (i.e., total numbers and size range of particulates) is a practical method for evaluating the infection-control performance of the HVAC system, with an emphasis on filter efficiency in removing respirable particles (<5 μm in diameter) or larger particles from the air. Particle size is reported in terms of the mass median aerodynamic diameter (MMAD), whereas count median aerodynamic diameter (CMAD) is useful with respect to particle concentrations.\nParticle counts in a given air space within the health-care facility should be evaluated against counts obtained in a comparison area. Particle counts indoors are commonly compared with the particulate levels of the outdoor air. This approach determines the \"rank order\" air quality from \"dirty\" (i.e., the outdoor air) to \"clean\" (i.e., air filtered through high-efficiency filters [90%-95% filtration]) to \"cleanest\" (i.e., HEPA-filtered air). 288 Comparisons from one indoor area to another may also provide useful information about the magnitude of an indoor air-quality problem. Making rank-order comparisons between clean, highly-filtered areas and dirty areas and/or outdoors is one way to interpret sampling results in the absence of air quality and action level standards. 35,289 In addition to verifying filter performance, particle counts can help determine if barriers and efforts to control dust dispersion from construction are effective. This type of monitoring is helpful when performed at various times and barrier perimeter locations during the project. Gaps or breaks in the barriers' joints or seals can then be identified and repaired. The American Conference of Governmental Industrial Hygienists (ACGIH) has set a threshold limit value-time weighted average (TLV®-TWA) of 10 mg/m 3 for nuisance dust that contains no asbestos and <1% crystalline silica. 290 Alternatively, OSHA has set permissible exposure limits (PELs) for inert or nuisance dust as follows: respirable fraction at 5 mg/m 3 and total dust at 15 mg/m 3 . 291 Although these standards are not measures of a bioaerosol, they are used for indoor air quality assessment in occupational settings and may be useful criteria in construction areas. Application of ACGIH guidance to health-care settings has not been standardized, but particulate counts in health-care facilities are likely to be well below this threshold value and approaching cleanroom standards in certain care areas (e.g., operating rooms). 100 Particle counters and anemometers are used in particulate evaluation. The anemometer measures air flow velocity, which can be used to determine sample volumes. Particulate sampling usually does not require microbiology laboratory services for the reporting of results.\nMicrobiologic sampling of air in health-care facilities remains controversial because of currently unresolved technical limitations and the need for substantial laboratory support (Box 6). Infection-control professionals, laboratorians, and engineers should determine if microbiologic and/or particle sampling is warranted and assess proposed methods for sampling. The most significant technical limitation of air sampling for airborne fungal agents is the lack of standards linking fungal spore levels with infection rates. Despite this limitation, several health-care institutions have opted to use microbiologic sampling when construction projects are anticipated and/or underway in efforts to assess the safety of the environment for immunocompromised patients. 35,289 Microbiologic air sampling should be limited to assays for airborne fungi; of those, the thermotolerant fungi (i.e., those capable of growing at 95°F-98.6°F [35°C-37°C]) are of particular concern because of their pathogenicity in immunocompromised hosts. 35 Use of selective media (e.g., Sabouraud dextrose agar and inhibitory mold agar) helps with the initial identification of recovered organisms.\nMicrobiologic sampling for fungal spores performed as part of various airborne disease outbreak investigations has also been problematic. 18,49,106,111,112,289 The precise source of a fungus is often difficult to trace with certainty, and sampling conducted after exposure may neither reflect the circumstances that were linked to infection nor distinguish between health-care acquired and community-acquired infections.\nBecause fungal strains may fluctuate rapidly in the environment, health-care acquired Aspergillus spp. infection cannot be confirmed or excluded if the infecting strain is not found in the health-care setting. 287 Sensitive molecular typing methods (e.g., randomly amplified polymorphic DNA (RAPD) techniques and a more recent DNA fingerprinting technique that detects restriction fragment length polymorphisms in fungal genomic DNA) to identify strain differences among Aspergillus spp., however, are becoming increasingly used in epidemiologic investigations of health-care acquired fungal infection (A.Streifel, University of Minnesota, 2000). 68,110,286,287,[292][293][294][295][296] During case cluster evaluation, microbiologic sampling may provide an isolate from the environment for molecular typing and comparison with patient isolates.\nTherefore, it may be prudent for the clinical laboratory to save Aspergillus spp. isolated from colonizations and invasive disease cases among patients in PE, oncology, and transplant services for these purposes. Sedimentation methods using settle plates and volumetric sampling methods using solid impactors are commonly employed when sampling air for bacteria and fungi. Settle plates have been used by numerous investigators to detect airborne bacteria or to measure air quality during medical procedures (e.g., surgery). 17,60,97,151,161,287 Settle plates, because they rely on gravity during sampling, tend to select for larger particles and lack sensitivity for respirable particles (e.g., individual fungal spores), especially in highly-filtered environments. Therefore, they are considered impractical for general use. 35,289,[298][299][300][301] Settle plates, however, may detect fungi aerosolized during medical procedures (e.g., during wound dressing changes), as described in a recent outbreak of aspergillosis among liver transplant patients. 302 The use of slit or sieve impactor samplers capable of collecting large volumes of air in short periods of time are needed to detect low numbers of fungal spores in highly filtered areas. 35,289 In some outbreaks, aspergillosis cases have occurred when fungal spore concentrations in PE ambient air ranged as low as 0.9-2.2 colony-forming units per cubic meter (CFU/m 3 ) of air. 18,94 On the basis of the expected spore counts in the ambient air and the performance parameters of various types of volumetric air samplers, investigators of a recent aspergillosis outbreak have suggested that an air volume of at least 1000 L (1 m 3 ) should be considered when sampling highly filtered areas. 283 Investigators have also suggested limits of 15 CFU/m 3 for gross colony counts of fungal organisms and <0.1 CFU/m 3 for Aspergillus fumigatus and other potentially opportunistic fungi in heavily filtered areas (≥12 ACH and filtration of ≥99.97% efficiency). 120 No correlation of these values with the incidence of health-care-associated fungal infection rates has been reported.\nAir sampling in health-care facilities, whether used to monitor air quality during construction, to verify filter efficiency, or to commission new space prior to occupancy, requires careful notation of the circumstances of sampling. Most air sampling is performed under undisturbed conditions. However, when the air is sampled during or after human activity (e.g., walking and vacuuming), a higher number of airborne microorganisms likely is detected. 297 The contribution of human activity to the significance of air sampling and its impact on health-care associated infection rates remain to be defined. Comparing microbiologic sampling results from a target area (e.g., an area of construction) to those from an unaffected location in the facility can provide information about distribution and concentration of potential airborne pathogens. A comparison of microbial species densities in outdoor air versus indoor air has been used to help pinpoint fungal spore bursts. Fungal spore densities in outdoor air are variable, although the degree of variation with the seasons appears to be more dramatic in the United States than in Europe. 92,287,303 Particulate and microbiologic air sampling have been used when commissioning new HVAC system installations; however, such sampling is particularly important for newly constructed or renovated PE or operating rooms. Particulate sampling is used as part of a battery of tests to determine if a new HVAC system is performing to specifications for filtration and the proper number of ACH. 268,288,304 Microbiologic air sampling, however, remains controversial in this application, because no standards for comparison purposes have been determined. If performed, sampling should be limited to determining the density of fungal spores per unit volume of air space. High numbers of spores may indicate contamination of air-handling system components prior to installation or a system deficiency when culture results are compared with known filter efficiencies and rates of air exchange.\n# e. External Demolition and Construction\nExternal demolition, planned building implosions, and dirt excavation generate considerable dust and debris that can contain airborne microorganisms. In one study, peak concentrations in outdoor air at grade level and HVAC intakes during site excavation averaged 20,000 CFU/m 3 for all fungi and 500 CFU/m 3 for Aspergillus fumigatus, compared with 19 CFU/m 3 and 4 CFU/m 3 , respectively, in the absence of construction. 280 Many health-care institutions are located in large, urban areas; building implosions are becoming a more frequent concern. Infection-control risk assessment teams, particularly those in facilities located in urban renewal areas, would benefit by developing risk management strategies for external demolition and construction as a standing policy. In light of the events of 11 September 2001, it may be necessary for the team to identify those dust exclusion measures that can be implemented rapidly in response to emergency situations (Table 8). Issues to be reviewed prior to demolition include a. proximity of the air intake system to the work site, b. adequacy of window seals and door seals, c. proximity of areas frequented by immunocompromised patients, and d. location of the underground utilities (D. Erickson, ASHE, 2000). 120,250,273,276,277,280,305 Minimizing the entry of outside dust into the HVAC system is crucial in reducing the risk for airborne contaminants. Facility engineers should be consulted about the potential impact of shutting down the system or increasing the filtration. Selected air handlers, especially those located close to excavation sites, may have to be shut off temporarily to keep from overloading the system with dust and debris. Care is needed to avoid significant facility-wide reductions in pressure differentials that may cause the building to become negatively pressured relative to the outside. To prevent excessive particulate overload and subsequent reductions in effectiveness of intake air systems that cannot be shut off temporarily, air filters must be inspected frequently for proper installation and function. Excessive dust penetration can be avoided if recirculated air is maximally utilized while outdoor air intakes are shut down. Scheduling demolition and excavation during the winter, when Aspergillus spp. spores may be present in lower numbers, can help, although seasonal variations in spore density differ around the world. 92,287,303 Dust control can be managed by misting the dirt and debris during heavy dust-generating activities. To decrease the amount of aerosols from excavation and demolition projects, nearby windows, especially in areas housing immunocompromised patients, can be sealed and window and door frames caulked or weatherstripped to prevent dust intrusion. 50,301,306 Monitoring for adherence to these control measures throughout demolition or excavation is crucial. Diverting pedestrian traffic away from the construction sites decreases the amount of dust tracked back into the health-care facility and minimizes exposure of high-risk patients to environmental pathogens. Additionally, closing entrances near construction or demolition sites might be beneficial; if this is not practical, creating an air lock (i.e., pressurizing the entry way) is another option.\n# f. Internal Demolition, Construction, Renovations, and Repairs\nThe focus of a properly implemented infection-control program during interior construction and repairs is containment of dust and moisture. This objective is achieved by a. educating construction workers about the importance of control measures b. preparing the site; c. notifying and issuing advisories for staff, patients, and visitors; d. moving staff and patients and relocating patients as needed; e. issuing standards of practice and precautions during activities and maintenance; f. monitoring for adherence to control measures during construction and providing prompt feedback about lapses in control g. monitoring HVAC performance; h. implementing daily clean-up, terminal cleaning and removal of debris upon completion; and i. ensuring the integrity of the water system during and after construction. These activities should be coordinated with engineering staff and infection-control professionals.\nPhysical barriers capable of containing smoke and dust will confine dispersed fungal spores to the construction zone. 279,284,307,308 The specific type of physical barrier required depends on the project's scope and duration and on local fire codes. Short-term projects that result in minimal dust dispersion (e.g., installation of new cables or wiring above ceiling tiles) require only portable plastic enclosures with negative pressure and HEPA filtration of the exhaust air from the enclosed work area. The placement of a portable industrial-grade HEPA filter device capable of filtration rate of 300-800 ft 3 /min. adjacent to the work area will help to remove fungal spores, but its efficacy is dependent on the supplied ACH and size of the area. If the project is extensive but short-term, dust-abatement, fire-resistant plastic curtains (e.g., Visqueen®) may be adequate. These should be completely airtight and sealed from ceiling to floor with overlapping curtains; 276,277,309 holes, tears, or other perforations should be repaired promptly with tape. A portable, industrial-grade HEPA filter unit on continuous operation is needed within the contained area, with the filtered air exhausted to the outside of the work zone. Patients should not remain in the room when dust-generating activities are performed. Tools to assist the decision-making process regarding selection of barriers based on an ICRA approach are available. 281 More elaborate barriers are indicated for long-term projects that generate moderate to large amounts of dust. These barrier structures typically consist of rigid, noncombustible walls constructed from sheet rock, drywall, plywood, or plaster board and covered with sheet plastic (e.g., Visqueen®). Barrier requirements to prevent the intrusion of dust into patient-care areas include a. installing a plastic dust abatement curtain before construction of the rigid barrier b. sealing and taping all joint edges including the top and bottom; c. extending the barrier from floor to floor, which takes into account the space [approximately 2-8 ft.] above the finished, lay-down ceiling; and d. fitting or sealing any temporary doors connecting the construction zone to the adjacent area. (See Box 7 for a list of the various construction and repair activities that require the use of some type of barrier.) Dust and moisture abatement and control rely primarily on the impermeable barrier containment approach; as construction continues, numerous opportunities can lead to dispersion of dust to other areas of the health-care facility. Infection-control measures that augment the use of barrier containment should be undertaken (Table 9).\nDust-control measures for clinical laboratories are an essential part of the infection-control strategy during hospital construction or renovation. Use of plastic or solid barriers may be needed if the ICRA determines that air flow from construction areas may introduce airborne contaminants into the laboratory space. In one facility, pseudofungemia clusters attributed to Aspergillus spp. and Penicillium spp. were linked to improper air flow patterns and construction projects adjacent to the laboratory; intrusion of dust and spores into a biological safety cabinet from construction activity immediately next to the cabinet resulted in a cluster of cultures contaminated with Aspergillus niger. 310,311 Reportedly, no barrier containment was used and the HEPA filtration system was overloaded with dust. In addition, an outbreak of pseudobacteremia caused by Bacillus spp. occurred in another hospital during construction above a storage area for blood culture bottles. 207 Airborne spread of Bacillus spp. spores resulted in contamination of the bottles' plastic lids, which were not disinfected or handled with proper aseptic technique prior to collection of blood samples. 1. Monitor the construction area daily for compliance with the infection-control plan. 2. Protective outer clothing for construction workers should be removed before entering clean areas. 3. Use mats with tacky surfaces within the construction zone at the entry; cover sufficient area so that both feet make contact with the mat while walking through the entry. 4. Construct an anteroom as needed where coveralls can be donned and removed. 5. Clean the construction zone and all areas used by construction workers with a wet mop. 6. If the area is carpeted, vacuum daily with a HEPA-filtered-equipped vacuum. 7. Provide temporary essential services (e.g., toilets) and worker conveniences (e.g, vending machines) in the construction zone as appropriate. 8. Damp-wipe tools if removed from the construction zone or left in the area. 9. Ensure that construction barriers remain well sealed; use particle sampling as needed. 10. Ensure that the clinical laboratory is free from dust contamination.\n# Infection-control measure\nSteps for implementation Complete the project.\n1. Flush the main water system to clear dust-contaminated lines. \n# Environmental Infection-Control Measures for Special Health-Care Settings\nAreas in health-care facilities that require special ventilation include a. operating rooms b. PE rooms used by high-risk, immunocompromised patients; and c. AII rooms for isolation of patients with airborne infections (e.g., those caused by M. tuberculosis, VZV, or measles virus).\nThe number of rooms required for PE and AII are determined by a risk assessment of the health-care facility. 6 Continuous, visual monitoring of air flow direction is required for new or renovated pressurized rooms. 120,256 \n# a. Protective Environments (PE)\nAlthough the exact configuration and specifications of PEs might differ among hospitals, these care areas for high-risk, immunocompromised patients are designed to minimize fungal spore counts in air by maintaining a. filtration of incoming air by using central or point-of-use HEPA filters b. directed room air flow [i.e., from supply on one side of the room, across the patient, and out through the exhaust on the opposite side of the room]; c. positive room air pressure of 2.5 Pa [0.01\" water gauge] relative to the corridor; d. well-sealed rooms; and e. ≥12 ACH. 44,120,251,254,[316][317][318][319] Air flow rates must be adjusted accordingly to ensure sufficient ACH, and these rates vary depending on certain factors (e.g., room air leakage area). For example, to provide ≥12 ACH in a typical patient room with 0.5 sq. ft. air leakage, the air flow rate will be minimally 125 cubic feet/min (cfm). 320,321 Higher air flow rates may be needed. A general ventilation diagram for a positive-pressure room is given in Figure 2. Directed room air flow in PE rooms is not laminar; parallel air streams are not generated. Studies attempting to demonstrate patient benefit from laminar air flow in a PE setting are equivocal. 316, 318, 319, 322 -327 Air flow direction at the entrances to these areas should be maintained and verified, preferably on a daily basis, using either a visual means of indication (e.g., smoke tubes and flutter strips) or manometers. Permanent installation of a visual monitoring device is indicated for new PE construction and renovation. 120 Facility service structures can interfere with the proper unidirectional air flow from the patients' rooms to the adjacent corridor. In one outbreak investigation, Aspergillus spp. infections in a critical care unit may have been associated with a pneumatic specimen transport system, a textile disposal duct system, and central vacuum lines for housekeeping, all of which disrupted proper air flow from the patients' rooms to the outside and allowed entry of fungal spores into the unit (M. McNeil, CDC, 2000). The use of surface fungicide treatments is becoming more common, especially for building materials. 329 Copper-based compounds have demonstrated anti-fungal activity and are often applied to wood or paint.\nCopper-8-quinolinolate was used on environmental surfaces contaminated with Aspergillus spp. to control one reported outbreak of aspergillosis.310 The compound was also incorporated into the fireproofing material of a newly constructed hospital to help decrease the environmental spore burden. 316\n# b. Airborne Infection Isolation (AII)\nAcute-care inpatient facilities need at least one room equipped to house patients with airborne infectious disease. Every health-care facility, including ambulatory and long-term care facilities, should undertake an ICRA to identify the need for AII areas. Once the need is established, the appropriate ventilation equipment can be identified. Air handling systems for this purpose need not be restricted to central systems. Guidelines for the prevention of health-care acquired TB have been published in response to multiple reports of health-care associated transmission of multi-drug resistant strains. 4,330 In reports documenting health-care acquired TB, investigators have noted a failure to comply fully with prevention measures in established guidelines. 331 -345 These gaps highlight the importance of prompt recognition of the disease, isolation of patients, proper treatment, and engineering controls. AII rooms are also appropriate for the care and management of smallpox patients. 6 Environmental infection control with respect to smallpox is currently being revisited (see Appendix E).\nSalient features of engineering controls for AII areas include a. use of negative pressure rooms with close monitoring of air flow direction using manometers or temporary or installed visual indicators [e.g., smoke tubes and flutter strips] placed in the room with the door closed b. minimum 6 ACH for existing facilities, ≥12 ACH for areas under renovation or for new construction; and c. air from negative pressure rooms and treatment rooms exhausted directly to the outside if possible. 4,120,248 As with PE, airflow rates need to be determined to ensure the proper numbers of ACH. 320,321 AII rooms can be constructed either with (Figure 3) or without (Figure 4) an anteroom. When the recirculation of air from AII rooms is unavoidable, HEPA filters should be installed in the exhaust duct leading from the room to the general ventilation system. In addition to UVGI fixtures in the room, UVGI can be placed in the ducts as an adjunct measure to HEPA filtration, but it can not replace the HEPA filter. 4 One of the components of airborne infection isolation is respiratory protection for health-care workers and visitors when entering AII rooms. 4,6,347 Recommendations of the type of respiratory protection are dependent on the patient's airborne infection (indicating the need for AII) and the risk of infection to persons entering the AII room. A more in-depth discussion of respiratory protection in this instance is presented in the current isolation guideline; 6 a revision of this guideline is in development. Coughinducing procedures (e.g., endotracheal intubation and suctioning of known or suspected TB patients, diagnostic sputum induction, aerosol treatments, and bronchoscopy) require similar precautions. [348][349][350] Additional engineering measures are necessary for the management of patients requiring PE (i.e., allogeneic HSCT patients) who concurrently have airborne infection. For this type of patient treatment, an anteroom (Figure 4) is required in new construction and renovation as per AIA guidelines. 120 The pressure differential of an anteroom can be positive or negative relative to the patient in the room. 120 An anteroom can act as an airlock (Figure 4). If the anteroom is positive relative to the air space in the patient's room, staff members do not have to mask prior to entry into the anteroom if air is directly exhausted to the outside and a minimum of 10 ACH (Figure 4, top diagram). 120 When an anteroom is negative relative to both the AII room and the corridor, health-care workers must mask prior to entering the anteroom (Figure 4, bottom diagram). If an AII room with an anteroom is not available, use of a portable, industrial-grade HEPA filter unit may help to increase the number of ACHs while facilitating the removal of fungal spores; however, a fresh air source must be present to achieve the proper air exchange rate. Incoming ambient air should receive HEPA filtration.\n# c. Operating Rooms\nOperating room air may contain microorganisms, dust, aerosol, lint, skin squamous epithelial cells, and respiratory droplets. The microbial level in operating room air is directly proportional to the number of people moving in the room. 351 One study documented lower infection rates with coagulase-negative staphylococci among patients when operating room traffic during the surgical procedure was limited. 352 Therefore, efforts should be made to minimize personnel traffic during operations. Outbreaks of SSIs caused by group A beta-hemolytic streptococci have been traced to airborne transmission from colonized operating-room personnel to patients. [150][151][152][153][154] Several potential health-care associated pathogens (e.g., Staphylococcus aureus and Staphylococcus epidermidis) and drug-resistant organisms have also been recovered from areas adjacent to the surgical field, 353 but the extent to which the presence of bacteria near the surgical field influences the development of postoperative SSIs is not clear. 354 Proper ventilation, humidity (<68%), and temperature control in the operating room is important for the comfort of surgical personnel and patients, but also in preventing environmental conditions that encourage growth and transmission of microorganisms. 355 Operating rooms should be maintained at positive pressure with respect to corridors and adjacent areas. 356 Operating rooms typically do not have a variable air handling system. Variable air handling systems are permitted for use in operating rooms only if they continue to provide a positive pressure with respect to the corridors and adjacent areas and the proper ACHs are maintained when the room is occupied. Conventional operating-room ventilation systems produce a minimum of about 15 ACH of filtered air for thermal control, three (20%) of which must be fresh air. 120,357,358 Air should be introduced at the ceiling and exhausted near the floor. 357,359 Laminar airflow and UVGI have been suggested as adjunct measures to reduce SSI risk for certain operations. Laminar airflow is designed to move particle-free air over the aseptic operating field at a uniform velocity (0.3-0.5 m/sec), sweeping away particles in its path. This air flow can be directed vertically or horizontally, and recirculated air is passed through a HEPA filter. [360][361][362][363] Neither laminar airflow nor UV light, however, has been conclusively shown to decrease overall SSI risk. 356,[364][365][366][367][368][369][370] Elective surgery on infectious TB patients should be postponed until such patients have received adequate drug therapy. The use of general anesthesia in TB patients poses infection-control challenges because intubation can induce coughing, and the anesthesia breathing circuit apparatus potentially can become contaminated. 371 Although operating room suites at 15 ACH exceed the air exchanges required transmission of TB to operating-room personnel. If feasible, intubation and extubation of the TB surgical patient should be performed in AII. AIA currently does not recommend changing pressure from positive to negative or setting it to neutral; most facilities lack the capability to do so. 120 When emergency surgery is indicated for a suspected/diagnosed infectious TB patient, taking specific infection-control measures is prudent (Box 8). + The placement of portable HEPA filter units in the operating room must be carefully evaluated for potential disruptions in normal air flow. The portable unit should be turned off while the surgical procedure is underway and turned on following extubation. Portable HEPA filter units previously placed in construction areas may be used in subsequent patient care, provided that all internal and external surfaces are cleaned and the filter's performance is verified with appropriate particle testing and is changed, if needed. \n# Other Aerosol Hazards in Health-Care Facilities\nIn addition to infectious bioaerosols, several crucial non-infectious, indoor air-quality issues must be addressed by health-care facilities. The presence of sensitizing and allergenic agents and irritants in the workplace (e.g., ethylene oxide, glutaraldehyde, formaldehyde, hexachlorophene, and latex allergens 375 ) is increasing. Asthma and dermatologic and systemic reactions often result with exposure to these chemicals. Anesthetic gases and aerosolized medications (e.g., ribavirin, pentamidine, and aminoglycosides) represent some of the emerging potentially hazardous exposures to health-care workers. Containment of the aerosol at the source is the first level of engineering control, but personal protective equipment (e.g., masks, respirators, and glove liners) that distances the worker from the hazard also may be needed.\nLaser plumes and surgical smoke represent another potential risk for health-care workers. [376][377][378] Lasers transfer electromagnetic energy into tissues, resulting in the release of a heated plume that includes particles, gases, tissue debris, and offensive smells. One concern is that aerosolized infectious material in the laser plume might reach the nasal mucosa of surgeons and adjacent personnel. Although some viruses (i.e., varicella-zoster virus, pseudorabies virus, and herpes simplex virus) do not aerosolize efficiently, 379,380 other viruses and bacteria (e.g., human papilloma virus [HPV], HIV, coagulasenegative Staphylococcus, Corynebacterium spp., and Neisseria spp.) have been detected in laser plumes. [381][382][383][384][385][386][387] The presence of an infectious agent in a laser plume may not, however, be sufficient to cause disease from airborne exposure, especially if the normal mode of transmission for the agent is not airborne. No evidence indicated that HIV or hepatitis B virus (HBV) has been transmitted via aerosolization and inhalation. 388 Although continuing studies are needed to fully evaluate the risk of laser plumes to surgical personnel, the prevention measures in these other guidelines should be followed: a. NIOSH recommendations, 378 b. the Recommended Practices for Laser Safety in Practice Settings developed by the Association of periOperative Registered Nurses [AORN], 389 c. the assessments of ECRI, 390-392 and d. the ANSI standard. 393 These guidelines recommend the use of a. respirators (N95 or N100) or full face shields and masks, 260 b. central wall-suction units with in-line filters to collect particulate matter from minimal plumes, and c. dedicated mechanical smoke exhaust systems with a high-efficiency filter to remove large amounts of laser plume.\nAlthough transmission of TB has occurred as a result of abscess management practices that lacked airborne particulate control measures and respiratory protection, use of a smoke evacuator or needle aspirator and a high degree of clinical awareness can help protect healthcare workers when excising and draining an extrapulmonary TB abscess. 137\n# D. Water 1. Modes of Transmission of Waterborne Diseases\nMoist environments and aqueous solutions in health-care settings have the potential to serve as reservoirs for waterborne microorganisms. Under favorable environmental circumstances (e.g., warm temperature and the presence of a source of nutrition), many bacterial and some protozoal microorganisms can either proliferate in active growth or remain for long periods in highly stable, environmentally resistant (yet infectious) forms. Modes of transmission for waterborne infections include direct contact [e.g., that required for hydrotherapy]; ingestion of water [e.g., through consuming contaminated ice]; indirect-contact transmission [e.g., from an improperly reprocessed medical device]; 6 inhalation of aerosols dispersed from water sources; 3 and aspiration of contaminated water.\nThe first three modes of transmission are commonly associated with infections caused by gram-negative bacteria and nontuberculous mycobacteria (NTM). Aerosols generated from water sources contaminated with Legionella spp. often serve as the vehicle for introducing legionellae to the respiratory tract. 394 \n# Waterborne Infectious Diseases in Health-Care Facilities a. Legionellosis\nLegionellosis is a collective term describing infection produced by Legionella spp., whereas Legionnaires disease is a multi-system illness with pneumonia. 395 The clinical and epidemiologic aspects of these diseases (Table 11) are discussed extensively in another guideline. 3 Although Legionnaires disease is a respiratory infection, infection-control measures intended to prevent healthcare-associated cases center on the quality of water-the principal reservoir for Legionella spp.\n# Format Change [November 2016]:\nThe format of this section was changed to improve readability and accessibility. The content is unchanged.\n# Table 11. Clinical and epidemiologic characteristics of legionellosis/Legionnaires disease\n\n# Modes of transmission\n• Aspiration of water, direct inhalation or water aerosols. 3,[394][395][396][397][398]400 Causative agent • Legionella pneumophila (90% of infections); L. micdadei, L. bozemanii, L. dumoffii, L. longbeachii, (14 additional species can cause infection in humans). [395][396][397][398][399] Source of exposure • Exposure to environmental sources of Legionella spp. (i.e., water or water aerosols). 31,33,[401][402][403][404][405][406][407][408][409][410][411][412][413][414] Clinical syndromes and diseases Two distinct illnesses: [397][398][399][415][416][417][418][419][420][421][422] • Pontiac fever [a milder, influenza-like illness]; and • progressive pneumonia that may be accompanied by cardiac, renal, and gastrointestinal involvement 3\nPatient populations at greatest risk • Immunosuppressed patients (e.g., transplant patients, cancer patients, and patients receiving corticosteroid therapy); • Immunocompromised patients (e.g., surgical patients, patients with underlying chronic lung disease, and dialysis patients); • Elderly persons; and • Patients who smoke. [395][396][397][423][424][425][426][427][428][429][430][431][432][433] \n# Occurrence\n• Proportion of community-acquired pneumonia caused by Legionella spp. ranges from 1%-5%; estimated annual incidence among the general population is 8,000-18,000 cases in the United States; the incidence of healthcare-associated pneumonia (0%-14%) may be underestimated if appropriate laboratory diagnostic methods are unavailable. 396,397,[434][435][436][437][438][439][440][441][442][443][444] Mortality rate • Mortality declined markedly during 1980-1998, from 34% to 12% for all cases; the mortality rate is higher among persons with health-care associated pneumonia compared with the rate among community-acquired pneumonia patients (14% for health-care associated pneumonia versus 10% for community-acquired pneumonia [1998 data]). [395][396][397]445 Legionella spp. are commonly found in various natural and man-made aquatic environments 446,447 and can enter health-care facility water systems in low or undetectable numbers. 448,449 Cooling towers, evaporative condensers, heated potable water distribution systems, and locally-produced distilled water can provide environments for multiplication of legionellae. [450][451][452][453][454] In several hospital outbreaks, patients have been infected through exposure to contaminated aerosols generated by cooling towers, showers, faucets, respiratory therapy equipment, and room-air humidifiers. [401][402][403][404][405][406][407][408][409][410]455 Factors that enhance colonization and amplification of legionellae in man-made water environments include a. temperatures of 77°F-107.6°F [25°C-42°C], [456][457][458][459][460] b. stagnation, 461 c. scale and sediment, 462 and d. presence of certain free-living aquatic amoebae that can support intracellular growth of legionellae. 462,463 The bacteria multiply within single-cell protozoa in the environment and within alveolar macrophages in humans.\n# b. Other Gram-Negative Bacterial Infections\nOther gram-negative bacteria present in potable water also can cause health-care associated infections.\nClinically important, opportunistic organisms in tap water include Pseudomonas aeruginosa, Pseudomonas spp., Burkholderia cepacia, Ralstonia pickettii, Stenotrophomonas maltophilia, and Sphingomonas spp.\n(Tables 12 and 13). Immunocompromised patients are at greatest risk of developing infection. Medical conditions associated with these bacterial agents range from colonization of the respiratory and urinary tracts to deep, disseminated infections that can result in pneumonia and bloodstream bacteremia. Colonization by any of these organisms often precedes the development of infection. The use of tap water in medical care (e.g., in direct patient care, as a diluent for solutions, as a water source for medical instruments and equipment, and during the final stages of instrument disinfection) therefore presents a potential risk for exposure. Colonized patients also can serve as a source of contamination, particularly for moist environments of medical equipment (e.g., ventilators).\nIn addition to Legionella spp., Pseudomonas aeruginosa and Pseudomonas spp. are among the most clinically relevant, gram-negative, health-care associated pathogens identified from water. These and other gram-negative, non-fermentative bacteria have minimal nutritional requirements (i.e., these organisms can grow in distilled water) and can tolerate a variety of physical conditions. These attributes are critical to the success of these organisms as health-care associated pathogens. Measures to prevent the spread of these organisms and other waterborne, gram-negative bacteria include hand hygiene, glove use, barrier precautions, and eliminating potentially contaminated environmental reservoirs. 464,465 Format Change [November 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged.\n# Table 12. Pseudomonas aeruginosa infections\n\n# Modes of transmission\n• Direct contact with water, aerosols; aspiration of water and inhalation of water aerosols; and indirect transfer from moist environmental surfaces via hands of health-care workers. 28,[502][503][504][505][506] Clinical syndromes and diseases • Septicemia, pneumonia (particularly ventilator-associated), chronic respiratory infections among cystic fibrosis patients, urinary tract infections, skin and soft-tissue infections (e.g., tissue necrosis and hemorrhage), burn-wound infections, folliculitis, endocarditis, central nervous system infections (e.g., meningitis and abscess), eye infections, and bone and joint infections. Environmental sources of pseudomonads in healthcare settings • Potable (tap) water, distilled water, antiseptic solutions contaminated with tap water, sinks, hydrotherapy pools, whirlpools and whirlpool spas, water baths, lithotripsy therapy tanks, dialysis water, eyewash stations, flower vases, and endoscopes with residual moisture in the channels. 28,29,466,468,[507][508][509][510][511][512][513][514][515][516][517][518][519][520] Environmental sources of pseudomonads in the community • Fomites (e.g., drug injection equipment stored in contaminated water). 494,495 Patient populations at greatest risk • Intensive care unit (ICU) patients (including neonatal ICU), transplant patients (organ and hematopoietic stem cell), neutropenic patients, burn therapy and hydrotherapy patients, patients with malignancies, cystic fibrosis patients, patients with underlying medical conditions, and dialysis patients. 28, 466, 467, 472, 477, 493, 506-508, 511, 512, 521-526 Format Change [November 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged. 527 • Contaminated solutions and disinfectants 528,529 • Dialysis machines 527 • Nebulizers [530][531][532] • Water baths 533 • Intrinsically-contaminated mouthwash 534 (This report describes contamination occurring during manufacture prior to use by the health-care facility staff. All other entries reflect extrinsic sources of contamination.) • Ventilator temperature probes 535 \n# Stenotrophomonas maltophlia, Sphingomonas spp.\n• Distilled water 536,537 • Contaminated solutions and disinfectants 529 • Dialysis machines 527 • Nebulizers [530][531][532] • Water 538 • Ventilator temperature probes 539 \n# Ralstonia pickettii\n• Fentanyl solutions 540 • Chlorhexidine 541\n• Distilled water 541 • Contaminated respiratory therapy solution 541,542 Serratia marcescens\n• Potable water 543 • Contaminated antiseptics (i.e., benzalkonium chloride and chlorhexidine) [544][545][546] • Contaminated disinfectants (i.e., quaternary ammonium compounds and glutaraldehyde) 547,548 Acinetobacter spp.\n• Medical equipment that collects moisture (e.g., mechanical ventilators, cool mist humidifiers, vaporizers, and mist tents) [549][550][551][552][553][554][555][556] • Room humidifiers 553,555 • Environmental surfaces [557][558][559][560][561][562][563][564] Enterobacter spp.\n• Humidifier water 565 • Intravenous fluids [566][567][568][569][570][571][572][573][574][575][576][577][578] • Unsterilized cotton swabs 573 • Ventilators 565,569 • Rubber piping on a suctioning machine 565,569 • Blood gas analyzers 570 Two additional gram-negative bacterial pathogens that can proliferate in moist environments are Acinetobacter spp. and Enterobacter spp. 571,572 Members of both genera are responsible for healthcareassociated episodes of colonization, bloodstream infections, pneumonia, and urinary tract infections among medically compromised patients, especially those in ICUs and burn therapy units. 566,[572][573][574][575][576][577][578][579][580][581][582][583] Infections caused by Acinetobacter spp. represent a significant clinical problem. Average infection rates are higher from July through October compared with rates from November through June. 584 Mortality rates associated with Acinetobacter bacteremia are 17%-52%, and rates as high as 71% have been reported for pneumonia caused by infection with either Acinetobacter spp. or Pseudomonas spp.Multidrug resistance, especially in third generation cephalosporins for Enterobacter spp., contributes to increased morbidity and mortality. 569,572 Patients and health-care workers contribute significantly to the environmental contamination of surfaces and equipment with Acinetobacter spp. and Enterobacter spp., especially in intensive care areas, because of the nature of the medical equipment (e.g., ventilators) and the moisture associated with this equipment. 549,571,572,585 Hand carriage and hand transfer are commonly associated with health-care-associated transmission of these organisms and for S. marcescens. 586 Enterobacter spp. are primarily spread in this manner among patients by the hands of health-care workers. 567,587 Acinetobacter spp. have been isolated from the hands of 4%-33% of health-care workers in some studies, [585][586][587][588][589][590] and transfer of an epidemic strain of Acinetobacter from patients' skin to health-care workers' hands has been demonstrated experimentally. 591 Acinetobacter infections and outbreaks have also been attributed to medical equipment and materials (e.g., ventilators, cool mist humidifiers, vaporizers, and mist tents) that may have contact with water of uncertain quality (e.g., rinsing a ventilator circuit in tap water). [549][550][551][552][553][554][555][556] Strict adherence to hand hygiene helps prevent the spread of both Acinetobacter spp. and Enterobacter spp. 577,592 Acinetobacter spp. have also been detected on dry environmental surfaces (e.g., bed rails, counters, sinks, bed cupboards, bedding, floors, telephones, and medical charts) in the vicinity of colonized or infected patients; such contamination is especially problematic for surfaces that are frequently touched. [557][558][559][560][561][562][563][564] In two studies, the survival periods of Acinetobacter baumannii and Acinetobacter calcoaceticus on dry surfaces approximated that for S. aureus (e.g., 26-27 days). 593,594 Because Acinetobacter spp. may come from numerous sources at any given time, laboratory investigation of health-care associated Acinetobacter infections should involve techniques to determine biotype, antibiotype, plasmid profile, and genomic fingerprinting (i.e., macrorestriction analysis) to accurately identify sources and modes of transmission of the organism(s). 595\n# c. Infections and Pseudo-Infections Due to Nontuberculous Mycobacteria\nNTM are acid-fast bacilli (AFB) commonly found in potable water. NTM include both saprophytic and opportunistic organisms. Many NTM are of low pathogenicity, and some measure of host impairment is necessary to enhance clinical disease. 596 The four most common forms of human disease associated with NTM are pulmonary disease in adults; cervical lymph node disease in children; skin, soft tissue, and bone infections; and disseminated disease in immunocompromised patients. 596,597 Person-to-person acquisition of NTM infection, especially among immunocompetent persons, does not appear to occur, and close contacts of patients are not readily infected, despite the high numbers of organisms harbored by such patients. 596,[598][599][600] NTM are spread via all modes of transmission associated with water. In addition to health-care associated outbreaks of clinical disease, NTM can colonize patients in health-care facilities through consumption of contaminated water or ice or through inhalation of aerosols. [601][602][603][604][605] Colonization following NTM exposure, particularly of the respiratory tract, occurs when a patient's local defense mechanisms are impaired; overt clinical disease does not develop. 606 The format of this section was changed to improve readability and accessibility. The content is unchanged.\n# Table 14a. Infections or colonizations\n\n# Pathogen Vehicles associated with infections or colonizations\n\n# Mycobacterium abscessus\n• Inadequately sterilized medical instruments 613 \n# Mycobacterium avium complex (MAC)\n• Potable water [614][615][616] \n# Mycobacterium chelonae\n• Dialysis, reprocessed dialyzers 31,32 • Inadequately-sterilized medical instruments, jet injectors 617,618 • Contaminated solutions 619,620 • Hydrotherapy tanks 621 \n# Mycobacterium fortuitum\n• Aerosols from showers or other water sources 605,606 • Ice 602\n• Inadequately sterilized medical instruments 603 • Hydrotherapy tanks 622 \n# Mycobacterium marinum\n• Hydrotherapy tanks 623 \n# Mycobacterium ulcerans\n• Potable water 624 • Laboratory solution (intrinsically contaminated 625 • Potable water ingestion prior to sputum specimen collection 626 \n# Mycobacterium kansasii\n• Potable water 627 \n# Mycobacterium terrae\n• Potable water 608 \n# Mycobacterium xenopi\n• Potable water 609,612,627 NTM can be isolated from both natural and man-made environments. Numerous studies have identified 632 Some NTM species (e.g., Mycobacterium xenopi) can survive in water at 113°F (45°C), and can be isolated from hot water taps, which can pose a problem for hospitals that lower the temperature of their hot water systems. 627 Other NTM (e.g., Mycobacterium kansasii, M. gordonae, M. fortuitum, and M. chelonae) cannot tolerate high temperatures and are associated more often with cold water lines and taps. 629 NTM have a high resistance to chlorine; they can tolerate free chlorine concentrations of 0.05-0.2 mg/L (0.05-0.2 ppm) found at the tap. 598,633,634 They are 20-100 times more resistant to chlorine compared with coliforms; slow-growing strains of NTM (e.g., Mycobacterium avium and M. kanasii) appear to be more resistant to chorine inactivation compared to fast-growing NTM. 635 Slow-growing NTM species have also demonstrated some resistance to formaldehyde and glutaraldehyde, which has posed problems for reuse of hemodialyzers. 31 The ability of NTM to form biofilms at fluid-surface interfaces (e.g., interior surfaces of water pipes) contributes to the organisms' resistance to chemical inactivation and provides a microenvironment for growth and proliferation. 636,637 \n# d. Cryptosporidiosis\nCryptosporidium parvum is a protozoan parasite that causes self-limiting gastroenteritis in normal hosts but can cause severe, life-threatening disease in immunocompromised patients. First recognized as a human pathogen in 1976, C. parvum can be present in natural and finished waters after fecal contamination from either human or animal sources. [638][639][640][641] The health risks associated with drinking potable water contaminated with minimal numbers of C. parvum oocysts are unknown. 642 It remains to be determined if immunosuppressed persons are more susceptible to lower doses of oocysts than are immunocompetent persons. One study demonstrated that a median 50% infectious dose (ID50) of 132 oocysts of calf origin was sufficient to cause infection among healthy volunteers. 643 In a second study, the same researchers found that oocysts obtained from infected foals (newborn horses) were infectious for human volunteers at median ID50 of 10 oocysts, indicating that different strains or species of Cryptosporidium may vary in their infectivity for humans. 644 In a small study population of 17 healthy adults with pre-existing antibody to C. parvum, the ID50 was determined to be 1,880 oocysts, more than 20-fold higher than in seronegative persons. 645 These data suggest that pre-existing immunity derived from previous exposures to Cryptosporidium offers some protection from infection and illness that ordinarily would result from exposure to low numbers of oocysts. 645,646 Oocysts, particularly those with thick walls, are environmentally resistant, but their survival under natural water conditions is poorly understood. Under laboratory conditions, some oocysts remain viable and infectious in cold (41°F [5°C]) for months. 641 The prevalence of Cryptosporidium in the U.S. drinking water supply is notable. Two surveys of approximately 300 surface water supplies revealed that 55%-77% of the water samples contained Cryptosporidium oocysts. 647,648 Because the oocysts are highly resistant to common disinfectants (e.g., chlorine) used to treat drinking water, filtration of the water is important in reducing the risk of waterborne transmission. Coagulation-floculation and sedimentation, when used with filtration, can collectively achieve approximately a 2.5 log10 reduction in the number of oocysts. 649 However, outbreaks have been associated with both filtered and unfiltered drinking water systems (e.g., the 1993 outbreak in Milwaukee, Wisconsin that affected 400,000 people). 641,[650][651][652] The presence of oocysts in the water is not an absolute indicator that infection will occur when the water is consumed, nor does the absence of detectable oocysts guarantee that infection will not occur. Healthcare associated outbreaks of cryptosporidiosis primarily have been described among groups of elderly patients and immunocompromised persons. 653 \n# Water Systems in Health-Care Facilities a. Basic Components and Point-of-Use Fixtures\nTreated municipal water enters a health-care facility via the water mains and is distributed throughout the building(s) by a network of pipes constructed of galvanized iron, copper, and polyvinylchloride (PVC). The pipe runs should be as short as is practical. Where recirculation is employed, the pipe runs should be insulated and long dead legs avoided in efforts to minimize the potential for water stagnation, which favors the proliferation of Legionella spp. and NTM. In high-risk applications (e.g., PE areas for severely immunosuppressed patients), insulated recirculation loops should be incorporated as a design minimal loss.\nEach water service main, branch main, riser, and branch (to a group of fixtures) has a valve and a means to reach the valves via an access panel. 120 Each fixture has a stop valve. Valves permit the isolation of a portion of the water system within a facility during repairs or maintenance. Vacuum breakers and other similar devices in the lines prevent water from back-flowing into the system. All systems that supply water should be evaluated to determine risk for potential back siphonage and cross connections.\nHealth-care facilities generate hot water from municipal water using a boiler system. Hot water heaters and storage vessels for such systems should have a drainage facility at the lowest point, and the heating element should be located as close as possible to the bottom of the vessel to facilitate mixing and to prevent water temperature stratification. Those hot or cold water systems that incorporate an elevated holding tank should be inspected and cleaned annually. Lids should fit securely to exclude foreign materials.\nThe most common point-of-use fixtures for water in patient-care areas are sinks, faucets, aerators, showers, and toilets; eye-wash stations are found primarily in laboratories. The potential for these fixtures to serve as a reservoir for pathogenic microorganisms has long been recognized (Table 15). 509,[654][655][656] Wet surfaces and the production of aerosols facilitate the multiplication and dispersion of microbes. The level of risk associated with aerosol production from point-of-use fixtures varies. Aerosols from shower heads and aerators have been linked to a limited number of clusters of gram-negative bacterial colonizations and infections, including Legionnaires disease, especially in areas where immunocompromised patients are present (e.g., surgical ICUs, transplant units, and oncology units). 412, 415,\n# 656-659\nIn one report, clinical infection was not evident among immunocompetent persons (e.g., hospital staff) who used hospital showers when Legionella pneumophila was present in the water system. 660 Given the infrequency of reported outbreaks associated with faucet aerators, consensus has not been reached regarding the disinfection of or removal of these devices from general use. If additional clusters of infections or colonizations occur in high-risk patient-care areas, it may be prudent to clean and decontaminate the aerators or to remove them. 658,659 ASHRAE recommends cleaning and monthly disinfection of aerators in high-risk patient-care areas as part of Legionella control measures. 661 Although aerosols are produced with toilet flushing, 662,663 no epidemiologic evidence suggests that these aerosols pose a direct infection hazard.\nAlthough not considered a standard point-of-use fixture, decorative fountains are being installed in increasing numbers in health-care facilities and other public buildings. Aerosols from a decorative fountain have been associated with transmission of Legionella pneumophila serogroup 1 infection to a small cluster of older adults. 664 This hotel lobby fountain had been irregularly maintained, and water in the fountain may have been heated by submersed lighting, all of which favored the proliferation of Legionella in the system. 664 Because of the potential for generations of infectious aerosols, a prudent prevention measure is to avoid locating these fixtures in or near high-risk patient-care areas and to adhere to written policies for routine fountain maintenance. 120 Follow public health guidelines.\n(See Tables 12-14)\n# Potable water Legionella Aerosol inhalation\nModerate: occasional welldescribed outbreaks.\nProvide supplemental treatment for water.\n(See \n# b. Water Temperature and Pressure\nHot water temperature is usually measured at the point of use or at the point at which the water line enters equipment requiring hot water for proper operation. 120 Generally, the hot water temperature in hospital patient-care areas is no greater than a temperature within the range of 105°F-120°F (40.6°C-49°C), depending on the AIA guidance issued at the year in which the facility was built. 120 Hot water temperature in patient-care areas of skilled nursing-care facilities is set within a slightly lower range of 95°F-110°F (35°C-43.3°C) depending on the AIA guidance at the time of facility construction. 120 Many states have adopted a temperature setting in these ranges into their health-care regulations and building codes. ASHRAE, however, has recommended higher settings. 661 Steam jets or booster heaters are usually needed to meet the hot water temperature requirements in certain service areas of the hospital (e.g., the kitchen [120°F (49°C)] or the laundry [160°F (71°C)]). 120 Additionally, water lines may need to be heated to a particular temperature specified by manufacturers of specific hospital equipment. Hot-water distribution systems serving patient-care areas are generally operated under constant recirculation to provide continuous hot water at each hot-water outlet. 120 If a facility is or has a hemodialysis unit, then continuously circulated, cold treated water is provided to that unit. 120 To minimize the growth and persistence of gram-negative waterborne bacteria (e.g., thermophilic NTM and Legionella spp.), 627,[703][704][705][706][707][708][709] cold water in health-care facilities should be stored and distributed at temperatures below 68°F (20°C); hot water should be stored above 140°F (60°C) and circulated with a minimum return temperature of 124°F (51°C), 661 or the highest temperature specified in state regulations and building codes. If the return temperature setting of 124°F (51°C) is permitted, then installation of preset thermostatic mixing valves near the point-of-use can help to prevent scalding. Valve maintenance is especially important in preventing valve failure, which can result in scalding. New shower systems in large buildings, hospitals, and nursing homes should be designed to permit mixing of hot and cold water near the shower head. The warm water section of pipe between the control valve and shower head should be self-draining. Where buildings can not be retrofitted, other approaches to minimize the growth of Legionella spp. include periodically increasing the temperature to at least 150°F [66°C] at the point of use [i.e., faucets] and adding additional chlorine and flushing the water. 661,710,711 Systems should be inspected annually to ensure that thermostats are functioning properly. Maintaining adequate pressure also helps to ensure the integrity of the piping system.\n# c. Infection-Control Impact of Water System Maintenance and Repair\nCorrective measures for water-system failures have not been studied in well-designed experiments; these measures are instead based on empiric engineering and infection-control principles. Health-care facilities can occasionally sustain both intentional cut-offs by the municipal water authority to permit new construction project tie-ins and unintentional disruptions in service when a water main breaks as a result of aging infrastructure or a construction accident. Vacuum breakers or other similar devices can prevent backflow of water in the facility's distribution system during water-disruption emergencies. 11 To be prepared for such an emergency, all health-care facilities need contingency plans that identify the total demand for potable water, the quantity of replacement water [e.g., bottled water] required for a minimum of 24 hours when the water system is down, mechanisms for emergency water distribution, and procedures for correcting drops in water pressure that affect operation of essential devices and equipment that are driven or cooled by a water system [Table 16]. 713\n# Format Change [November 2016]:\nThe format of this section was changed to improve readability and accessibility. The content is unchanged. Detailed, up-to-date plans for hot and cold water piping systems should be readily available for maintenance and repair purposes in case of system problems. Opening potable water systems for repair or construction and subjecting systems to water-pressure changes can result in water discoloration and dramatic increases in the concentrations of Legionella spp. and other gram-negative bacteria. The maintenance of a chlorine residual at all points within the piping system also offers some protection from entry of contamination to the pipes in the event of inadvertent cross-connection between potable and nonpotable water lines. As a minimum preventive measure, ASHRAE recommends a thorough flushing of the system. 661 High-temperature flushing or hyperchlorination may also be appropriate strategies to decrease potentially high concentrations of waterborne organisms. The decision to pursue either of these remediation strategies, however, should be made on a case-by-case basis. If only a portion of the system is involved, high temperature flushing or chlorination can be used on only that portion of the system. 661 When shock decontamination of hot water systems is necessary (e.g., after disruption caused by construction and after cross-connections), the hot water temperature should be raised to 160°F-170°F (71°C-77°C) and maintained at that level while each outlet around the system is progressively flushed. A minimum flush time of 5 minutes has been recommended; 3 the optimal flush time is not known, however, and longer flush times may be necessary. 714 The number of outlets that can be flushed simultaneously depends on the capacity of the water heater and the flow capability of the system. Appropriate safety procedures to prevent scalding are essential. When possible, flushing should be performed when the fewest building occupants are present (e.g., during nights and weekends).\nWhen thermal shock treatment is not possible, shock chlorination may serve as an alternative method. 661 Experience with this method of decontamination is limited, however, and high levels of free chlorine can corrode metals. Chlorine should be added, preferably overnight, to achieve a free chlorine residual of at least 2 mg/L (2 ppm) throughout the system. 661 This may require chlorination of the water heater or tank to levels of 20-50 mg/L (20-50 ppm). The pH of the water should be maintained at 7.0-8.0. 661 After completion of the decontamination, recolonization of the hot water system is likely to occur unless proper temperatures are maintained or a procedure such as continuous supplemental chlorination is continued.\nInterruptions of the water supply and sewage spills are situations that require immediate recovery and remediation measures to ensure the health and safety of patients and staff. 715 When delivery of potable water through the municipal distribution system has been disrupted, the public water supplier must issue a \"boil water\" advisory if microbial contamination presents an immediate public health risk to customers. The hospital engineer should oversee the restoration of the water system in the facility and clear it for use when appropriate. Hospitals must maintain a high level of surveillance for waterborne disease among patients and staff after the advisory is lifted. 642 Flooding from either external (e.g., from a hurricane) or internal sources (e.g., a water system break) usually results in property damage and a temporary loss of water and sanitation. [716][717][718] JCAHO requires all hospitals to have plans that address facility response for recovery from both internal and external disasters. 713,719 The plans are required to discuss a. general emergency preparedness, b. staffing, c. regional planning among area hospitals, d. emergency supply of potable water, e. infection control and medical services needs, f. climate control, and g. remediation.\nThe basic principles of structural recovery from flooding are similar to those for recovery from sewage contamination (Box 9 and 10). Following a major event (e.g., flooding), facilities may elect to conduct microbial sampling of water after the system is restored to verify that water quality has been returned to safe levels (<500 CFU/mL, heterotrophic plate count). This approach may help identify point-of-use fixtures that may harbor contamination as a result of design or engineering features. 720 Medical records should be allowed to dry and then either photocopied or placed in plastic covers before returning them to the record.\nMoisture meters can be used to assess water-damaged structural materials. If porous structural materials for walls have a moisture content of >20% after 72 hours, the affected material should be removed. 266,278,313 The management of water-damaged structural materials is not strictly limited to major water catastrophes (e.g., flooding and sewage intrusions); the same principles are used to evaluate the damage from leaking roofs, point-of-use fixtures, and equipment. Additional sources of moisture include condensate on walls from boilers and poorly engineered humidification in HVAC systems. An exception to these recommendations is made for hemodialysis units where water is further treated either by portable water treatment or large-scale water treatment systems usually involving reverse osmosis (RO). In the United States, >97% of dialysis facilities use RO treatment for their water. 721 However, changing pre-treatment filters and disinfecting the system to prevent colonization of the RO membrane and microbial contamination down-stream of the pre-treatment filter are prudent measures.\n# Box 10. Contingency planning for flooding\nGeneral emergency preparedness • Ensure that emergency electrical generators are not located in flood-prone areas of the facility.\n• Develop alternative strategies for moving patients, water containers, medical records, equipment, and supplies in the event that the elevators are inoperable. • Establish in advance a centralized base of operations with batteries, flashlights, and cellular phones.\n• Ensure sufficient supplies of sandbags to place at the entrances and the area around boilers, incinerators, and generators. • Establish alternative strategies for bringing core employees to the facility if high water prevents travel.\n# Staffing Patterns\n• Temporarily reassign licensed staff as needed to critical care areas to provide manual ventilation and to perform vital assessments on patients. • Designate a core group of employees to remain on site to keep all services operational if the facility remains open. • Train all employees in emergency preparedness procedures.\n# Regional planning among are facilities for disaster management\n• Incorporate community support and involvement (e.g., media alerts, news, and transportation).\n• Develop in advance strategies for transferring patients, as needed.\n• Develop strategies for sharing supplies and providing essential services among participating facilities (e.g., central sterile department services, and laundry services). • Identify sources for emergency provisions (e.g., blood, emergency vehicles, and bottled water).\n# Medical services and infection control\n• Use alcohol-based hand rubs in general patient-care areas.\n• Postpone elective surgeries until full services are restored, or transfer these patients to other facilities.\n• Consider using portable dialysis machines. (Portable dialysis machines require less water compared to the larger units situated in dialysis settings.) • Provide an adequate supply of tetanus and hepatitis A immunizations for patients and staff.\n# Climate control\n• Provide adequate water for cooling towers. (Water for cooling towers may need to be trucked in, especially if the tower uses a potable water source.) * Material in this box was compiled from references 713, 716-719.\n# Strategies for Controlling Waterborne Microbial Contamination a. Supplemental Treatment of Water with Heat and/or Chemicals\nIn addition to using supplemental treatment methods as remediation measures after inadvertent contamination of water systems, health-care facilities sometimes use special measures to control waterborne microorganisms on a sustained basis. This decision is most often associated with outbreaks of legionellosis and subsequent efforts to control legionellae, 722 although some facilities have tried supplemental measures to better control thermophilic NTM. 627 The primary disinfectant for both cold and hot water systems is chlorine. However, chlorine residuals are expected to be low, and possibly nonexistent, in hot water tanks because of extended retention time in the tank and elevated water temperature. Flushing, especially that which removes sludge from the bottom of the tank, probably provides the most effective treatment of water systems. Unlike the situation for disinfecting cooling towers, no equivalent recommendations have been made for potable water systems, although specific intervention strategies have been published. 403,723 The principal approaches to disinfection of potable systems are heat flushing using temperatures 160°F-170°F (71°-77°C), hyperchlorination, and physical cleaning of hot-water tanks. 3,403,661 Potable systems are easily recolonized and may require continuous intervention (e.g., raising of hot water temperatures or continuous chlorination). 403,711 Chlorine solutions lose potency over time, thereby rendering the stocking of large quantities of chlorine impractical.\nSome hospitals with hot water systems identified as the source of Legionella spp. have performed emergency decontamination of their systems by pulse (i.e., one-time) thermal disinfection/superheating or hyperchlorination. 711,714,724,725 After either of these procedures, hospitals either maintain their heated water with a minimum return temperature of 124°F (51°C) and cold water at <68°F (<20°C) or chlorinate their hot water to achieve 1-2 mg/L (1-2 ppm) of free residual chlorine at the tap. 26, 437, 709-711, 726, 727 Additional measures (e.g., physical cleaning or replacement of hot-water storage tanks, water heaters, faucets, and shower heads) may be required to help eliminate accumulations of scale and sediment that protect organisms from the biocidal effects of heat and chlorine. 457,711 Alternative methods for controlling and eradicating legionellae in water systems (e.g., treating water with chlorine dioxide, heavy metal ions [i.e., copper/silver ions], ozone, and UV light) have limited the growth of legionellae under laboratory and operating conditions. [728][729][730][731][732][733][734][735][736][737][738][739][740][741][742] Further studies on the long-term efficacy of these treatments are needed before these methods can be considered standard applications.\nRenewed interest in the use of chloramines stems from concerns about adverse health effects associated with disinfectants and disinfection by-products. 743 Monochloramine usage minimizes the formation of disinfection by-products, including trihalomethanes and haloacetic acids. Monochloramine can also reach distal points in a water system and can penetrate into bacterial biofilms more effectively than free chlorine. 744 However, monochloramine use is limited to municipal water treatment plants and is currently not available to health-care facilities as a supplemental water-treatment approach. A recent study indicated that 90% of Legionnaires disease outbreaks associated with drinking water could have been prevented if monochloramine rather than free chlorine has been used for residual disinfection. 745 In a retrospective comparison of health-care associated Legionnaires disease incidence in central Texas hospitals, the same research group documented an absence of cases in facilities located in communities with monochloramine-treated municipal water. 746 Additional data are needed regarding the effectiveness of using monochloramine before its routine use as a disinfectant in water systems can be recommended.\nNo data have been published regarding the effectiveness of monochloramine installed at the level of the health-care facility.\nAdditional filtration of potable water systems is not routinely necessary. Filters are used in water lines in dialysis units, however, and may be inserted into the lines for specific equipment (e.g., endoscope washers and disinfectors) for the purpose of providing bacteria-free water for instrument reprocessing. Additionally, an RO unit is usually added to the distribution system leading to PE areas.\n# b. Primary Prevention of Legionnaires Disease (No Cases Identified)\nThe primary and secondary environmental infection-control strategies described in this section on the guideline pertain to health-care facilities without transplant units. Infection-control measures specific to PE or transplant units (i.e., patient-care areas housing patients at the highest risk for morbidity and mortality from Legionella spp. infection) are described in the subsection titled Preventing Legionnaires Disease in Protective Environments.\nHealth-care facilities use at least two general strategies to prevent health-care associated legionellosis when no cases or only sporadic cases have been detected. The first is an environmental surveillance approach involving periodic culturing of water samples from the hospital's potable water system to monitor for Legionella spp. [747][748][749][750] If any sample is culture-positive, diagnostic testing is recommended for all patients with health-care associated pneumonia. 748,749 In-house testing is recommended for facilities with transplant programs as part of a comprehensive treatment/management program. If ≥30% of the samples are culture-positive for Legionella spp., decontamination of the facility's potable water system is warranted. 748 The premise for this approach is that no cases of health-care associated legionellosis can occur if Legionella spp. are not present in the potable water system, and, conversely, cases of health-care associated legionellosis could potentially occur if Legionella spp. are cultured from the water. 26,751 Physicians who are informed that the hospital's potable water system is culture-positive for Legionella spp. are more likely to order diagnostic tests for legionellosis.\nA potential advantage of the environmental surveillance approach is that periodic culturing of water is less costly than routine laboratory diagnostic testing for all patients who have health-care associated pneumonia. The primary argument against this approach is that, in the absence of cases, the relationship between water-culture results and legionellosis risk remains undefined. 3 Legionnella spp. can be present in the water systems of buildings 752 without being associated with known cases of disease. 437,707,753 In a study of 84 hospitals in Québec, 68% of the water systems were found to be colonized with Legionella spp., and 26% were colonized at >30% of sites sampled; cases of Legionnaires disease, however, were infrequently reported from these hospitals. 707 Other factors also argue against environmental surveillance. Interpretation of results from periodic water culturing might be confounded by differing results among the sites sampled in a single water system and by fluctuations in the concentration of Legionella spp. at the same site. 709,754 In addition, the risk for illness after exposure to a given source might be influenced by several factors other than the presence or concentration of organisms, including a. the degree to which contaminated water is aerosolized into respirable droplets, b. the proximity of the infectious aerosol to the potential host, c. the susceptibility of the host, and d. the virulence properties of the contaminating strain. [755][756][757] Thus, data are insufficient to assign a level of disease risk even on the basis of the number of colonyforming units detected in samples from areas for immunocompetent patients. Conducting environmental surveillance would obligate hospital administrators to initiate water-decontamination programs if Legionella spp. are identified. Therefore, periodic monitoring of water from the hospital's potable water system and from aerosol-producing devices is not widely recommended in facilities that have not experienced cases of health-care associated legionellosis. 661,758 The second strategy to prevent and control health-care associated legionellosis is a clinical approach, in which providers maintain a high index of suspicion for legionellosis and order appropriate diagnostic tests (i.e., culture, urine antigen, and direct fluorescent antibody [DFA] serology) for patients with health-care associated pneumonia who are at high risk for legionellosis and its complications. 437,759,760 The testing of autopsy specimens can be included in this strategy should a death resulting from healthcare-associated pneumonia occur. Identification of one case of definite or two cases of possible healthcare-associated Legionnaires disease should prompt an epidemiologic investigation for a hospital source of Legionella spp., which may involve culturing the facility's water for Legionella. Routine maintenance of cooling towers, and use of sterile water for the filling and terminal rinsing of nebulization devices and ventilation equipment can help to minimize potential sources of contamination. Circulating potable water temperatures should match those outlined in the subsection titled Water Temperature and Pressure, as permitted by state code.\n# c. Secondary Prevention of Legionnaires Disease (With Identified Cases)\nThe indications for a full-scale environmental investigation to search for and subsequently decontaminate identified sources of Legionella spp. in health-care facilities without transplant units have not been clarified; these indications would likely differ depending on the facility. Case categories for health-care associated Legionnaires disease in facilities without transplant units include definite cases (i.e., laboratory-confirmed cases of legionellosis that occur in patients who have been hospitalized continuously for ≥10 days before the onset of illness) and possible cases (i.e., laboratory-confirmed infections that occur 2-9 days after hospital admission). 3 In settings in which as few as one to three health-care associated cases are recognized over several months, intensified surveillance for Legionnaires disease has frequently identified numerous additional cases. 405,408,432,453,739,759,760 This finding suggests the need for a low threshold for initiating an investigation after laboratory confirmation of cases of healthcare associated legionellosis. When developing a strategy for responding to such a finding, however, infection-control personnel should consider the level of risk for health-care-associated acquisition of, and mortality from, Legionella spp. infection at their particular facility.\nAn epidemiologic investigation conducted to determine the source of Legionella spp. involves several important steps (Box 11). Laboratory assessment is crucial in supporting epidemiologic evidence of a link between human illness and a specific environmental source. 761 Strain determination from subtype analysis is most frequently used in these investigations. 410,[762][763][764] Once the environmental source is established and confirmed with laboratory support, supplemental water treatment strategies can be initiated as appropriate.\n# Box 11. Steps in an epidemiologic investigation for legionellosis\n• Review medical and microbiologic records. \n•\n# d. Preventing Legionnaires Disease in Protective Environments\nThis subsection outlines infection-control measures applicable to those health-care facilities providing care to severely immunocompromised patients. Indigenous microorganisms in the tap water of these facilities may pose problems for such patients. These measures are designed to prevent the generation of potentially infectious aerosols from water and the subsequent exposure of PE patients or other immunocompromised patients (e.g., transplant patients) (Table 17). Infection-control measures that address the use of water with medical equipment (e.g., ventilators, nebulizers, and equipment humidifiers) are described in other guidelines and publications. 3,455 If one case of laboratory-confirmed, health-care associated Legionnaires disease is identified in a patient in a solid-organ transplant program or in PE (i.e., an inpatient in PE for all or part of the 2-10 days prior to onset of illness) or if two or more laboratory-confirmed cases occur among patients who had visited an outpatient PE setting, the hospital should report the cases to the local and state health departments. The hospital should then initiate a thorough epidemiologic and environmental investigation to determine the likely environmental sources of Legionella spp. 9 The source of Legionella should be decontaminated or removed. Isolated cases may be difficult to investigate. Because transplant recipients are at substantially higher risk for disease and death from legionellosis compared with other hospitalized patients, periodic culturing for Legionella spp. in water samples from the potable water in the solid-organ transplant and/or PE unit can be performed as part of an overall strategy to prevent Legionnaires disease in PE units. 9,431,710,769 The optimal methodology (i.e., frequency and number of sites) for environmental surveillance cultures in PE units has not been determined, and the cost-effectiveness of this strategy has not been evaluated. Because transplant recipients are at high risk for Legionnaires disease and because no data are available to determine a safe concentration of legionellae organisms in potable water, the goal of environmental surveillance for Legionella spp. should be to maintain water systems with no detectable organisms. 9,431 Culturing for legionellae may be used to assess the effectiveness of water treatment or decontamination methods, a practice that provides benefits to both patients and health-care workers. 767,770 Format Change [November 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged. • Use water that is not contaminated with Legionella spp. for patients' sponge baths. 9 • Provide sterile water for drinking, tooth brushing, or for flushing nasogastric tubes. 9,412 • Perform supplemental treatment of the water for the unit. 732 • Consider periodic monitoring (i.e., culturing) of the unit water supply for Legionella spp. Protecting patient-care devices and instruments from inadvertent tap water contamination during room cleaning procedures is also important in any immunocompromised patient-care area. In a recent outbreak of gram-negative bacteremias among open-heart-surgery patients, pressure-monitoring equipment that was assembled and left uncovered overnight prior to the next day's surgeries was inadvertently contaminated with mists and splashing water from a hose-disinfectant system used for cleaning. 771 \n# Cooling Towers and Evaporative Condensers\nModern health-care facilities maintain indoor climate control during warm weather by use of cooling towers (large facilities) or evaporative condensers (smaller buildings). A cooling tower is a wet-type, evaporative heat transfer device used to discharge to the atmosphere waste heat from a building's air conditioning condensers (Figure 5). 772,773 Warm water from air-conditioning condensers is piped to the cooling tower where it is sprayed downward into a counter-or cross-current air flow. To accelerate heat transfer to the air, the water passes over the fill, which either breaks water into droplets or causes it to spread into a thin film. 772,773 Most systems use fans to move air through the tower, although some large industrial cooling towers rely on natural draft circulation of air. The cooled water from the tower is piped back to the condenser, where it again picks up heat generated during the process of chilling the system's refrigerant. The water is cycled back to the cooling tower to be cooled. Closed-circuit cooling towers and evaporative condensers are also evaporative heat-transfer devices. In these systems, the process fluid (e.g., water, ethylene glycol/water mixture, oil, or a condensing refrigerant) does not directly contact the cooling air, but is contained inside a coil assembly. 661 Water temperatures are approximate and may differ substantially according to system use and design. Warm water from the condenser (or chiller) is sprayed downward into a counter-or cross-current air flow. Water passes over the fill (a component of the system designed to increase the surface area of the water exposed to air), and heat from the water is transferred to the air. Some of the water becomes aerosolized during this process, although the volume of aerosol discharged to the air can be reduced by the placement of a drift eliminator. Water cooled in the tower returns to the heat source to cool refrigerant from the air conditioning unit.\nCooling towers and evaporative condensers incorporate inertial stripping devices called drift eliminators to remove water droplets generated within the unit. Although the effectiveness of these eliminators varies substantially depending on design and condition, some water droplets in the size range of <5 μm will likely leave the unit, and some larger droplets leaving the unit may be reduced to ≤5 μm by evaporation. Thus, even with proper operation, a cooling tower or evaporative condenser can generate and expel respirable water aerosols. If either the water in the unit's basin or the make-up water (added to replace water lost to evaporation) contains Legionella spp. or other waterborne microorganisms, these organisms can be aerosolized and dispersed from the unit. 774 Clusters of both Legionnaires disease and Pontiac fever have been traced to exposure to infectious water aerosols originating from cooling towers and evaporative condensers contaminated with Legionella spp. Although most of these outbreaks have been community-acquired episodes of pneumonia, [775][776][777][778][779][780][781][782] health-care associated Legionnaires disease has been linked to cooling tower aerosol exposure. 404,405 Contaminated aerosols from cooling towers on hospital premises gained entry to the buildings either through open windows or via air handling system intakes located near the tower equipment.\nCooling towers and evaporative condensers provide ideal ecological niches for Legionella spp. The typical temperature of the water in cooling towers ranges from 85°F-95°F (29°C-35°C), although temperatures can be above 120°F (49°C) and below 70°F (21°C) depending on system heat load, ambient temperature, and operating strategy. 661 An Australian study of cooling towers found that legionellae colonized or multiplied in towers with basin temperatures above 60.8°F (16°C), and multiplication became explosive at temperatures above 73.4°F (23°C). 783 Water temperature in closed-circuit cooling towers and evaporative condensers is similar to that in cooling towers. Considerable variation in the piping arrangement occurs. In addition, stagnant areas or dead legs may be difficult to clean or penetrate with biocides.\nSeveral documents address the routine maintenance of cooling towers, evaporative condensers, and whirlpool spas. 661, 784-787 They suggest following manufacturer's recommendations for cleaning and biocide treatment of these devices; all health-care facilities should ensure proper maintenance for their cooling towers and evaporative condensers, even in the absence of Legionella spp (Appendix C). Because cooling towers and evaporative condensers can be shut down during periods when air conditioning is not needed, this maintenance cleaning and treatment should be performed before starting up the system for the first time in the warm season. 782 Emergency decontamination protocols describing cleaning procedures and hyperchlorination for cooling towers have been developed for towers implicated in the transmission of legionellosis. 786, 787\n# Dialysis Water Quality and Dialysate\n\n# a. Rationale for Water Treatment in Hemodialysis\nHemodialysis, hemofiltration, and hemodiafiltration require special water-treatment processes to prevent adverse patient outcomes of dialysis therapy resulting from improper formulation of dialysate with water containing high levels of certain chemical or biological contaminants. The Association for the Advancement of Medical Instrumentation (AAMI) has established chemical and microbiologic standards for the water used to prepare dialysate, substitution fluid, or to reprocess hemodialyzers for renal replacement therapy. [788][789][790][791][792] The AAMI standards address: a. equipment and processes used to purify water for the preparation of concentrates and dialysate and the reprocessing of dialyzers for multiple use and b. the devices used to store and distribute this water. Future revisions to these standards may include hemofiltration and hemodiafiltration.\nWater treatment systems used in hemodialysis employ several physical and/or chemical processes either singly or in combination (Figure 6). These systems may be portable units or large systems that feed several rooms. In the United States, >97% of maintenance hemodialysis facilities use RO alone or in combination with deionization. 793 Many acute-care facilities use portable hemodialysis machines with attached portable water treatment systems that use either deionization or RO. These machines were exempted from earlier versions of AAMI recommendations, but given current knowledge about toxic exposures to and inflammatory processes in patients new to dialysis, these machines should now come into compliance with current AAMI recommendations for hemodialysis water and dialysate quality. 788,789 Previous recommendations were based on the assumption that acute-care patients did not experience the same degree of adverse effects from short-term, cumulative exposures to either chemicals or microbiologic agents present in hemodialysis fluids compared with the effects encountered by patients during chronic, maintenance dialysis. 788,789 Additionally, JCAHO is reviewing inpatient practices and record-keeping for dialysis (acute and maintenance) for adherence to AAMI standards and recommended practices. Neither the water used to prepare dialysate nor the dialysate itself needs to be sterile, but tap water can not be used without additional treatment. Infections caused by rapid-growing NTM (e.g., Mycobacterium chelonae and M. abscessus) present a potential risk to hemodialysis patients (especially those in hemodialyzer reuse programs) if disinfection procedures to inactivate mycobacteria in the water (lowlevel disinfection) and the hemodialyzers (high-level disinfection) are inadequate. 31,32,633 Other factors associated with microbial contamination in dialysis systems could involve the water treatment system, the water and dialysate distribution systems, and the type of hemodialyzer. 666,667,[794][795][796][797][798][799] Understanding the various factors and their influence on contamination levels is the key to preventing high levels of microbial contamination in dialysis therapy.\nIn several studies, pyrogenic reactions were demonstrated to have been caused by lipopolysaccharide or endotoxin associated with gram-negative bacteria. 794,[800][801][802][803] Early studies demonstrated that parenteral exposure to endotoxin at a concentration of 1 ng/kg body weight/hour was the threshold dose for producing pyrogenic reactions in humans, and that the relative potencies of endotoxin differ by bacterial species. 804,805 Gram-negative water bacteria (e.g., Pseudomonas spp.) have been shown to multiply rapidly in a variety of hospital-associated fluids that can be used as supply water for hemodialysis (e.g., distilled water, deionized water, RO water, and softened water) and in dialysate (a balanced salt solution made with this water). 806 Several studies have demonstrated that the attack rates of pyrogenic reactions are directly associated with the number of bacteria in dialysate. 666,667,807 These studies provided the rationale for setting the heterotrophic bacteria standards in the first AAMI hemodialysis guideline at ≤2,000 CFU/mL in dialysate and one log lower (≤200 CFU/mL) for the water used to prepare dialysate. 668,788 If the level of bacterial contamination exceeded 200 CFU/mL in water, this level could be amplified in the system and effectively constitute a high inoculum for dialysate at the start of a dialysis treatment. 807,808 Pyrogenic reactions did not appear to occur when the level of contamination was below 2,000 CFU/mL in dialysate unless the source of the endotoxin was exogenous to the dialysis system (i.e., present in the community water supply). Endotoxins in a community water supply have been linked to the development of pyrogenic reactions among dialysis patients. 794 Whether endotoxin actually crosses the dialyzer membrane is controversial. Several investigators have shown that bacteria growing in dialysate-generated products that could cross the dialyzer membrane. 809,810 Gram-negative bacteria growing in dialysate have produced endotoxins that in turn stimulated the production of anti-endotoxin antibodies in hemodialysis patients; 801,811 these data suggest that bacterial endotoxins, although large molecules, cross dialyzer membranes either intact or as fragments. The use of the very permeable membranes known as high-flux membranes (which allow large molecules [e.g., β2 microglobulin] to traverse the membrane) increases the potential for passage of endotoxins into the blood path. Several studies support this contention. In one such study, an increase in plasma endotoxin concentrations during dialysis was observed when patients were dialyzed against dialysate containing 10 3 -10 4 CFU/mL Pseudomonas spp. 812 In vitro studies using both radiolabeled lipopolysaccharide and biologic assays have demonstrated that biologically active substances derived from bacteria found in dialysate can cross a variety of dialyzer membranes. 802,[813][814][815][816] Patients treated with high-flux membranes have had higher levels of anti-endotoxin antibodies than subjects or patients treated with conventional membranes. 817 Finally, since 1989, 19%-22% of dialysis centers have reported pyrogenic reactions in the absence of septicemia. 818,819 Investigations of adverse outcomes among patients using reprocessed dialyzers have demonstrated a greater risk for developing pyrogenic reactions when the water used to reprocess these devices contained >6 ng/mL endotoxin and >10 4 CFU/mL bacteria. 820 In addition to the variability in endotoxin assays, host factors also are involved in determining whether a patient will mount a response to endotoxin. 803 Outbreak investigations of pyrogenic reactions and bacteremias associated with hemodialyzer reuse have demonstrated that pyrogenic reactions are prevented once the endotoxin level in the water used to reprocess the dialyzers is returned to below the AAMI standard level. 821 Reuse of dialyzers and use of bicarbonate dialysate, high-flux dialyzer membranes, or high-flux dialysis may increase the potential for pyrogenic reactions if the water in the dialysis setting does not meet standards. [796][797][798] Although investigators have been unable to demonstrate endotoxin transfer across dialyzer membranes, 803,822,823 the preponderance of reports now supports the ability of endotoxin to transfer across at least some high-flux membranes under some operating conditions. In addition to the acute risk of pyrogenic reactions, indirect evidence in increasingly demonstrating that chronic exposure to low amounts of endotoxin may play a role in some of the long-term complications of hemodialysis therapy. Patients treated with ultrafiltered dialysate for 5-6 months have demonstrated a decrease in serum β2 microglobulin concentrations and a decrease in markers of an inflammatory response. [824][825][826] In studies of longer duration, use of microbiologically ultrapure dialysate has been associated with a decreased incidence of β2 microglobulin-associated amyloidosis. 827,828 Although patient benefit likely is associated with the use of ultrapure dialysate, no consensus has been reached regarding the potential adoption of this as standard in the United States. Debate continues regarding the bacterial and endotoxin limits for dialysate. As advances in water treatment and hemodialysis processes occur, efforts are underway to move improved technology from the manufacturer out into the user community. Cost-benefit studies, however, have not been done, and substantially increased costs to implement newer water treatment modalities are anticipated.\nTo reconcile AAMI documents with current International Organization for Standardization (ISO) format, AAMI has determined that its hemodialysis standards will be discussed in the following four installments: RD 5 for hemodialysis equipment, RD 62 for product water quality, RD 47 for dialyzer reprocessing, and RD 52 for dialysate quality. The Renal Diseases and Dialysis Committee of AAMI is expected to finalize and promulgated the dialysate standard pertinent to the user community (RD 52), adopting by reference the bacterial and endotoxin limits in product water as currently outlined in the AAMI standard that applies to systems manufacturers (RD 62). At present, the user community should continue to observe water quality and dialysate standards as outlined in AAMI RD 5 (Hemodialysis Systems, 1992) and AAMI RD 47 (Reuse of Hemodialyzers, 1993) until the new RD 52 standard becomes available (Table 18). 789, 791 RD 47-1993).\nThe current AAMI standard directed at systems manufacturers (RD 62 [Water Treatment Equipment for Hemodialysis Applications, 2001]) now specifies that all product water used to prepare dialysate or to reprocess dialyzers for multiple use should contain <2 endotoxin units per milliliter (EU/mL). 792 A level of 2 EU/mL was chosen as the upper limit for endotoxin because this level is easily achieved with contemporary water treatment systems using RO and/or ultrafiltration. CDC has advocated monthly endotoxin testing along with microbiologic assays of water, because endotoxin activity may not correspond to the total heterotrophic plate counts. 829 Additionally, the current AAMI standard RD 62 for manufacturers includes action levels for product water. Because 48 hours can elapse between the time of sampling water for microbial contamination and the time when results are received, and because bacterial proliferation can be rapid, action levels for microbial counts and endotoxin concentrations are reported as 50 CFU/mL and 1 EU/mL, respectively, in this revision of the standard. 792 These recommendations will allow users to initiate corrective action before levels exceed the maximum levels established by the standard.\nIn hemodialysis, the net movement of water is from the blood to the dialysate, although within the dialyzer, local movement of water from the dialysate to the blood through the phenomenon of backfiltration may occur, particularly in dialyzers with highly permeable membranes. 830 In contrast, hemofiltration and hemodiaflltration feature infusion of large volumes of electrolyte solution (20-70 L) into the blood. Increasingly, this electrolyte solution is being prepared on-line from water and concentrate. Because of the large volumes of fluid infused, AAMI considered the necessity of setting more stringent requirements for water to be used in this application, but this organization has not yet established these because of lack of expert consensus and insufficient experience with on-line therapies in the United States. On-line hemofiltration and hemodiafiltration systems use sequential ultrafiltration as the final step in the preparation of infusion fluid. Several experts from AAMI concur that these point-ofuse ultrafiltration systems should be capable of further reducing the bacteria and endotoxin burden of solutions prepared from water meeting the requirements of the AAMI standard to a safe level for infusion.\n# b. Microbial Control Strategies\nThe strategy for controlling massive accumulations of gram-negative water bacteria and NTM in dialysis systems primarily involves preventing their growth through proper disinfection of water-treatment systems and hemodialysis machines. Gram-negative water bacteria, their associated lipopolysaccharides (bacterial endotoxins), and NTM ultimately come from the community water supply, and levels of these bacteria can be amplified depending on the water treatment system, dialysate distribution system, type of dialysis machine, and method of disinfection (Table 19). 634,794,831 Control strategies are designed to reduce levels of microbial contamination in water and dialysis fluid to relatively low levels but not to completely eradicate it.\n# Format Change [November 2016]:\nThe format of this section was changed to improve readability and accessibility. The content is unchanged. • Size Oversized diameter and length decrease fluid flow and increase bacterial reservoir for both treated water and centrally-prepared dialysate.\n# • Construction\nRough joints, dead ends, unused branches, and polyvinyl chloride (PVC) piping can act as bacterial reservoirs.\n# • Elevation\nOutlet taps should be located at the highest elevation to prevent loss of disinfectant; keep a recirculation loop in the system; flush unused ports routinely.\n# • Storage tanks\nTanks are undesirable because they act as a reservoir for water bacteria; if tanks are present, they must be routinely scrubbed and disinfected.\n# Dialysis machines\n• Single-pass Disinfectant should have contact with all parts of the machine that are exposed to water or dialysis fluid.\n# • Recirculating single-pass or recirculating (batch)\nRecirculating pumps and machine design allow for massive contamination levels if not properly disinfected; overnight chemical germicide treatment is recommended.\nTwo components of hemodialysis water distribution systems -pipes (particularly those made of polyvinyl chloride [PVC]) and storage tanks -can serve as reservoirs of microbial contamination. Hemodialysis systems frequently use pipes that are wider and longer than are needed to handle the required flow, which slows the fluid velocity and increases both the total fluid volume and the wetted surface area of the system. Gram-negative bacteria in fluids remaining in pipes overnight multiply rapidly and colonize the wet surfaces, producing bacterial populations and endotoxin quantities in proportion to the volume and surface area. Such colonization results in formation of protective biofilm that is difficult to remove and protects the bacteria from disinfection. 832 Routine (i.e., monthly), low-level disinfection of the pipes can help to control bacterial contamination of the distribution system. Additional measures to protect pipes from contaminations include a. situating all outlet taps at equal elevation and at the highest point of the system so that the disinfectant cannot drain from pipes by gravity before adequate contact time has elapsed and b. eliminating rough joints, dead-end pipes, and unused branches and taps that can trap fluid and serve as reservoirs of bacteria capable of continuously inoculating the entire volume of the system. 800\nMaintain a flow velocity of 3-5 ft/sec.\nA storage tank in the distribution system greatly increases the volume of fluid and surface area available and can serve as a niche for water bacteria. Storage tanks are therefore not recommended for use in dialysis systems unless they are frequently drained and adequately disinfected, including scrubbing the sides of the tank to remove bacterial biofilm. An ultrafilter should be used distal to the storage tank. 808,833 Microbiologic sampling of dialysis fluids is recommended because gram-negative bacteria can proliferate rapidly in water and dialysate in hemodialysis systems; high levels of these organisms place patients at risk for pyrogenic reactions or health-care associated infection. 667,668,808 Health-care facilities are advised to sample dialysis fluids at least monthly using standard microbiologic assay methods for waterborne microorganisms. 788,793,799,[834][835][836] Product water used to prepare dialysate and to reprocess hemodialyzers for reuse on the same patient should also be tested for bacterial endotoxin on a monthly basis. 792,829,837 (See Appendix C for information about water sampling methods for dialysis.)\nCross-contamination of dialysis machines and inadequate disinfection measures can facilitate the spread of waterborne organisms to patients. Steps should be taken to ensure that dialysis equipment is performing correctly and that all connectors, lines, and other components are specific for the equipment, in good repair, and properly in place. A recent outbreak of gram-negative bacteremias among dialysis patients was attributed to faulty valves in a drain port of the machine that allowed backflow of saline used to flush the dialyzer before patient use. 838,839 This backflow contaminated the drain priming connectors, which contaminated the blood lines and exposed the patients to high concentrations of gram-negative bacteria. Environmental infection control in dialysis settings also includes low-level disinfection of housekeeping surfaces and spot decontamination of spills of blood (see Environmental Services in Part I of this guideline for further information).\n# c. Infection-Control Issues in Peritoneal Dialysis\nPeritoneal dialysis (PD), most commonly administered as continuous ambulatory peritoneal dialysis (CAPD) and continual cycling peritoneal dialysis (CCPD), is the third most common treatment for end-stage renal disease (ESRD) in the United States, accounting for 12% of all dialysis patients. 840 Peritonitis is the primary complication of CAPD, with coagulase-negative staphylococci the most clinically significant causative organisms. 841 Other organisms that have been found to produce peritonitis include Staphylococcus aureus, Mycobacterium fortuitum, M. mucogenicum, Stenotrophomonas maltophilia, Burkholderia cepacia, Corynebacterium jeikeium, Candida spp., and other fungi. [842][843][844][845][846][847][848][849][850] Substantial morbidity is associated with peritoneal dialysis infections. Removal of peritoneal dialysis catheters usually is required for treatment of peritonitis caused by fungi, NTM, or other bacteria that are not cleared within the first several days of effective antimicrobial treatment. Furthermore, recurrent episodes of peritonitis may lead to fibrosis and loss of the dialysis membrane.\nMany reported episodes of peritonitis are associated with exit-site or tunneled catheter infections. Risk factors for the development of peritonitis in PD patients include 1. under dialysis, 2. immune suppression, 3. prolonged antimicrobial treatment, 4. patient age [more infections occur in younger patients and older hospitalized patients], 5. length of hospital stay, and 6. hypoalbuminemia. 844,851,852 Concern has been raised about infection risk associated with the use of automated cyclers in both inpatient and outpatient settings; however, studies suggest that PD patients who use automated cyclers have much lower infection rates. 853 One study noted that a closed-drainage system reduced the incidence of systemrelated peritonitis among intermittent peritoneal dialysis (IPD) patients from 3.6 to 1.5 cases/100 patient days. 854 The association of peritonitis with management of spent dialysate fluids requires additional study. Therefore, ensuring that the tip of the waste line is not submerged beneath the water level in a toilet or in a drain is prudent.\n# Ice Machines and Ice\nMicroorganisms may be present in ice, ice-storage chests, and ice-making machines. The two main sources of microorganisms in ice are the potable water from which it is made and a transferral of organisms from hands (Table 20). Ice from contaminated ice machines has been associated with patient colonization, blood stream infections, pulmonary and gastrointestinal illnesses, and pseudoinfections. 602,603,683,684,854,855 Microorganisms in ice can secondarily contaminate clinical specimens and medical solutions that require cold temperatures for either transport or holding. 601,620 An outbreak of surgical-site infections was interrupted when sterile ice was used in place of tap water ice to cool cardioplegia solutions. 601 Format Change [November 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged.\n# Table 20. Microorganisms and their sources in ice and ice machines\nFrom potable water • Legionella spp. 684,685,857,858 • Nontuberculous mycobacteria (NTM) 602,603,859 • Pseudomonas aeruginosa 859 • Burkholderia cepacia 859,860 • Stenotrophomonas maltophilia 860 • Flavobacterium spp. 860 From fecally-contaminated water • Norwalk virus [861][862][863] • Giardia lamblia 864 • Cryptosporidium parvum 685 From hand-transfer of organisms • Acinetobacter spp. 859 • Coagulase-negative staphylococci 859 • Salmonella enteriditis 865 • Cryptosporidium parvum 685 In a study comparing the microbial populations of hospital ice machines with organisms recovered from ice samples gathered from the community, samples from 27 hospital ice machines yielded low numbers (<10 CFU/mL) of several potentially opportunistic microorganisms, mainly gram-negative bacilli. 859 During the survey period, no health-care associated infections were attributed to the use of ice. Ice from community sources had higher levels of microbial contamination (75%-95% of 194 samples had total heterotrophic plate counts <500 CFU/mL, with the proportion of positive cultures dependent on the incubation temperature) and showed evidence of fecal contamination from the source water. 859 Thus, ice machines in health-care settings are no more heavily contaminated compared with ice machines in the community. If the source water for ice in a health-care facility is not fecally contaminated, then ice from clean ice machines and chests should pose no increased hazard for immunocompetent patients. Some waterborne bacteria found in ice could potentially be a risk to immunocompromised patients if they consume ice or drink beverages with ice. For example, Burkholderia cepacia in ice could present an infection risk for cystic fibrosis patients. 859,860 Therefore, protecting immunosuppressed and otherwise medically at-risk patients from exposure to tap water and ice potentially contaminated with opportunistic pathogens is prudent. 9 No microbiologic standards for ice, ice-making machines, or ice storage equipment have been established, although several investigators have suggested the need for such standards. 859,866 Culturing of ice machines is not routinely recommended, but it may be useful as part of an epidemiologic investigation. [867][868][869] Sampling might also help determine the best schedule for cleaning open ice-storage chests. Recommendations for a regular program of maintenance and disinfection have been published. [866][867][868][869] Health-care facilities are advised to clean ice-storage chests on a regular basis. Open ice chests may require a more frequent cleaning schedule compared with chests that have covers. Portable ice chests and containers require cleaning and low-level disinfection before the addition of ice intended for consumption. Ice-making machines may require less frequent cleaning, but their maintenance is important to proper performance. The manufacturer's instructions for both the proper method of cleaning and/or maintenance should be followed. These instructions may also recommend an EPA-registered disinfectant to ensure chemical potency, materials compatibility, and safety. In the event that instructions and suitable EPA-registered disinfectants are not available for this process, then a generic approach to cleaning, disinfecting, and maintaining ice machines and dispensers can be used (Box 12).\nIce and ice-making machines also may be contaminated via improper storage or handling of ice by patients and/or staff. 684-686, 855-858, 870 Suggested steps to avoid this means of contamination include a. minimizing or avoiding direct hand contact with ice intended for consumption, b. using a hard-surface scoop to dispense ice, and c. installing machines that dispense ice directly into portable containers at the touch of a control. 687,869 Box 12. General steps for cleaning and maintaining ice machines, dispensers, and storage chests*+ 1. Disconnect unit from power supply. 2. Remove and discard ice from bin or storage chest. 3. Allow unit to warm to room temperature. 4. Disassemble removable parts of machine that make contact with water to make ice. 5. Thoroughly clean machine and parts with water and detergent. 6. Dry external surfaces of removable parts before reassembling. 7. Check for any needed repair. 8. Replace feeder lines, as appropriate (e.g., when damaged, old, or difficult to clean). 9. Ensure presence of an air space in tubing leading from water inlet into water distribution system of machine. 10. Inspect for rodent or insect infestations under the unit and treat, as needed. 11. Check door gaskets (open compartment models) for evidence of leakage or dripping into the storage chest. 12. Clean the ice-storage chest or bin with fresh water and detergent; rinse with fresh tap water. 13. Sanitize machine by circulating a 50-100 parts per million (ppm) solution of sodium hypochlorite (i.e., 4-8 mL sodium hypochlorite/gallon of water) through the ice-making and storage systems for 2 hours (100 ppm solution), or 4 hours (50 ppm solution). 14. Drain sodium hypochlorite solutions and flush with fresh tap water. 15. Allow all surfaces of equipment to dry before returning to service. * Material in this box is adapted from reference 869. + These general guidelines should be used only where manufacturer-recommended methods and EPA-registered disinfectants are not available.\n# Hydrotherapy Tanks and Pools\n\n# a. General Information\nHydrotherapy equipment (e.g., pools, whirlpools, whirlpool spas, hot tubs, and physiotherapy tanks) traditionally has been used to treat patients with certain medical conditions (e.g., burns, 871,872 septic ulcers, lesions, amputations, 873 orthopedic impairments and injuries, arthritis, 874 and kidney lithotripsy). 654 Wound-care medicine is increasingly moving away from hydrotherapy, however, in favor of bedside pulsed-lavage therapy using sterile solutions for cleaning and irrigation. 492,[875][876][877][878] Several episodes of health-care associated infections have been linked to use of hydrotherapy equipment ( Infection control for hydrotherapy tanks, pools, or birthing tanks presents unique challenges because indigenous microorganisms are always present in the water during treatments. In addition, some studies have found free living amoebae (i.e., Naegleria lovaniensis), which are commonly found in association with Naegleria fowleri, in hospital hydrotherapy pools. 890 Although hydrotherapy is at times appropriate for patients with wounds, burns, or other types of non-intact skin conditions (determined on a case-bycase basis), this equipment should not be considered \"semi-critical\" in accordance with the Spaulding classification. 891 Microbial data to evaluate the risk of infection to patients using hydrotherapy pools and birthing tanks are insufficient. Nevertheless, health-care facilities should maintain stringent cleaning and disinfection practices in accordance with the manufacturer's instructions and with relevant scientific literature until data supporting more rigorous infection-control measures become available. Factors that should be considered in therapy decisions in this situation would include a. availability of alternative aseptic techniques for wound management and b. a risk-benefit analysis of using traditional hydrotherapy.\n# b. Hydrotherapy Tanks\nHydrotherapy tanks (e.g., whirlpools, Hubbard tanks and whirlpool bath tubs) are shallow tanks constructed of stainless steel, plexiglass, or tile. They are closed-cycle water systems with hydrojets to circulate, aerate, and agitate the water. The maximum water temperature range is 50°F-104°F (10°C-40°C). The warm water temperature, constant agitation and aeration, and design of the hydrotherapy tanks provide ideal conditions for bacterial proliferation if the equipment is not properly maintained, cleaned, and disinfected. The design of the hydrotherapy equipment should be evaluated for potential infection-control problems that can be associated with inaccessible surfaces that can be difficult to clean and/or remain wet in between uses (i.e., recessed drain plates with fixed grill plates). 887 Associated equipment (e.g., parallel bars, plinths, Hoyer lifts, and wheelchairs) can also be potential reservoirs of microorganisms, depending on the materials used in these items (i.e., porous vs. non-porous materials) and the surfaces that may become wet during use. Patients with active skin colonizations and wound infections can serve as sources of contamination for the equipment and the water. Contamination from spilled tub water can extend to drains, floors, and walls. [680][681][682][683] Health-care associated colonization or infection can result from exposure to endogenous sources of microorganisms (autoinoculation) or exogenous sources (via cross-contamination from other patients previously receiving treatment in the unit).\nAlthough some facilities have used tub liners to minimize environmental contamination of the tanks, the use of a tub liner does not eliminate the need for cleaning and disinfection. Draining these small pools and tanks after each patient use, thoroughly cleaning with a detergent, and disinfecting according to manufacturers' instructions have reduced bacterial contamination levels in the water from 10 4 CFU/mL to <10 CFU/mL. 892 A chlorine residual of 15 ppm in the water should be obtained prior to the patient's therapy session (e.g., by adding 15 grams of calcium hypochlorite 70% [e.g., HTH®] per 100 gallons of water). 892 A study of commercial and residential whirlpools found that superchlorination or draining, cleaning, disinfection, and refilling of whirlpools markedly reduced densities of Pseudomonas aeruginosa in whirlpool water. 893 The bacterial populations were rapidly replenished, however, when disinfectant concentrations dropped below recommended levels for recreational use (i.e., chlorine at 3.0 ppm or bromine at 6.0 ppm). When using chlorine, however, knowing whether the community drinking-water system is disinfected with chloramine is important, because municipal utilities adjust the pH of the water to the basic side to enhance chloramine formation. Because chlorine is not very effective at pH levels above 8, it may be necessary to re-adjust the pH of the water to a more acidic level. 894 A few reports describe the addition of antiseptic chemicals to hydrotherapy tank water, especially for burn patient therapy. [895][896][897] One study involving a minimal number of participants demonstrated a reduction in the number of Pseudomonas spp. and other gram-negative bacteria from both patients and equipment surfaces when chloramine-T (\"chlorazene\") was added to the water. 898 Chloramine-T has not, however, been approved for water treatment in the United States.\n# c. Hydrotherapy Pools\nHydrotherapy pools typically serve large numbers of patients and are usually heated to 91.4°F-98.6°F (31°C-37°C). The temperature range is more narrow (94°F-96.8°F [35°C-36°C]) for pediatric and geriatric patient use. 899 Because the size of hydrotherapy pools precludes draining after patient use, proper management is required to maintain the proper balance of water conditioning (i.e., alkalinity, hardness, and temperature) and disinfection. The most widely used chemicals for disinfection of pools are chlorine and chlorine compounds -calcium hypochlorite, sodium hypochlorite, lithium hypochlorite, chloroisocyanurates, and chlorine gas. Solid and liquid formulations of chlorine chemicals are the easiest and safest to use. 900 Other halogenated compounds have also been used for pool-water disinfection, albeit on a limited scale. Bromine, which forms bactericidal bromamines in the presence of ammonia, has limited use because of its association with contact dermatitis. 901 Iodine does not bleach hair, swim suits, or cause eye irritation, but when introduced at proper concentrations, it gives water a greenish-yellowish cast. 892 In practical terms, maintenance of large hydrotherapy pools (e.g., those used for exercise) is similar to that for indoor public pools (i.e., continuous filtration, chlorine residuals no less than 0.4 ppm, and pH of 7.2-7.6). 902,903 Supply pipes and pumps also need to be maintained to eliminate the possibility of this equipment serving as a reservoir for waterborne organisms. 904 Specific standards for chlorine residual and pH of the water are addressed in local and state regulations. Patients who are fecally incontinent or who have draining wounds should refrain from using these pools until their condition improves.\n# d. Birthing Tanks and Other Equipment\nThe use of birthing tanks, whirlpool spas, and whirlpools is a recent addition to obstetrical practice. 905 Few studies on the potential risks associated with these pieces of equipment have been conducted. In one study of 32 women, a newborn contracted a Pseudomonas infection after being birthed in such a tank, the strain of which was identical to the organism isolated from the tank water. 906 Another report documented identical strains of P. aeruginosa isolates from a newborn with sepsis and on the environmental surfaces of a tub that the mother used for relaxation while in labor. 907 Other studies have shown no significant increases in the rates of post-immersion infections among mothers and infants. 908,909 Because the water and the tub surfaces routinely become contaminated with the mother's skin flora and blood during labor and delivery, birthing tanks and other tub equipment must be drained after each patient use and the surfaces thoroughly cleaned and disinfected. Health-care facilities are advised to follow the manufacturer's instructions for selection of disinfection method and chemical germicide. The range of chlorine residuals for public whirlpools and whirlpool spas is 2-5 ppm. 910 Use of an inflatable tub is an alternative solution, but this item must be cleaned and disinfected between patients if it is not considered a single-use unit.\nRecreational tanks and whirlpool spas are increasingly being used as hydrotherapy equipment. Although such home equipment appears to be suitable for hydrotherapy, they are neither designed nor constructed to function in this capacity. Additionally, manufacturers generally are not obligated to provide the healthcare facility with cleaning and disinfecting instructions appropriate for medical equipment use, and the U.S. Food and Drug Administration (FDA) does not evaluate recreational equipment. Health-care facilities should therefore carefully evaluate this \"off-label\" use of home equipment before proceeding with a purchase.\n# Miscellaneous Medical/Dental Equipment Connected to Main Water Systems a. Automated Endoscope Reprocessors\nThe automated endoscopic reprocessor (AER) is classified by the FDA as an accessory for the flexible endoscope. 654 A properly operating AER can provide a more consistent, reliable method of decontaminating and terminal reprocessing for endoscopes between patient procedures than manual reprocessing methods alone. 911 An endoscope is generally subjected to high-level disinfection using a liquid chemical sterilant or a high-level disinfectant. Because the instrument is a semi-critical device, the optimal rinse fluid for a disinfected endoscope would be sterile water. 3 Sterile water, however, is expensive and difficult to produce in sufficient quantities and with adequate quality assurance for instrument rinsing in an AER. 912,913 Therefore, one option to be used for AERs is rinse water that has been passed through filters with a pore size of 0.1-0.2 μm to render the water \"bacteria-free.\" These filters usually are located in the water line at or near the port where the mains water enters the equipment. The product water (i.e., tap water passing through these filters) in these applications is not considered equivalent in microbial quality to that for membrane-filtered water as produced by pharmaceutical firms. Membrane filtration in pharmaceutical applications is intended to ensure the microbial quality of polished product water.\nWater has been linked to the contamination of flexible fiberoptic endoscopes in the following two scenarios: a. rinsing a disinfected endoscope with unfiltered tap water, followed by storage of the instrument without drying out the internal channels and b. contamination of AERs from tap water inadvertently introduced into the equipment.\nIn the latter instance, the machine's water reservoirs and fluid circuitry become contaminated with waterborne, heterotrophic bacteria (e.g., Pseudomonas aeruginosa and NTM), which can survive and persist in biofilms attached to these components. [914][915][916][917] Colonization of the reservoirs and water lines of the AER becomes problematic if the required cleaning, disinfection, and maintenance are not performed on the equipment as recommended by the manufacturer. 669,916,917 Use of the 0.1-0.2-μm filter in the water line helps to keep bacterial contamination to a minimum, 670,911,917 but filters may fail and allow bacteria to pass through to the equipment and then to the instrument undergoing reprocessing. 671-674, 913, 918 Filters also require maintenance for proper performance. 670,911,912,918,919 Heightened awareness of the proper disinfection of the connectors that hook the instrument to the AER may help to further reduce the potential for contaminating endoscopes during reprocessing. 920 An emerging issue in the field of endoscopy is that of the possible role of rinse water monitoring and its potential to help reduce endoscopy/bronchoscopyassociated infections. 918 Studies have linked deficiencies in endoscope cleaning and/or disinfecting processes to the incidence of post-endoscopic adverse outcomes. [921][922][923][924] Several clusters have been traced to AERs of older designs and these were associated with water quality. 675,[914][915][916] Regardless of whether manual or automated terminal reprocessing is used for endoscopes, the internal channels of the instrument should be dried before storage. 925 The presence of residual moisture in the internal channels encourages the proliferation of waterborne microorganisms, some of which may be pathogenic. One of the most frequently used methods employs 70% isopropyl alcohol to flush the internal channels, followed by forced air drying of these channels and hanging the endoscope vertically in a protected cabinet; this method ensures internal drying of the endoscope, lessens the potential for proliferation of waterborne microorganisms, 669,913,917,922,926,927 and is consistent with professional organization guidance for endoscope reprocessing. 928 An additional problem with waterborne microbial contamination of AERs centers on increased microbial resistance to alkaline glutaraldehyde, a widely used liquid chemical sterilant/high-level disinfectant. 669,929 Opportunistic waterborne microorganisms (e.g., Mycobacterium chelonae, Methylobacterium spp.) have been associated with pseudo-outbreaks and colonization; infection caused by these organisms has been associated with procedures conducted in clinical settings (e.g., bronchoscopy). 669,913,[929][930][931] Increasing microbial resistance to glutaraldehyde has been attributed to improper use of the disinfectant in the equipment, allowing the dilution of glutaraldehyde to fall below the manufacturer's recommended minimal use concentration. 929 \n# b. Dental Unit Water Lines\nDental unit water lines (DUWLs) consist of small-bore plastic tubing that delivers water used for general, non-surgical irrigation and as a coolant to dental handpieces, sonic and ultrasonic scalers, and air-water syringes; municipal tap water is the source water for these lines. The presence of biofilms of waterborne bacteria and fungi (e.g., Legionella spp., Pseudomonas aeruginosa, and NTM) in DUWLs has been established. 636,637,694,695,[932][933][934] Biofilms continually release planktonic microorganisms into the water, the titers of which can exceed 1H10 6 CFU/mL. 694 However, scientific evidence indicates that immunocompetent persons are only at minimal risk for substantial adverse health effects after contact with water from a dental unit. Nonetheless, exposing patients or dental personnel to water of uncertain microbiological quality is not consistent with universally accepted infection-control principles. 935 In 1993, CDC issued guidelines relative to water quality in a dental setting. These guidelines recommend that all dental instruments that use water (including high-speed handpieces) should be run to discharge water for 20-30 seconds after each patient and for several minutes before the start of each clinic day. 936 This practice can help to flush out any patient materials that many have entered the turbine, air, or waterlines. 937,938 The 1993 guidance also indicated that waterlines be flushed at the beginning of the clinic day. Although these guidelines are designed to help reduce the number of microorganisms present in treatment water, they do not address the issue of reducing or preventing biofilm formation in the waterlines. Research published subsequent to the 1993 dental infection control guideline suggests that flushing the lines at the beginning of the day has only minimal effect on the status of the biofilm in the lines and does not reliably improve the quality of water during dental treatment. [939][940][941] Updated recommendations on infection-control practices for water line use in dentistry will be available in late 2003. 942 The numbers of microorganisms in water used as coolant or irrigant for non-surgical dental treatment should be as low as reasonably achievable and, at a minimum, should meet nationally recognized standards for safe drinking water. 935,943 Only minimal evidence suggests that water meeting drinking water standards poses a health hazard for immunocompetent persons. The EPA, the American Public Health Association (APHA), and the American Water Works Association (AWWA) have set a maximum limit of 500 CFU/mL for aerobic, heterotrophic, mesophilic bacteria in drinking water in municipal distribution systems. 944,945 This standard is achievable, given improvements in water-line technology. Dentists should consult with the manufacturer of their dental unit to determine the best equipment and method for maintaining and monitoring good water quality. 935,946 \n# E. Environmental Services 1. Principles of Cleaning and Disinfecting Environmental Surfaces\nAlthough microbiologically contaminated surfaces can serve as reservoirs of potential pathogens, these surfaces generally are not directly associated with transmission of infections to either staff or patients. The transferral of microorganisms from environmental surfaces to patients is largely via hand contact with the surface. 947,948 Although hand hygiene is important to minimize the impact of this transfer, cleaning and disinfecting environmental surfaces as appropriate is fundamental in reducing their potential contribution to the incidence of healthcare-associated infections.\nThe principles of cleaning and disinfecting environmental surfaces take into account the intended use of the surface or item in patient care. CDC retains the Spaulding classification for medical and surgical instruments, which outlines three categories based on the potential for the instrument to transmit infection if the instrument is microbiologically contaminated before use. 949,950 These categories are \"critical,\" \"semicritical,\" and \"noncritical.\" In 1991, CDC proposed an additional category designated \"environmental surfaces\" to Spaulding's original classification 951 to represent surfaces that generally do not come into direct contact with patients during care. Environmental surfaces carry the least risk of disease transmission and can be safely decontaminated using less rigorous methods than those used on medical instruments and devices. Environmental surfaces can be further divided into medical equipment surfaces (e.g., knobs or handles on hemodialysis machines, x-ray machines, instrument carts, and dental units) and housekeeping surfaces (e.g., floors, walls, and tabletops). 951 The following factors influence the choice of disinfection procedure for environmental surfaces: a. the nature of the item to be disinfected, b. the number of microorganisms present, c. the innate resistance of those microorganisms to the inactivating effects of the germicide, d. the amount of organic soil present, e. the type and concentration of germicide used, f. duration and temperature of germicide contact, and g. if using a proprietary product, other specific indications and directions for use. 952,953 Cleaning is the necessary first step of any sterilization or disinfection process. Cleaning is a form of decontamination that renders the environmental surface safe to handle or use by removing organic matter, salts, and visible soils, all of which interfere with microbial inactivation. [954][955][956][957][958][959][960] The physical action of scrubbing with detergents and surfactants and rinsing with water removes large numbers of microorganisms from surfaces. 957 If the surface is not cleaned before the terminal reprocessing procedures are started, the success of the sterilization or disinfection process is compromised.\nSpaulding proposed three levels of disinfection for the treatment of devices and surfaces that do not require sterility for safe use. These disinfection levels are \"high-level,\" \"intermediate-level,\" and \"low level.\" 949,950 The basis for these levels is that microorganisms can usually be grouped according to their innate resistance to a spectrum of physical or chemical germicidal agents (Table 22). This information, coupled with the instrument/surface classification, determines the appropriate level of terminal disinfection for an instrument or surface. The process of high-level disinfection, an appropriate standard of treatment for heat-sensitive, semicritical medical instruments (e.g., flexible, fiberoptic endoscopes), inactivates all vegetative bacteria, mycobacteria, viruses, fungi, and some bacterial spores. High-level disinfection is accomplished with powerful, sporicidal chemicals (e.g., glutaraldehyde, peracetic acid, and hydrogen peroxide) that are not appropriate for use on housekeeping surfaces. These liquid chemical sterilants/high-level disinfectants are highly toxic. [961][962][963] Use of these chemicals for applications other than those indicated in their label instructions (i.e., as immersion chemicals for treating heat-sensitive medical instruments) is not appropriate. 964 Intermediate-level disinfection does not necessarily kill bacterial spores, but it does inactivate Mycobacterium tuberculosis var. bovis, which is substantially more resistant to chemical germicides than ordinary vegetative bacteria, fungi, and medium to small viruses (with or without lipid envelopes). Chemical germicides with sufficient potency to achieve intermediate-level disinfection include chlorine-containing compounds (e.g., sodium hypochlorite), alcohols, some phenolics, and some iodophors. Low-level disinfection inactivates vegetative bacteria, fungi, enveloped viruses (e.g., human immunodeficiency virus [HIV], and influenza viruses), and some non-enveloped viruses (e.g., adenoviruses). Low-level disinfectants include quaternary ammonium compounds, some phenolics, and some iodophors. Sanitizers are agents that reduce the numbers of bacterial contaminants to safe levels as judged by public health requirements, and are used in cleaning operations, particularly in food service and dairy applications. Germicidal chemicals that have been approved by FDA as skin antiseptics are not appropriate for use as environmental surface disinfectants. 951 The selection and use of chemical germicides are largely matters of judgment, guided by product label instructions, information, and regulations. Liquid sterilant chemicals and high-level disinfectants intended for use on critical and semi-critical medical/dental devices and instruments are regulated exclusively by the FDA as a result of recent memoranda of understanding between FDA and the EPA that delineates agency authority for chemical germicide regulation. 965,966 A common misconception in the use of surface disinfectants in health-care settings relates to the underlying purpose for use of proprietary products labeled as a \"tuberculocidal\" germicide. Such products will not interrupt and prevent the transmission of TB in health-care settings because TB is not acquired from environmental surfaces. The tuberculocidal claim is used as a benchmark by which to measure germicidal potency. Because mycobacteria have the highest intrinsic level of resistance among the vegetative bacteria, viruses, and fungi, any germicide with a tuberculocidal claim on the label (i.e., an intermediate-level disinfectant) is considered capable of inactivating a broad spectrum of pathogens, including much less resistant organisms such the bloodborne pathogens (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], and HIV). It is this broad spectrum capability, rather than the product's specific potency against mycobacteria, that is the basis for protocols and OSHA regulations indicating the appropriateness of using tuberculocidal chemicals for surface disinfection. 967\n# General Cleaning Strategies for Patient-Care Areas\nThe number and types of microorganisms present on environmental surfaces are influenced by the following factors: a. number of people in the environment, b. amount of activity, c. amount of moisture, d. presence of material capable of supporting microbial growth, e. rate at which organisms suspended in the air are removed, and f. type of surface and orientation [i.e., horizontal or vertical]. 968 Strategies for cleaning and disinfecting surfaces in patient-care areas take into account a. potential for direct patient contact, b. degree and frequency of hand contact, and c. potential contamination of the surface with body substances or environmental sources of microorganisms (e.g., soil, dust, and water).\n# a. Cleaning of Medical Equipment\nManufacturers of medical equipment should provide care and maintenance instructions specific to their equipment. These instructions should include information about a. the equipments' compatibility with chemical germicides, b. whether the equipment is water-resistant or can be safely immersed for cleaning, and c. how the equipment should be decontaminated if servicing is required. 967 In the absence of manufacturers' instructions, non-critical medical equipment (e.g., stethoscopes, blood pressure cuffs, dialysis machines, and equipment knobs and controls) usually only require cleansing followed by low-to intermediate-level disinfection, depending on the nature and degree of contamination.\nEthyl alcohol or isopropyl alcohol in concentrations of 60%-90% (v/v) is often used to disinfect small surfaces (e.g., rubber stoppers of multiple-dose medication vials, and thermometers) 952, 969 and occasionally external surfaces of equipment (e.g., stethoscopes and ventilators). However, alcohol evaporates rapidly, which makes extended contact times difficult to achieve unless items are immersed, a factor that precludes its practical use as a large-surface disinfectant. 951 Alcohol may cause discoloration, swelling, hardening, and cracking of rubber and certain plastics after prolonged and repeated use and may damage the shellac mounting of lenses in medical equipment. 970 Barrier protection of surfaces and equipment is useful, especially if these surfaces are a. touched frequently by gloved hands during the delivery of patient care, b. likely to become contaminated with body substances, or c. difficult to clean. Impervious-backed paper, aluminum foil, and plastic or fluid-resistant covers are suitable for use as barrier protection.\nAn example of this approach is the use of plastic wrapping to cover the handle of the operatory light in dental-care settings. 936,942 Coverings should be removed and discarded while the health-care worker is still gloved. 936,942 The health-care worker, after ungloving and performing hand hygiene, must cover these surfaces with clean materials before the next patient encounter.\n# b. Cleaning Housekeeping Surfaces\nHousekeeping surfaces require regular cleaning and removal of soil and dust. Dry conditions favor the persistence of gram-positive cocci (e.g., coagulase-negative Staphylococcus spp.) in dust and on surfaces, whereas moist, soiled environments favor the growth and persistence of gram-negative bacilli. 948,971,972 Fungi are also present on dust and proliferate in moist, fibrous material.\nMost, if not all, housekeeping surfaces need to be cleaned only with soap and water or a detergent/disinfectant, depending on the nature of the surface and the type and degree of contamination.\nCleaning and disinfection schedules and methods vary according to the area of the health-care facility, type of surface to be cleaned, and the amount and type of soil present. Disinfectant/detergent formulations registered by EPA are used for environmental surface cleaning, but the actual physical removal of microorganisms and soil by wiping or scrubbing is probably as important, if not more so, than any antimicrobial effect of the cleaning agent used. 973 Therefore, cost, safety, product-surface compatibility, and acceptability by housekeepers can be the main criteria for selecting a registered agent. If using a proprietary detergent/disinfectant, the manufacturers' instructions for appropriate use of the product should be followed. 974 Consult the products' material safety data sheets (MSDS) to determine appropriate precautions to prevent hazardous conditions during product application. Personal protective equipment (PPE) used during cleaning and housekeeping procedures should be appropriate to the task.\nHousekeeping surfaces can be divided into two groups -those with minimal hand-contact (e.g., floors, and ceilings) and those with frequent hand-contact (\"high touch surfaces\"). The methods, thoroughness, and frequency of cleaning and the products used are determined by health-care facility policy. 6 However, high-touch housekeeping surfaces in patient-care areas (e.g., doorknobs, bedrails, light switches, wall areas around the toilet in the patient's room, and the edges of privacy curtains) should be cleaned and/or disinfected more frequently than surfaces with minimal hand contact. Infection-control practitioners typically use a risk-assessment approach to identify high-touch surfaces and then coordinate an appropriate cleaning and disinfecting strategy and schedule with the housekeeping staff.\nHorizontal surfaces with infrequent hand contact (e.g., window sills and hard-surface flooring) in routine patient-care areas require cleaning on a regular basis, when soiling or spills occur, and when a patient is discharged from the facility. 6 Regular cleaning of surfaces and decontamination, as needed, is also advocated to protect potentially exposed workers. 967 Cleaning of walls, blinds, and window curtains is recommended when they are visibly soiled. 972,973,975 Disinfectant fogging is not recommended for general infection control in routine patient-care areas. 2,976 Further, paraformaldehyde, which was once used in this application, is no longer registered by EPA for this purpose. Use of paraformaldehyde in these circumstances requires either registration or an exemption issued by EPA under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). Infection control, industrial hygienists, and environmental services supervisors should assess the cleaning procedures, chemicals used, and the safety issues to determine if a temporary relocation of the patient is needed when cleaning in the room.\nExtraordinary cleaning and decontamination of floors in health-care settings is unwarranted. Studies have demonstrated that disinfection of floors offers no advantage over regular detergent/water cleaning and has minimal or no impact on the occurrence of health-care associated infections. 947,948,[977][978][979][980] Additionally, newly cleaned floors become rapidly recontaminated from airborne microorganisms and those transferred from shoes, equipment wheels, and body substances. 971,975,981 Nevertheless, healthcare institutions or contracted cleaning companies may choose to use an EPA-registered detergent/disinfectant for cleaning low-touch surfaces (e.g., floors) in patient-care areas because of the difficulty that personnel may have in determining if a spill contains blood or body fluids (requiring a detergent/disinfectant for clean-up) or when a multi-drug resistant organism is likely to be in the environment. Methods for cleaning non-porous floors include wet mopping and wet vacuuming, dry dusting with electrostatic materials, and spray buffing. 973,[982][983][984] Methods that produce minimal mists and aerosols or dispersion of dust in patient-care areas are preferred. 9,20,109,272 Part of the cleaning strategy is to minimize contamination of cleaning solutions and cleaning tools. Bucket solutions become contaminated almost immediately during cleaning, and continued use of the solution transfers increasing numbers of microorganisms to each subsequent surface to be cleaned. 971,981,985 Cleaning solutions should be replaced frequently. A variety of \"bucket\" methods have been devised to address the frequency with which cleaning solutions are replaced. 986,987 Another source of contamination in the cleaning process is the cleaning cloth or mop head, especially if left soaking in dirty cleaning solutions. 971,[988][989][990] Laundering of cloths and mop heads after use and allowing them to dry before re-use can help to minimize the degree of contamination. 990 A simplified approach to cleaning involves replacing soiled cloths and mop heads with clean items each time a bucket of detergent/disinfectant is emptied and replaced with fresh, clean solution (B. Stover, Kosair Children's Hospital, 2000). Disposable cleaning cloths and mop heads are an alternative option, if costs permit.\nAnother reservoir for microorganisms in the cleaning process may be dilute solutions of the detergents or disinfectants, especially if the working solution is prepared in a dirty container, stored for long periods of time, or prepared incorrectly. 547 Gram-negative bacilli (e.g., Pseudomonas spp. and Serratia marcescens) have been detected in solutions of some disinfectants (e.g., phenolics and quaternary ammonium compounds). 547,991 Contemporary EPA registration regulations have helped to minimize this problem by asking manufacturers to provide potency data to support label claims for detergent/disinfectant properties under real-use conditions (e.g., diluting the product with tap water instead of distilled water). Application of contaminated cleaning solutions, particularly from small-quantity aerosol spray bottles or with equipment that might generate aerosols during operation, should be avoided, especially in high-risk patient areas. 992,993 Making sufficient fresh cleaning solution for daily cleaning, discarding any remaining solution, and drying out the container will help to minimize the degree of bacterial contamination. Containers that dispense liquid as opposed to spray-nozzle dispensers (e.g., quart-sized dishwashing liquid bottles) can be used to apply detergent/disinfectants to surfaces and then to cleaning cloths with minimal aerosol generation. A pre-mixed, \"ready-to-use\" detergent/disinfectant solution may be used if available.\n# c. Cleaning Special Care Areas\nGuidelines have been published regarding cleaning strategies for isolation areas and operating rooms. 6,7 The basic strategies for areas housing immunosuppressed patients include a. wet dusting horizontal surfaces daily with cleaning cloths pre-moistened with detergent or an EPAregistered hospital disinfectant or disinfectant wipes; 94, 98463 b. using care when wet dusting equipment and surfaces above the patient to avoid patient contact with the detergent/disinfectant; c. avoiding the use of cleaning equipment that produces mists or aerosols; d. equipping vacuums with HEPA filters, especially for the exhaust, when used in any patient-care area housing immunosuppressed patients; 9, 94, 986 and e. regular cleaning and maintenance of equipment to ensure efficient particle removal.\nWhen preparing the cleaning cloths for wet-dusting, freshly prepared solutions of detergents or disinfectants should be used rather than cloths that have soaked in such solutions for long periods of time. Dispersal of microorganisms in the air from dust or aerosols is more problematic in these settings than elsewhere in health-care facilities. Vacuum cleaners can serve as dust disseminators if they are not operating properly. 994 Doors to immunosuppressed patients' rooms should be closed when nearby areas are being vacuumed. 9 Bacterial and fungal contamination of filters in cleaning equipment is inevitable, and these filters should be cleaned regularly or replaced as per equipment manufacturer instructions.\nMats with tacky surfaces placed in operating rooms and other patient-care areas only slightly minimize the overall degree of contamination of floors and have little impact on the incidence rate of health-careassociated infection in general. 351,971,983 An exception, however, is the use of tacky mats inside the entry ways of cordoned-off construction areas inside the health-care facility; these mats help to minimize the intrusion of dust into patient-care areas.\nSpecial precautions for cleaning incubators, mattresses, and other nursery surfaces have been recommended to address reports of hyperbilirubinemia in newborns linked to inadequately diluted solutions of phenolics and poor ventilation. [995][996][997] These medical conditions have not, however, been associated with the use of properly prepared solutions of phenolics. Non-porous housekeeping surfaces in neonatal units can be disinfected with properly diluted or pre-mixed phenolics, followed by rinsing with clean water. 997 However, phenolics are not recommended for cleaning infant bassinets and incubators during the stay of the infant. Infants who remain in the nursery for an extended period should be moved periodically to freshly cleaned and disinfected bassinets and incubators. 997 If phenolics are used for cleaning bassinets and incubators after they have been vacated, the surfaces should be rinsed thoroughly with water and dried before either piece of equipment is reused. Cleaning and disinfecting protocols should allow for the full contact time specified for the product used. Bassinet mattresses should be replaced, however, if the mattress cover surface is broken. 997\n# Cleaning Strategies for Spills of Blood and Body Substances\nNeither HBV, HCV, nor HIV has ever been transmitted from a housekeeping surface (i.e., floors, walls, or countertops). Nonetheless, prompt removal and surface disinfection of an area contaminated by either blood or body substances are sound infection-control practices and OSHA requirements. 967 Studies have demonstrated that HIV is inactivated rapidly after being exposed to commonly used chemical germicides at concentrations that are much lower than those used in practice. [998][999][1000][1001][1002][1003] HBV is readily inactivated with a variety of germicides, including quaternary ammonium compounds. 1004 Embalming fluids (e.g., formaldehyde) are also capable of completely inactivating HIV and HBV. 1005,1006 OSHA has revised its regulation for disinfecting spills of blood or other potentially infectious material to include proprietary products whose label includes inactivation claims for HBV and HIV, provided that such surfaces have not become contaminated with agent(s) or volumes of or concentrations of agent(s) for which a higher level of disinfection is recommended. 1007 These registered products are listed in EPA's List D -Registered Antimicrobials Effective Against Hepatitis B Virus and Human HIV-1, which may include products tested against duck hepatitis B virus (DHBV) as a surrogate for HBV. 1008,1009 Additional lists of interest include EPA's List C -Registered Antimicrobials Effective Against Human HIV-1 and EPA's List E -Registered Antimicrobials Effective Against Mycobacterium spp., Hepatitis B Virus, and Human HIV-1.\nSodium hypochlorite solutions are inexpensive and effective broad-spectrum germicidal solutions. 1010,1011 Generic sources of sodium hypochlorite include household chlorine bleach or reagent grade chemical. Concentrations of sodium hypochlorite solutions with a range of 5,000-6,150 ppm (1:10 v/v dilution of household bleaches marketed in the United States) to 500-615 ppm (1:100 v/v dilution) free chlorine are effective depending on the amount of organic material (e.g., blood, mucus, and urine) present on the surface to be cleaned and disinfected. 1010, 1011 EPA-registered chemical germicides may be more compatible with certain materials that could be corroded by repeated exposure to sodium hypochlorite, especially the 1:10 dilution. Appropriate personal protective equipment (e.g., gloves and goggles) should be worn when preparing and using hypochlorite solutions or other chemical germicides. 967 Despite laboratory evidence demonstrating adequate potency against bloodborne pathogens (e.g., HIV and HBV), many chlorine bleach products available in grocery and chemical-supply stores are not registered by the EPA for use as surface disinfectants. Use of these chlorine products as surface disinfectants is considered by the EPA to be an \"unregistered use.\" EPA encourages the use of registered products because the agency reviews them for safety and performance when the product is used according to label instructions. When unregistered products are used for surface disinfection, users do so at their own risk.\nStrategies for decontaminating spills of blood and other body fluids differ based on the setting in which they occur and the volume of the spill. 1010 In patient-care areas, workers can manage small spills with cleaning and then disinfecting using an intermediate-level germicide or an EPA-registered germicide from the EPA List D or E. 967,1007 For spills containing large amounts of blood or other body substances, workers should first remove visible organic matter with absorbent material (e.g., disposable paper towels discarded into leak-proof, properly labeled containment) and then clean and decontaminate the area. 1002, 1003, 1012 If the surface is nonporous and a generic form of a sodium hypochlorite solution is used (e.g., household bleach), a 1:100 dilution is appropriate for decontamination assuming that a. the worker assigned to clean the spill is wearing gloves and other personal protective equipment appropriate to the task, b. most of the organic matter of the spill has been removed with absorbent material, and c. the surface has been cleaned to remove residual organic matter.\nA recent study demonstrated that even strong chlorine solutions (i.e., 1:10 dilution of chlorine bleach) may fail to totally inactivate high titers of virus in large quantities of blood, but in the absence of blood these disinfectants can achieve complete viral inactivation. 1011 This evidence supports the need to remove most organic matter from a large spill before final disinfection of the surface. Additionally, EPAregistered proprietary disinfectant label claims are based on use on a pre-cleaned surface. 951,954 Managing spills of blood, body fluids, or other infectious materials in clinical, public health, and research laboratories requires more stringent measures because of a. the higher potential risk of disease transmission associated with large volumes of blood and body fluids and b. high numbers of microorganisms associated with diagnostic cultures.\nThe use of an intermediate-level germicide for routine decontamination in the laboratory is prudent. 954 Recommended practices for managing large spills of concentrated infectious agents in the laboratory include a. confining the contaminated area, b. flooding the area with a liquid chemical germicide before cleaning, and c. decontaminating with fresh germicidal chemical of at least intermediate-level disinfectant potency. 1010 A suggested technique when flooding the spill with germicide is to lay absorbent material down on the spill and apply sufficient germicide to thoroughly wet both the spill and the absorbent material. 1013 If using a solution of household chlorine bleach, a 1:10 dilution is recommended for this purpose. EPAregistered germicides should be used according to the manufacturers' instructions for use dilution and contact time. Gloves should be worn during the cleaning and decontamination procedures in both clinical and laboratory settings. PPE in such a situation may include the use of respiratory protection (e.g., an N95 respirator) if clean-up procedures are expected to generate infectious aerosols. Protocols for cleaning spills should be developed and made available on record as part of good laboratory practice. 1013 Workers in laboratories and in patient-care areas of the facility should receive periodic training in environmentalsurface infection-control strategies and procedures as part of an overall infection-control and safety curriculum.\n# Carpeting and Cloth Furnishings a. Carpeting\nCarpeting has been used for more than 30 years in both public and patient-care areas of health-care facilities. Advantages of carpeting in patient-care areas include a. its noise-limiting characteristics b. the \"humanizing\" effect on health care; and c. its contribution to reductions in falls and resultant injuries, particularly for the elderly. [1014][1015][1016] Compared to hard-surface flooring, however, carpeting is harder to keep clean, especially after spills of blood and body substances. It is also harder to push equipment with wheels (e.g., wheelchairs, carts, and gurneys) on carpeting.\nSeveral studies have documented the presence of diverse microbial populations, primarily bacteria and fungi, in carpeting; 111, 1017-1024 the variety and number of microorganisms tend to stabilize over time. New carpeting quickly becomes colonized, with bacterial growth plateauing after about 4 weeks. 1019 Vacuuming and cleaning the carpeting can temporarily reduce the numbers of bacteria, but these populations soon rebound and return to pre-cleaning levels. 1019,1020,1023 Bacterial contamination tends to increase with higher levels of activity. [1018][1019][1020]1025 Soiled carpeting that is or remains damp or wet provides an ideal setting for the proliferation and persistence of gram-negative bacteria and fungi. 1026 Carpeting that remains damp should be removed, ideally within 72 hours.\nDespite the evidence of bacterial growth and persistence in carpeting, only limited epidemiologic evidence demonstrates that carpets influence health-care associated infection rates in areas housing immunocompetent patients. 1023,1025,1027 This guideline, therefore, includes no recommendations against the use of carpeting in these areas. Nonetheless, avoiding the use of carpeting is prudent in areas where spills are likely to occur (e.g., laboratories, areas around sinks, and janitor closets) and where patients may be at greater risk of infection from airborne environmental pathogens (e.g., HSCT units, burn units, ICUs, and ORs). 111,1028 An outbreak of aspergillosis in an HSCT unit was recently attributed to carpet contamination and a particular method of carpet cleaning. 111 A window in the unit had been opened repeatedly during the time of a nearby building fire, which allowed fungal spore intrusion into the unit. After the window was sealed, the carpeting was cleaned using a \"bonnet buffing\" machine, which dispersed Aspergillus spores into the air. 111 Wet vacuuming was instituted, replacing the dry cleaning method used previously; no additional cases of invasive aspergillosis were identified.\nThe care setting and the method of carpet cleaning are important factors to consider when attempting to minimize or prevent production of aerosols and dispersal of carpet microorganisms into the air. 94,111 Both vacuuming and shampooing or wet cleaning with equipment can disperse microorganisms to the air. 111,994 Vacuum cleaners should be maintained to minimize dust dispersal in general, and be equipped with HEPA filters, especially for use in high-risk patient-care areas. 9, 94, 986 Some formulations of carpetcleaning chemicals, if applied or used improperly, can be dispersed into the air as a fine dust capable of causing respiratory irritation in patients and staff. 1029 Cleaning equipment, especially those that engage in wet cleaning and extraction, can become contaminated with waterborne organisms (e.g., Pseudomonas aeruginosa) and serve as a reservoir for these organisms if this equipment is not properly maintained. Substantial numbers of bacteria can then be transferred to carpeting during the cleaning process. 1030 Therefore, keeping the carpet cleaning equipment in good repair and allowing such equipment to dry between uses is prudent.\nCarpet cleaning should be performed on a regular basis determined by internal policy. Although spills of blood and body substances on non-porous surfaces require prompt spot cleaning using standard cleaning procedures and application of chemical germicides, 967 similar decontamination approaches to blood and body substance spills on carpeting can be problematic from a regulatory perspective. 1031 Most, if not all, modern carpet brands suitable for public facilities can tolerate the activity of a variety of liquid chemical germicides. However, according to OSHA, carpeting contaminated with blood or other potentially infectious materials cannot be fully decontaminated. 1032 Therefore, facilities electing to use carpeting for high-activity patient-care areas may choose carpet tiles in areas at high risk for spills. 967,1032 In the event of contamination with blood or other body substances, carpet tiles can be removed, discarded, and replaced. OSHA also acknowledges that only minimal direct skin contact occurs with carpeting, and therefore, employers are expected to make reasonable efforts to clean and sanitize carpeting using carpet detergent/cleaner products. 1032 Over the last few years, some carpet manufacturers have treated their products with fungicidal and/or bactericidal chemicals. Although these chemicals may help to reduce the overall numbers of bacteria or fungi present in carpet, their use does not preclude the routine care and maintenance of the carpeting. Limited evidence suggests that chemically treated carpet may have helped to keep health-care-associated aspergillosis rates low in one HSCT unit, 111 but overall, treated carpeting has not been shown to prevent the incidence of health-care associated infections in care areas for immunocompetent patients.\n# b. Cloth Furnishings\nUpholstered furniture and furnishings are becoming increasingly common in patient-care areas. These furnishings range from simple cloth chairs in patients' rooms to a complete decorating scheme that gives the interior of the facility more the look of an elegant hotel. 1033 Even though pathogenic microorganisms have been isolated from the surfaces of cloth chairs, no epidemiologic evidence suggests that general patient-care areas with cloth furniture pose increased risks of health-care associated infection compared with areas that contain hard-surfaced furniture. 1034,1035 Allergens (e.g., dog and cat dander) have been detected in or on cloth furniture in clinics and elsewhere in hospitals in concentrations higher than those found on bed linens. 1034,1035 These allergens presumably are transferred from the clothing of visitors. Researchers have therefore suggested that cloth chairs should be vacuumed regularly to keep the dust and allergen levels to a minimum. This recommendation, however, has generated concerns that aerosols created from vacuuming could place immunocompromised patients or patients with preexisting lung disease (e.g., asthma) at risk for development of health-care associated, environmental airborne disease. 9, 20, 109, 988 Recovering worn, upholstered furniture (especially the seat cushion) with covers that are easily cleaned (e.g., vinyl), or replacing the item is prudent; minimizing the use of upholstered furniture and furnishings in any patient-care areas where immunosuppressed patients are located (e.g., HSCT units) reduces the likelihood of disease. 9\n# Flowers and Plants in Patient-Care Areas\nFresh flowers, dried flowers, and potted plants are common items in health-care facilities. In 1974, clinicians isolated an Erwinia sp. post mortem from a neonate diagnosed with fulminant septicemia, meningitis, and respiratory distress syndrome. 1038 Because Erwinia spp. are plant pathogens, plants brought into the delivery room were suspected to be the source of the bacteria, although the case report did not definitively establish a direct link. Several subsequent studies evaluated the numbers and diversity of microorganisms in the vase water of cut flowers. These studies revealed that high concentrations of bacteria, ranging from 10 4 -10 10 CFU/mL, were often present, especially if the water was changed infrequently. 515,702,1039 The major group of microorganisms in flower vase water was gram-negative bacteria, with Pseudomonas aeruginosa the most frequently isolated organism. 515, 702, 1039, 1040 P. aeruginosa was also the primary organism directly isolated from chrysanthemums and other potted plants. 1041,1042 However, flowers in hospitals were not significantly more contaminated with bacteria compared with flowers in restaurants or in the home. 702 Additionally, no differences in the diversity and degree of antibiotic resistance of bacteria have been observed in samples isolated from hospital flowers versus those obtained from flowers elsewhere. 702 Despite the diversity and large numbers of bacteria associated with flower-vase water and potted plants, minimal or no evidence indicates that the presence of plants in immunocompetent patient-care areas poses an increased risk of health-care associated infection. 515 In one study involving a limited number of surgical patients, no correlation was observed between bacterial isolates from flowers in the area and the incidence and etiology of postoperative infections among the patients. 1040 Similar conclusions were reached in a study that examined the bacteria found in potted plants. 1042 Nonetheless, some precautions for general patient-care settings should be implemented, including a. limiting flower and plant care to staff with no direct patient contact, b. advising health-care staff to wear gloves when handling plants, c. washing hands after handling plants, d. changing vase water every 2 days and discharging the water into a sink outside the immediate patient environment, and e. cleaning and disinfecting vases after use. 702 Some researchers have examined the possibility of adding a chemical germicide to vase water to control bacterial populations. Certain chemicals (e.g., hydrogen peroxide and chlorhexidine) are well tolerated by plants. 1040,1043,1044 Use of these chemicals, however, was not evaluated in studies to assess impact on health-care associated infection rates. Modern florists now have a variety of products available to add to vase water to extend the life of cut flowers and to minimize bacterial clouding of the water.\nFlowers (fresh and dried) and ornamental plants, however, may serve as a reservoir of Aspergillus spp., and dispersal of conidiospores into the air from this source can occur. 109 Health-care associated outbreaks of invasive aspergillosis reinforce the importance of maintaining an environment as free of Aspergillus spp. spores as possible for patients with severe, prolonged neutropenia. Potted plants, fresh-cut flowers, and dried flower arrangements may provide a reservoir for these fungi as well as other fungal species (e.g., Fusarium spp.). 109,1045,1046 Researchers in one study of bacteria and flowers suggested that flowers and vase water should be avoided in areas providing care to medically at-risk patients (e.g., oncology patients and transplant patients), although this study did not attempt to correlate the observations of bacterial populations in the vase water with the incidence of health-care associated infections. 515 Another study using molecular epidemiology techniques demonstrated identical Aspergillus terreus types among environmental and clinical specimens isolated from infected patients with hematological malignancies. 1046 Therefore, attempts should be made to exclude flowers and plants from areas where immunosuppressed patients are be located (e.g., HSCT units). 9, 1046\n# Pest Control\nCockroaches, flies and maggots, ants, mosquitoes, spiders, mites, midges, and mice are among the typical arthropod and vertebrate pest populations found in health-care facilities. Insects can serve as agents for the mechanical transmission of microorganisms, or as active participants in the disease transmission process by serving as a vector. [1047][1048][1049] Arthropods recovered from health-care facilities have been shown to carry a wide variety of pathogenic microorganisms. [1050][1051][1052][1053][1054][1055][1056] Studies have suggested that the diversity of microorganisms associated with insects reflects the microbial populations present in the indoor health-care environment; some pathogens encountered in insects from hospitals were either absent from or present to a lesser degree in insects trapped from residential settings. [1057][1058][1059][1060] Some of the microbial populations associated with insects in hospitals have demonstrated resistance to antibiotics. 1048,1059,[1061][1062][1063] Insect habitats are characterized by warmth, moisture, and availability of food. 1064 Insects forage in and feed on substrates, including but not limited to food scraps from kitchens/cafeteria, foods in vending machines, discharges on dressings either in use or discarded, other forms of human detritis, medical wastes, human wastes, and routine solid waste. [1057][1058][1059][1060][1061] Cockroaches, in particular, have been known to feed on fixed sputum smears in laboratories. 1065,1066 Both cockroaches and ants are frequently found in the laundry, central sterile supply departments, and anywhere in the facility where water or moisture is present (e.g., sink traps, drains and janitor closets). Ants will often find their way into sterile packs of items as they forage in a warm, moist environment. 1057 Cockroaches and other insects frequent loading docks and other areas with direct access to the outdoors.\nAlthough insects carry a wide variety of pathogenic microorganisms on their surfaces and in their gut, the direct association of insects with disease transmission (apart from vector transmission) is limited, especially in health-care settings; the presence of insects in itself likely does not contribute substantially to health-care associated disease transmission in developed countries. However, outbreaks of infection attributed to microorganisms carried by insects may occur because of infestation coupled with breaks in standard infection-control practices. 1063 Studies have been conducted to examine the role of houseflies as possible vectors for shigellosis and other forms of diarrheal disease in non-health-care settings. 1046, 1067 When control measures aimed at reducing the fly population density were implemented, a concomitant reduction in the incidence of diarrheal infections, carriage of Shigella organisms, and mortality caused by diarrhea among infants and young children was observed.\nMyiasis is defined as a parasitosis in which the larvae of any of a variety of flies use living or necrotic tissue or body substances of the host as a nutritional source. 1068 Larvae from health-care acquired myiasis have been observed in nares, wounds, eyes, ears, sinuses, and the external urogenital structures. [1069][1070][1071] Patients with this rare condition are typically older adults with underlying medical conditions (e.g., diabetes, chronic wounds, and alcoholism) who have a decreased capacity to ward off the flies. Persons with underlying conditions who live or travel to tropical regions of the world are especially at risk. 1070,1071 Cases occur in the summer and early fall months in temperate climates when flies are most active. 1071 An environmental assessment and review of the patient's history are necessary to verify that the source of the myiasis is health-care acquired and to identify corrective measures. 1069,1072 Simple prevention measures (e.g., installing screens on windows) are important in reducing the incidence of myiasis. 1072 From a public health and hygiene perspective, arthropod and vertebrate pests should be eradicated from all indoor environments, including health-care facilities. 1073,1074 Modern approaches to institutional pest management usually focus on a. eliminating food sources, indoor habitats, and other conditions that attract pests b. excluding pests from the indoor environments; and c. applying pesticides as needed. 1075 Sealing windows in modern health-care facilities helps to minimize insect intrusion. When windows need to be opened for ventilation, ensuring that screens are in good repair and closing doors to the outside can help with pest control. Insects should be kept out of all areas of the health-care facility, especially ORs and any area where immunosuppressed patients are located. A pest-control specialist with appropriate credentials can provide a regular insect-control program that is tailored to the needs of the facility and uses approved chemicals and/or physical methods. Industrial hygienists can provide information on possible adverse reactions of patients and staff to pesticides and suggest alternative methods for pest control, as needed. ) represent crucial and growing concerns for infection control. Although the term GISA is technically a more accurate description of the strains isolated to date (most of which are classified as having intermediate resistance to both vancomycin and teicoplanin), the term \"glycopeptide\" may not be recognized by many clinicians. Thus, the label of VISA, which emphasizes a change in minimum inhibitory concentration (MICs) to vancomycin, is similar to that of VRE and is more meaningful to clinicians. 1076 According to National Nosocomial Infection Surveillance (NNIS) statistics for infections acquired among ICU patients in the United States in 1999, 52.3% of infections resulting from S. aureus were identified as MRSA infections, and 25.2% of enterococcal infections were attributed to VRE. These figures reflect a 37% and a 43% increase, respectively, since 1994-1998. 1077 People represent the primary reservoir of S. aureus. 1078 Although S. aureus has been isolated from a variety of environmental surfaces (e.g., stethoscopes, floors, charts, furniture, dry mops, and hydrotherapy tanks), the role of environmental contamination in transmission of this organism in health care appears to be minimal. [1079][1080][1081][1082] S. aureus contamination of surfaces and tanks within burn therapy units, however, may be a major factor in the transmission of infection among burn patients. 1083 Colonized patients are the principal reservoir of VRE, and patients who are immunosuppressed (e.g., transplant patients) or otherwise medically at-risk (e.g., ICU patients, cardio-thoracic surgical patients, patients previously hospitalized for extended periods, and those having received multi-antimicrobial or vancomycin therapy) are at greatest risk for VRE colonization. [1084][1085][1086][1087] The mechanisms by which crosscolonization take place are not well defined, although recent studies have indicated that both MRSA and VRE may be transmitted either a. directly from patient to patient, b. indirectly by transient carriage on the hands of health-care workers, 1088-1091 or c. by hand transfer of these gram-positive organisms from contaminated environmental surfaces and patient-care equipment. 1084,1087,[1092][1093][1094][1095][1096][1097] In one survey, hand carriage of VRE in workers in a long-term care facility ranged from 13%-41%. 1098 Many of the environmental surfaces found to be contaminated with VRE in outbreak investigations have been those that are touched frequently by the patient or the health-care worker. 1099 Such high-touch surfaces include bedrails, doorknobs, bed linens, gowns, overbed tables, blood pressure cuffs, computer table, bedside tables, and various medical equipment. 22,1087,1094,1095,[1100][1101][1102] Contamination of environmental surfaces with VRE generally occurs in clinical laboratories and areas where colonized patients are present, 1087, 1092, 1094, 1095, 1103 but the potential for contamination increases when such patients have diarrhea 1087 or have multiple body-site colonization. 1104 Additional factors that can be important in the dispersion of these pathogens to environmental surfaces are misuse of glove techniques by healthcare workers (especially when cleaning fecal contamination from surfaces) and patient, family, and visitor hygiene.\n# Special Pathogen Concerns a. Antibiotic-Resistant Gram-Positive Cocci\nInterest in the importance of environmental reservoirs of VRE increased when laboratory studies demonstrated that enterococci can persist in a viable state on dry environmental surfaces for extended periods of time (7 days to 4 months) 1099,1105 and multiple strains can be identified during extensive periods of surveillance. 1104 VRE can be recovered from inoculated hands of health-care workers (with or without gloves) for up to 60 minutes. 22 The presence of either MRSA, VISA, or VRE on environmental surfaces, however, does not mean that patients in the contaminated areas will become colonized. Strict adherence to hand hygiene/handwashing and the proper use of barrier precautions help to minimize the potential for spread of these pathogens. Published recommendations for preventing the spread of vancomycin resistance address isolation measures, including patient cohorting and management of patient-care items. 5 Direct patient-care items (e.g., blood pressure cuffs) should be disposable whenever possible when used in contact isolation settings for patients with multiply resistant microorganisms. 1102 1114,1115 These represented isolated cases, and neither the family members nor the health-care providers of these case-patients had evidence of colonization or infection with VRSA. Conventional environmental infection-control measures (i.e., cleaning and then disinfecting surfaces using EPA-registered disinfectants with label claims for S. aureus) were used during the environmental investigation of these two cases; 1110-1112 however, studies have yet to evaluate the potential intrinsic resistance of these VRSA strains to surface disinfectants.\nStandard procedures during terminal cleaning and disinfection of surfaces, if performed incorrectly, may be inadequate for the elimination of VRE from patient rooms. 1113,[1116][1117][1118] Given the sensitivity of VRE to hospital disinfectants, current disinfecting protocols should be effective if they are diligently carried out and properly performed. Health-care facilities should be sure that housekeeping staff use correct procedures for cleaning and disinfecting surfaces in VRE-contaminated areas, which include using sufficient amounts of germicide at proper use dilution and allowing adequate contact time. 1118\n# b. Clostridium difficile\nClostridium difficile is the most frequent etiologic agent for health-care associated diarrhea. 1119,1120 In one hospital, 30% of adults who developed health-care associated diarrhea were positive for C. difficile. 1121 One recent study employing PCR-ribotyping techniques demonstrated that cases of C. difiicile-acquired diarrhea occurring in the hospital included patients whose infections were attributed to endogenous C. difficile strains and patients whose illnesses were considered to be health-care-associated infections. 1122 Most patients remain asymptomatic after infection, but the organism continues to be shed in their stools. Risk factors for acquiring C. difficile-associated infection include a. exposure to antibiotic therapy, particularly with beta-lactam agents; 1123 b. gastrointestinal procedures and surgery; 1124 c. advanced age; and d. indiscriminate use of antibiotics. [1125][1126][1127][1128] Of all the measures that have been used to prevent the spread of C. difficile-associated diarrhea, the most successful has been the restriction of the use of antimicrobial agents. 1129,1130 C. difficile is an anaerobic, gram-positive bacterium. Normally fastidious in its vegetative state, it is capable of sporulating when environmental conditions no longer support its continued growth. The capacity to form spores enables the organism to persist in the environment (e.g., in soil and on dry surfaces) for extended periods of time. Environmental contamination by this microorganism is well known, especially in places where fecal contamination may occur. 1131 The environment (especially housekeeping surfaces) rarely serves as a direct source of infection for patients. 1024,[1132][1133][1134][1135][1136] However, direct exposure to contaminated patient-care items (e.g., rectal thermometers) and high-touch surfaces in patients' bathrooms (e.g., light switches) have been implicated as sources of infection. 1130,1135,1136,1138 Transfer of the pathogen to the patient via the hands of health-care workers is thought to be the most likely mechanism of exposure. 24,1133,1139 Standard isolation techniques intended to minimize enteric contamination of patients, health-care-workers' hands, patient-care items, and environmental surfaces have been published. 1140 Handwashing remains the most effective means of reducing hand contamination. Proper use of gloves is an ancillary measure that helps to further minimize transfer of these pathogens from one surface to another.\nThe degree to which the environment becomes contaminated with C. difficile spores is proportional to the number of patients with C. difficile-associated diarrhea, 24,1132,1135 although asymptomatic, colonized patients may also serve as a source of contamination. Few studies have examined the use of specific chemical germicides for the inactivation of C. difficile spores, and no well-controlled trials have been conducted to determine efficacy of surface disinfection and its impact on health-care associated diarrhea. Some investigators have evaluated the use of chlorine-containing chemicals (e.g., 1,000 ppm hypochlorite at recommended use-dilution, 5,000 ppm sodium hypochlorite [1:10 v/v dilution], 1:100 v/v dilutions of unbuffered hypochlorite, and phosphate-buffered hypochlorite [1,600 ppm]). One of the studies demonstrated that the number of contaminated environmental sites was reduced by half, 1135 whereas another two studies demonstrated declines in health-care associated C. difficile infections in a HSCT unit 1141 and in two geriatric medical units 1142 during a period of hypochlorite use. The presence of confounding factors, however, was acknowledged in one of these studies. 1142 The recommended approach to environmental infection control with respect to C. difficile is meticulous cleaning followed by disinfection using hypochlorite-based germicides as appropriate. 952,1130,1143 However, because no EPAregistered surface disinfectants with label claims for inactivation of C. difficile spores are available, the recommendation is based on the best available evidence from the scientific literature.\n# c. Respiratory and Enteric Viruses in Pediatric-Care Settings\nAlthough the viruses mentioned in this guideline are not unique to the pediatric-care setting in healthcare facilities, their prevalence in these areas, especially during the winter months, is substantial. Children (particularly neonates) are more likely to develop infection and substantial clinical disease from these agents compared with adults and therefore are more likely to require supportive care during their illness.\nCommon respiratory viruses in pediatric-care areas include rhinoviruses, respiratory syncytial virus (RSV), adenoviruses, influenza viruses, and parainfluenza viruses. Transmission of these viruses occurs primarily via direct contact with small-particle aerosols or via hand contamination with respiratory secretions that are then transferred to the nose or eyes. Because transmission primarily requires close personal contact, contact precautions are appropriate to interrupt transmission. 6 Hand contamination can occur from direct contact with secretions or indirectly from touching high-touch environmental surfaces that have become contaminated with virus from large droplets. The indirect transfer of virus from one persion to other via hand contact with frequently-touched fomites was demonstrated in a study using a bacteriophage whose environmental stability approximated that of human viral pathogens (e.g., poliovirus and parvovirus). 1144 The impact of this mode of transmission with respect to human respiratory-and enteric viruses is dependent on the ability of these agents to survive on environmental surfaces. Infectious RSV has been recovered from skin, porous surfaces, and non-porous surfaces after 30 minutes, 1 hour, and 7 hours, respectively. 1145 Parainfluenza viruses are known to persist for up to 4 hours on porous surfaces and up to 10 hours on non-porous surfaces. 1146 Rhinoviruses can persist on porous surfaces and non-porous surfaces for approximately 1 and 3 hours respectively; study participants in a controlled environment became infected with rhinoviruses after first touching a surface with dried secretions and then touching their nasal or conjunctival mucosa. 1147 Although the efficiency of direct transmission of these viruses from surfaces in uncontrolled settings remains to be defined, these data underscore the basis for maintaining regular protocols for cleaning and disinfecting of high-touch surfaces.\nThe clinically important enteric viruses encountered in pediatric care settings include enteric adenovirus, astroviruses, caliciviruses, and rotavirus. Group A rotavirus is the most common cause of infectious diarrhea in infants and children. Transmission of this virus is primarily fecal-oral, however, the role of fecally contaminated surfaces and fomites in rotavirus transmission is unclear. During one epidemiologic investigation of enteric disease among children attending day care, rotavirus contamination was detected on 19% of inanimate objects in the center. 1148,1149 In an outbreak in a pediatric unit, secondary cases of rotavirus infection clustered in areas where children with rotaviral diarrhea were located. 1150 Astroviruses cause gastroenteritis and diarrhea in newborns and young children and can persist on fecally contaminated surfaces for several months during periods of relatively low humidity. 1151,1152 Outbreaks of small roundstructured viruses (i.e., caliciviruses [Norwalk virus and Norwalk-like viruses]) can affect both patients and staff, with attack rates of ≥50%. 1153 Routes of person-to-person transmission include fecal-oral spread and aerosols generated from vomiting. [1154][1155][1156] Fecal contamination of surfaces in care settings can spread large amounts of virus to the environment. Studies that have attempted to use low-and intermediate-level disinfectants to inactivate rotavirus suspended in feces have demonstrated a protective effect of high concentrations of organic matter. 1157,1158 Intermediate-level disinfectants (e.g., alcoholic quaternary ammonium compounds, and chlorine solutions) can be effective in inactivating enteric viruses provided that a cleaning step to remove most of the organic matter precedes terminal disinfection. 1158 These findings underscore the need for proper cleaning and disinfecting procedures where contamination of environmental surfaces with body substances is likely. EPA-registered surface disinfectants with label claims for these viral agents should be used in these settings. Using disposable, protective barrier coverings may help to minimize the degree of surface contamination. 936\n# d. Severe Acute Respiratory Syndrome (SARS) Virus\nIn November 2002 an atypical pneumonia of unknown etiology emerged in Asia and subsequently developed into an international outbreak of respiratory illness among persons in 29 countries during the first six months of 2003. \"Severe acute respiratory syndrome\" (SARS) is a viral upper respiratory infection associated with a newly described coronavirus (SARS-associated Co-V [SARS-CoV]). SARS-CoV is an enveloped RNA virus. It is present in high titers in respiratory secretions, stool, and blood of infected persons. The modes of transmission determined from epidemiologic investigations were primarily forms of direct contact (i.e., large droplet aerosolization and person-to-person contact). Respiratory secretions were presumed to be the major source of virus in these situations; airborne transmission of virus has not been completely ruled out. Little is known about the impact of fecal-oral transmission and SARS.\nThe epidemiology of SARS-CoV infection is not completely understood, and therefore recommended infection control and prevention measures to contain the spread of SARS will evolve as new information becomes available. 1159 At present there is no indication that established strategies for cleaning (i.e., to remove the majority of bioburden) and disinfecting equipment and environmental surfaces need to be changed for the environmental infection control of SARS. In-patient rooms housing SARS patients should be cleaned and disinfected at least daily and at the time of patient transfer or discharge. More frequent cleaning and disinfection may be indicated for high-touch surfaces and following aerosolproducing procedures (e.g., intubation, bronchoscopy, and sputum production). While there are presently no disinfectant products registered by EPA specifically for inactivation of SARS-CoV, EPA-registered hospital disinfectants that are equivalent to low-and intermediate-level germicides may be used on precleaned, hard, non-porous surfaces in accordance with manufacturer's instructions for environmental surface disinfection. Monitoring adherence to guidelines established for cleaning and disinfection is an important component of environmental infection control to contain the spread of SARS.\n# e. Creutzfeldt-Jakob Disease (CJD) in Patient-Care Areas\nCreutzfeldt-Jakob disease (CJD) is a rare, invariably fatal, transmissible spongiform encephalopathy (TSE) that occurs worldwide with an average annual incidence of 1 case per million population. [1160][1161][1162] CJD is one of several TSEs affecting humans; other diseases in this group include kuru, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker syndrome. A TSE that affects a younger population (compared to the age range of CJD cases) has been described primarily in the United Kingdom since 1996. 1163 This variant form of CJD (vCJD) is clinically and neuropathologically distinguishable from classic CJD; epidemiologic and laboratory evidence suggests a causal association for bovine spongiform encephalopathy (BSE [Mad Cow disease]) and vCJD. [1163][1164][1165][1166] The agent associated with CJD is a prion, which is an abnormal isoform of a normal protein constituent of the central nervous system. [1167][1168][1169] The mechanism by which the normal form of the protein is converted to the abnormal, disease-causing prion is unknown. The tertiary conformation of the abnormal prion protein appears to confer a heightened degree of resistance to conventional methods of sterilization and disinfection. 1170,1171 Although about 90% of CJD cases occur sporadically, a limited number of cases are the result of a direct exposure to prion-containing material (usually central nervous system tissue or pituitary hormones) acquired as a result of health care (iatrogenic cases). These cases have been linked to a. pituitary hormone therapy [from human sources as opposed to hormones prepared through the use of recombinant technology], 1170-1174 b. transplants of either dura mater or corneas, [1175][1176][1177][1178][1179][1180][1181] and c. neurosurgical instruments and depth electrodes. [1182][1183][1184][1185] In the cases involving instruments and depth electrodes, conventional cleaning and terminal reprocessing methods of the day failed to fully inactivate the contaminating prions and are considered inadequate by today's standards.\nPrion inactivation studies involving whole tissues and tissue homogenates have been conducted to determine the parameters of physical and chemical methods of sterilization or disinfection necessary for complete inactivation; 1170, 1186-1191 however, the application of these findings to environmental infection control in health-care settings is problematic. No studies have evaluated the effectiveness of medical instrument reprocessing in inactivating prions. Despite a consensus that abnormal prions display some extreme measure of resistance to inactivation by either physical or chemical methods, scientists disagree about the exact conditions needed for sterilization. Inactivation studies utilizing whole tissues present extraordinary challenges to any sterilizing method. 1192 Additionally, the experimental designs of these studies preclude the evaluation of surface cleaning as a part of the total approach to pathogen inactivation. 951,1192 Some researchers have recommended the use of either a 1:2 v/v dilution of sodium hypochorite (approximately 20,000 ppm), full-strength sodium hypochlorite (50,000-60,000 ppm), or 1-2 N sodium hydroxide (NaOH) for the inactivation of prions on certain surfaces (e.g., those found in the pathology laboratory). 1170,1188 Although these chemicals may be appropriate for the decontamination of laboratory, operating-room, or autopsy-room surfaces that come into contact with central nervous system tissue from a known or suspected patient, this approach is not indicated for routine or terminal cleaning of a room previously occupied by a CJD patient. Both chemicals pose hazards for the healthcare worker doing the decontamination. NaOH is caustic and should not make contact with the skin. Sodium hypochlorite solutions (i.e., chlorine bleach) can corrode metals (e.g., aluminum). MSDS information should be consulted when attempting to work with concentrated solutions of either chemical. Currently, no EPAregistered products have label claims for prion inactivation; therefore, this guidance is based on the best available evidence from the scientific literature.\nEnvironmental infection-control strategies must based on the principles of the \"chain of infection,\" regardless of the disease of concern. 13 Although CJD is transmissible, it is not highly contagious. All iatrogenic cases of CJD have been linked to a direct exposure to prion-contaminated central nervous system tissue or pituitary hormones. The six documented iatrogenic cases associated with instruments and devices involved neurosurgical instruments and devices that introduced residual contamination directly to the recipient's brain. No evidence suggests that vCJD has been transmitted iatrogenically or that either CJD or vCJD has been transmitted from environmental surfaces (e.g., housekeeping surfaces). Therefore, routine procedures are adequate for terminal cleaning and disinfection of a CJD patient's room. Additionally, in epidemiologic studies involving highly transfused patients, blood was not identified as a source for prion transmission. [1193][1194][1195][1196][1197][1198] Routine procedures for containing, decontaminating, and disinfecting surfaces with blood spills should be adequate for proper infection control in these situations. 951,1199 Guidance for environmental infection control in ORs and autopsy areas has been published. 1197,1199 Hospitals should develop risk-assessment procedures to identify patients with known or suspected CJD in efforts to implement prion-specific infection-control measures for the OR and for instrument reprocessing. 1200 This assessment also should be conducted for older patients undergoing non-lesionous neurosurgery when such procedures are being done for diagnosis. Disposable, impermeable coverings should be used during these autopsies and neurosurgeries to minimize surface contamination. Surfaces that have become contaminated with central nervous system tissue or cerebral spinal fluid should be cleaned and decontaminated by a. removing most of the tissue or body substance with absorbent materials, b. wetting the surface with a sodium hypochlorite solution containing ≥5,000 ppm or a 1 N NaOH solution, and c. rinsing thoroughly. 951,[1197][1198][1199]1201 The optimum duration of contact exposure in these instances is unclear. Some researchers recommend a 1-hour contact time on the basis of tissue-inactivation studies, 1197,1198,1201 whereas other reviewers of the subject draw no conclusions from this research. 1199 Factors to consider before cleaning a potentially contaminated surface are a. the degree to which gross tissue/body substance contamination can be effectively removed and b. the ease with which the surface can be cleaned.\n# F. Environmental Sampling\nThis portion of Part I addresses the basic principles and methods of sampling environmental surfaces and other environmental sources for microorganisms. The applied strategies of sampling with respect to environmental infection control have been discussed in the appropriate preceding subsections.\n# General Principles: Microbiologic Sampling of the Environment\nBefore 1970, U.S. hospitals conducted regularly scheduled culturing of the air and environmental surfaces (e.g., floors, walls, and table tops). 1202 By 1970, CDC and the American Hospital Association (AHA) were advocating the discontinuation of routine environmental culturing because rates of healthcare-associated infection had not been associated with levels of general microbial contamination of air or environmental surfaces, and because meaningful standards for permissible levels of microbial contamination of environmental surfaces or air did not exist. 1203-1205During 1970, 25% of U.S. hospitals reduced the extent of such routine environmental culturing -a trend that has continued. 1206,1207 Random, undirected sampling (referred to as \"routine\" in previous guidelines) differs from the current practice of targeted sampling for defined purposes. 2,1204 Previous recommendations against routine sampling were not intended to discourage the use of sampling in which sample collection, culture, and interpretation are conducted in accordance with defined protocols. 2 In this guideline, targeted microbiologic sampling connotes a monitoring process that includes a. a written, defined, multidisciplinary protocol for sample collection and culturing b. analysis and interpretation of results using scientifically determined or anticipatory baseline values for comparison; and c. expected actions based on the results obtained.\nInfection control, in conjunction with laboratorians, should assess the health-care facility's capability to conduct sampling and determine when expert consultation and/or services are needed.\nMicrobiologic sampling of air, water, and inanimate surfaces (i.e., environmental sampling) is an expensive and time-consuming process that is complicated by many variables in protocol, analysis, and interpretation. It is therefore indicated for only four situations. 1208 The first is to support an investigation of an outbreak of disease or infections when environmental reservoirs or fomites are implicated epidemiologically in disease transmission. 161,1209,1210 It is important that such culturing be supported by epidemiologic data. Environmental sampling, as with all laboratory testing, should not be conducted if there is no plan for interpreting and acting on the results obtained. 11,1211,1212 Linking microorganisms from environmental samples with clinical isolates by molecular epidemiology is crucial whenever it is possible to do so.\nThe second situation for which environmental sampling may be warranted is in research. Well-designed and controlled experimental methods and approaches can provide new information about the spread of health-care associated diseases. 126, 129 A classic example is the study of environmental microbial contamination that compared health-care associated infection rates in an old hospital and a new facility before and shortly after occupancy. 947 The third indication for sampling is to monitor a potentially hazardous environmental condition, confirm the presence of a hazardous chemical or biological agent, and validate the successful abatement of the hazard. This type of sampling can be used to: a. detect bioaerosols released from the operation of health-care equipment (e.g., an ultrasonic cleaner)\nand determine the success of repairs in containing the hazard, 1213 b. detect the release of an agent of bioterrorism in an indoor environmental setting and determine its successful removal or inactivation, and c. sample for industrial hygiene or safety purposes (e.g., monitoring a \"sick building\").\nThe fourth indication is for quality assurance to evaluate the effects of a change in infection-control practice or to ensure that equipment or systems perform according to specifications and expected outcomes. Any sampling for quality-assurance purposes must follow sound sampling protocols and address confounding factors through the use of properly selected controls. Results from a single environmental sample are difficult to interpret in the absence of a frame of reference or perspective. Evaluations of a change in infection-control practice are based on the assumption that the effect will be measured over a finite period, usually of short duration. Conducting quality-assurance sampling on an extended basis, especially in the absence of an adverse outcome, is usually unjustified. A possible exception might be the use of air sampling during major construction periods to qualitatively detect breaks in environmental infection-control measures. In one study, which began as part of an investigation of an outbreak of health-care associated aspergillosis, airborne concentrations of Aspergillus spores were measured in efforts to evaluate the effectiveness of sealing hospital doors and windows during a period of construction of a nearby building. 50 Other examples of sampling for quality-assurance purposes may include commissioning newly constructed space in special care areas (i.e., ORs and units for immunosuppressed patients) or assessing a change in housekeeping practice. However, the only types of routine environmental microbiologic sampling recommended as part of a quality-assurance program are a. the biological monitoring of sterilization processes by using bacterial spores 1214 and b. the monthly culturing of water used in hemodialysis applications and for the final dialysate use dilution. Some experts also advocate periodic environmental sampling to evaluate the microbial/particulate quality for regular maintenance of the air handling system (e.g., filters) and to verify that the components of the system meet manufacturer's specifications (A. Streifel, University of Minnesota, 2000). Certain equipment in health-care settings (e.g., biological safety cabinets) may also be monitored with air flow and particulate sampling to determine performance or as part of adherence to a certification program; results can then be compared with a predetermined standard of performance. These measurements, however, usually do not require microbiologic testing.\n# Air Sampling\nBiological contaminants occur in the air as aerosols and may include bacteria, fungi, viruses, and pollens. 1215,1216 Aerosols are characterized as solid or liquid particles suspended in air. Talking for 5 minutes and coughing each can produce 3,000 droplet nuclei; sneezing can generate approximately 40,000 droplets which then evaporate to particles in the size range of 0.5-12 μm. 137,1217 Particles in a biological aerosol usually vary in size from <1 μm to ≥50 μm. These particles may consist of a single, unattached organism or may occur in the form of clumps composed of a number of bacteria. Clumps can also include dust and dried organic or inorganic material. Vegetative forms of bacterial cells and viruses may be present in the air in a lesser number than bacterial spores or fungal spores. Factors that determine the survival of microorganisms within a bioaerosol include a. the suspending medium, b. temperature, c. relative humidity, d. oxygen sensitivity, and e. exposure to UV or electromagnetic radiation. 1215 Many vegetative cells will not survive for lengthy periods of time in the air unless the protective cover (e.g., dried organic or inorganic matter). 1216 Pathogens that resist drying (e.g., Staphylococcus spp., Streptococcus spp., and fungal spores) can survive for long periods and can be carried considerable distances via air and still remain viable. They may also settle on surfaces and become airborne again as secondary aerosols during certain activities (e.g., sweeping and bed making). 1216,1218 Microbiologic air sampling is used as needed to determine the numbers and types of microorganisms, or particulates, in indoor air. 289 Air sampling for quality control is, however, problematic because of lack of uniform air-quality standards. Although airborne spores of Aspergillus spp. can pose a risk for neutropenic patients, the critical number (i.e., action level) of these spores above which outbreaks of aspergillosis would be expected to occur has not been defined. Health-care professionals considering the use of air sampling should keep in mind that the results represent indoor air quality at singular points in time, and these may be affected by a variety of factors, including a. indoor traffic, b. visitors entering the facility, c. temperature, d. time of day or year, e. relative humidity, f. relative concentration of particles or organisms, and g) the performance of the air-handling system components.\nTo be meaningful, air-sampling results must be compared with those obtained from other defined areas, conditions, or time periods.\nSeveral preliminary concerns must be addressed when designing a microbiologic air sampling strategy (Box 13). Because the amount of particulate material and bacteria retained in the respiratory system is largely dependent on the size of the inhaled particles, particle size should be determined when studying airborne microorganisms and their relation to respiratory infections. Particles >5 μm are efficiently trapped in the upper respiratory tract and are removed primarily by ciliary action. 1219 Particles ≤5 μm in diameter reach the lung, but the greatest retention in the alveoli is of particles 1-2 μm in diameter. [1220][1221][1222] \n# Box 13. Preliminary concerns for conducting air sampling\n• Consider the possible characteristics and conditions of the aerosol, including size range of particles, relative amount of inert material, concentration of microorganisms, and environmental factors.\n• Determine the type of sampling instruments, sampling time, and duration of the sampling program.\n• Determine the number of samples to be taken.\n• Ensure that adequate equipment and supplies are available.\n• Determine the method of assay that will ensure optimal recovery of microorganisms.\n• Select a laboratory that will provide proper microbiologic support.\n• Ensure that samples can be refrigerated if they cannot be assayed in the laboratory promptly.\nBacteria, fungi, and particulates in air can be identified and quantified with the same methods and equipment (Table 23). The basic methods include a. impingement in liquids, b. impaction on solid surfaces, c. sedimentation, d. filtration, e. centrifugation, f. electrostatic precipitation, and g. thermal precipitation. 1218 Of these, impingement in liquids, impaction on solid surfaces, and sedimentation (on settle plates) have been used for various air-sampling purposes in health-care settings. 289 Several instruments are available for sampling airborne bacteria and fungi (Box 14). Some of the samplers are self-contained units requiring only a power supply and the appropriate collecting medium, but most require additional auxiliary equipment (e.g., a vacuum pump and an airflow measuring device [i.e., a flowmeter or anemometer]). Sedimentation or depositional methods use settle plates and therefore need no special instruments or equipment. Selection of an instrument for air sampling requires a clear understanding of the type of information desired and the particular determinations that must be made (Box 14). Information may be needed regarding a. one particular organism or all organisms that may be present in the air, b. the concentration of viable particles or of viable organisms, c. the change in concentration with time, and d. the size distribution of the collected particles.\nBefore sampling begins, decisions should be made regarding whether the results are to be qualitative or quantitative. Comparing quantities of airborne microorganisms to those of outdoor air is also standard operating procedure. Infection-control professionals, hospital epidemiologists, industrial hygienists, and laboratory supervisors, as part of a multidisciplinary team, should discuss the potential need for microbial air sampling to determine if the capacity and expertise to conduct such sampling exists within the facility and when it is appropriate to enlist the services of an environmental microbiologist consultant. \n# Box 14. Selecting an air sampling device*\nThe following factors must be considered when choosing an air sampling instrument:\n• Viability and type of the organism to be sampled\n• Compatibility with the selected method of analysis\n• Sensitivity of particles to sampling • Assumed concentrations and particle size\n• Whether airborne clumps must be broken (i.e., total viable organism count vs. particle count)\n• Volume of air to be sampled and length of time sampler is to be continuously operated Liquid impinger and solid impactor samplers are the most practical for sampling bacteria, particles, and fungal spores, because they can sample large volumes of air in relatively short periods of time. 289 Solid impactor units are available as either \"slit\" or \"sieve\" designs. Slit impactors use a rotating disc as support for the collecting surface, which allows determinations of concentration over time. Sieve impactors commonly use stages with calibrated holes of different diameters. Some impactor-type samplers use centrifugal force to impact particles onto agar surfaces. The interior of either device must be made sterile to avoid inadvertent contamination from the sampler. Results obtained from either sampling device can be expressed as organisms or particles per unit volume of air (CFU/m 3 ).\nSampling for bacteria requires special attention, because bacteria may be present as individual organisms, as clumps, or mixed with or adhering to dust or covered with a protective coating of dried organic or inorganic substances. Reports of bacterial concentrations determined by air sampling therefore must indicate whether the results represent individual organisms or particles bearing multiple cells. Certain types of samplers (e.g., liquid impingers) will completely or partially disintegrate clumps and large particles; the sampling result will therefore reflect the total number of individual organisms present in the air.\nThe task of sizing a bioaerosol is simplified through the use of sieves or slit impactors because these samplers will separate the particles and microorganisms into size ranges as the sample is collected. These samplers must, however, be calibrated first by sampling aerosols under similar use conditions. 1225 The use of settle plates (i.e., the sedimentation or depositional method) is not recommended when sampling air for fungal spores, because single spores can remain suspended in air indefinitely. 289 Settle plates have been used mainly to sample for particulates and bacteria either in research studies or during epidemiologic investigations. 161,[1226][1227][1228][1229] Results of sedimentation sampling are typically expressed as numbers of viable particles or viable bacteria per unit area per the duration of sampling time (i.e., CFU/area/time); this method can not quantify the volume of air sampled. Because the survival of microorganisms during air sampling is inversely proportional to the velocity at which the air is taken into the sampler, 1215 one advantage of using a settle plate is its reliance on gravity to bring organisms and particles into contact with its surface, thus enhancing the potential for optimal survival of collected organisms. This process, however, takes several hours to complete and may be impractical for some situations.\nAir samplers are designed to meet differing measurement requirements. Some samplers are better suited for one form of measurement than others. No one type of sampler and assay procedure can be used to collect and enumerate 100% of airborne organisms. The sampler and/or sampling method chosen should, however, have an adequate sampling rate to collect a sufficient number of particles in a reasonable time period so that a representative sample of air is obtained for biological analysis. Newer analytical techniques for assaying air samples include PCR methods and enzyme-linked immunosorbent assays (ELISAs).\n# Water Sampling\nA detailed discussion of the principles and practices of water sampling has been published. 945 Water sampling in health-care settings is used detect waterborne pathogens of clinical significance or to determine the quality of finished water in a facility's distribution system. Routine testing of the water in a health-care facility is usually not indicated, but sampling in support of outbreak investigations can help determine appropriate infection-control measures. Water-quality assessments in dialysis settings have been discussed in this guideline (see Water, Dialysis Water Quality and Dialysate, and Appendix C).\nHealth-care facilities that conduct water sampling should have their samples assayed in a laboratory that uses established methods and quality-assurance protocols. Water specimens are not \"static specimens\" at ambient temperature; potential changes in both numbers and types of microbial populations can occur during transport. Consequently, water samples should be sent to the testing laboratory cold (i.e., at approximately 39.2°F [4°C]) and testing should be done as soon as practical after collection (preferably within 24 hours).\nBecause most water sampling in health-care facilities involves the testing of finished water from the facility's distribution system, a reducing agent (i.e., sodium thiosulfate [Na2S2O3]) needs to be added to neutralize residual chlorine or other halogen in the collected sample. If the water contains elevated levels of heavy metals, then a chelating agent should be added to the specimen. The minimum volume of water to be collected should be sufficient to complete any and all assays indicated; 100 mL is considered a suitable minimum volume. Sterile collection equipment should always be used.\nSampling from a tap requires flushing of the water line before sample collection. If the tap is a mixing faucet, attachments (e.g., screens and aerators) must be removed, and hot and then cold water must be run through the tap before collecting the sample. 945 If the cleanliness of the tap is questionable, disinfection with 500-600 ppm sodium hypochlorite (1:100 v/v dilution of chlorine bleach) and flushing the tap should precede sample collection.\nMicroorganisms in finished or treated water often are physically damaged (\"stressed\") to the point that growth is limited when assayed under standard conditions. Such situations lead to false-negative readings and misleading assessments of water quality. Appropriate neutralization of halogens and chelation of heavy metals are crucial to the recovery of these organisms. The choice of recovery media and incubation conditions will also affect the assay. Incubation temperatures should be closer to the ambient temperature of the water rather than at 98.6°F (37°C), and recovery media should be formulated to provide appropriate concentrations of nutrients to support organisms exhibiting less than rigorous growth. 945 High-nutrient content media (e.g., blood agar and tryptic soy agar [TSA]) may actually inhibit the growth of these damaged organisms. Reduced nutrient media (e.g., diluted peptone and R2A) are preferable for recovery of these organisms. 945 Use of aerobic, heterotrophic plate counts allows both a qualitative and quantitative measurement for water quality. If bacterial counts in water are expected to be high in number (e.g., during waterborne outbreak investigations), assaying small quantities using pour plates or spread plates is appropriate. 945 Membrane filtration is used when low-count specimens are expected and larger sampling volumes are required (≥100 mL). The sample is filtered through the membrane, and the filter is applied directly faceup onto the surface of the agar plate and incubated.\nUnlike the testing of potable water supplies for coliforms (which uses standardized test and specimen collection parameters and conditions), water sampling to support epidemiologic investigations of disease outbreaks may be subjected to modifications dictated by the circumstances present in the facility. Assay methods for waterborne pathogens may also not be standardized. Therefore, control or comparison samples should be included in the experimental design. Any departure from a standard method should be fully documented and should be considered when interpreting results and developing strategies. Assay methods specific for clinically significant waterborne pathogens (e.g., Legionella spp., Aeromonas spp., Pseudomonas spp., and Acinetobacter spp.) are more complicated and costly compared with both methods used to detect coliforms and other standard indicators of water quality.\n# Environmental Surface Sampling\nRoutine environmental-surface sampling (e.g., surveillance cultures) in health-care settings is neither cost-effective nor warranted. 951, 1225 When indicated, surface sampling should be conducted with multidisciplinary approval in adherence to carefully considered plans of action and policy (Box 15).\n# Box 15. Undertaking environmental-surface sampling*\nThe following factors should be considered before engaging in environmental-surface sampling:\n• Background information from the literature and present activities (i.e., preliminary results from an epidemiologic investigation)\n• Location of surfaces to be sampled Surface sampling is used currently for research, as part of an epidemiologic investigation, or as part of a comprehensive approach for specific quality assurance purposes. As a research tool, surface sampling has been used to determine a. potential environmental reservoirs of pathogens, 564,[1230][1231][1232] b. survival of microorganisms on surfaces, 1232,1233 and c. the sources of the environmental contamination. 1023 Some or all of these approaches can also be used during outbreak investigations. 1232 Discussion of surface sampling of medical devices and instruments is beyond the scope of this document and is deferred to future guidelines on sterilization and disinfection issues.\nMeaningful results depend on the selection of appropriate sampling and assay techniques. 1214 The media, reagents, and equipment required for surface sampling are available from any well-equipped microbiology laboratory and laboratory supplier. For quantitative assessment of surface organisms, nonselective, nutrient-rich agar media and broth (e.g., TSA and brain-heart infusion broth [BHI] with or without 5% sheep or rabbit blood supplement) are used for the recovery of aerobic bacteria. Broth media are used with membrane-filtration techniques. Further sample work-up may require the use of selective media for the isolation and enumeration of specific groups of microorganisms. Examples of selective media are MacConkey agar (MAC [selects for gram-negative bacteria]), Cetrimide agar (selects for Pseudomonas aeruginosa), or Sabouraud dextrose-and malt extract agars and broths (select for fungi). Qualitative determinations of organisms from surfaces require only the use of selective or non-selective broth media.\nEffective sampling of surfaces requires moisture, either already present on the surface to be sampled or via moistened swabs, sponges, wipes, agar surfaces, or membrane filters. 1214,[1234][1235][1236] Dilution fluids and rinse fluids include various buffers or general purpose broth media (Table 24). If disinfectant residuals are expected on surfaces being sampled, specific neutralizer chemicals should be used in both the growth media and the dilution or rinse fluids. Lists of the neutralizers, the target disinfectant active ingredients, and the use concentrations have been published. 1214,1237 Alternatively, instead of adding neutralizing chemicals to existing culture media (or if the chemical nature of the disinfectant residuals is unknown), the use of either a. commercially available media including a variety of specific and nonspecific neutralizers or b. double-strength broth media will facilitate optimal recovery of microorganisms.\nThe inclusion of appropriate control specimens should be included to rule out both residual antimicrobial activity from surface disinfectants and potential toxicity caused by the presence of neutralizer chemicals carried over into the assay system. 1214 Several methods can be used for collecting environmental surface samples (Table 25). Specific stepbystep discussions of each of the methods have been published. 1214,1239 For best results, all methods should incorporate aseptic techniques, sterile equipment, and sterile recovery media. Sample/rinse methods are frequently chosen because of their versatility. However, these sampling methods are the most prone to errors caused by manipulation of the swab, gauze pad, or sponge. 1238 Additionally, no microbiocidal or microbiostatic agents should be present in any of these items when used for sampling. 1238 Each of the rinse methods requires effective elution of microorganisms from the item used to sample the surface. Thorough mixing of the rinse fluids after elution (e.g., via manual or mechanical mixing using a vortex mixer, shaking with or without glass beads, and ultrasonic bath) will help to remove and suspend material from the sampling device and break up clumps of organisms for a more accurate count. 1238 In some instances, the item used to sample the surface (e.g., gauze pad and sponge) may be immersed in the rinse fluids in a sterile bag and subjected to stomaching. 1238 This technique, however, is suitable only for soft or absorbent items that will not puncture the bag during the elution process.\nIf sampling is conducted as part of an epidemiologic investigation of a disease outbreak, identification of isolates to species level is mandatory, and characterization beyond the species level is preferred. 1214 When interpreting the results of the sampling, the expected degree of microbial contamination associated with the various categories of surfaces in the Spaulding classification must be considered. Environmental surfaces should be visibly clean; recognized pathogens in numbers sufficient to result in secondary transfer to other animate or inanimate surfaces should be absent from the surface being sampled. 1214 Although the interpretation of a sample with positive microbial growth is self-evident, an environmental surface sample, especially that obtained from housekeeping surfaces, that shows no growth does not represent a \"sterile\" surface. Sensitivities of the sampling and assay methods (i.e., level of detection) must be taken into account when no-growth samples are encountered. Properly collected control samples will help rule out extraneous contamination of the surface sample.\n# G. Laundry and Bedding\n\n# General Information\nLaundry in a health-care facility may include bed sheets and blankets, towels, personal clothing, patient apparel, uniforms, scrub suits, gowns, and drapes for surgical procedures. 1245 Although contaminated textiles and fabrics in health-care facilities can be a source of substantial numbers of pathogenic microorganisms, reports of health-care associated diseases linked to contaminated fabrics are so few in number that the overall risk of disease transmission during the laundry process likely is negligible. When the incidence of such events are evaluated in the context of the volume of items laundered in health-care settings (estimated to be 5 billion pounds annually in the United States), 1246 existing control measures (e.g., standard precautions) are effective in reducing the risk of disease transmission to patients and staff. Therefore, use of current control measures should be continued to minimize the contribution of contaminated laundry to the incidence of health-care associated infections. The control measures described in this section of the guideline are based on principles of hygiene, common sense, and consensus guidance; they pertain to laundry services utilized by health-care facilities, either inhouse or contract, rather than to laundry done in the home.\n# Epidemiology and General Aspects of Infection Control\nContaminated textiles and fabrics often contain high numbers of microorganisms from body substances, including blood, skin, stool, urine, vomitus, and other body tissues and fluids. When textiles are heavily contaminated with potentially infective body substances, they can contain bacterial loads of 10 6 -10 8 CFU/100 cm 2 of fabric. 1247 Disease transmission attributed to health-care laundry has involved contaminated fabrics that were handled inappropriately (i.e., the shaking of soiled linens). Bacteria (Salmonella spp., Bacillus cereus), viruses (hepatitis B virus [HBV]), fungi (Microsporum canis), and ectoparasites (scabies) presumably have been transmitted from contaminated textiles and fabrics to workers via a. direct contact or b. aerosols of contaminated lint generated from sorting and handling contaminated textiles. [1248][1249][1250][1251][1252] In these events, however, investigations could not rule out the possibility that some of these reported infections were acquired from community sources. Through a combination of soil removal, pathogen removal, and pathogen inactivation, contaminated laundry can be rendered hygienically clean. Hygienically clean laundry carries negligible risk to health-care workers and patients, provided that the clean textiles, fabric, and clothing are not inadvertently contaminated before use.\nOSHA defines contaminated laundry as \"laundry which has been soiled with blood or other potentially infectious materials or may contain sharps.\" 967 The purpose of the laundry portion of the standard is to protect the worker from exposure to potentially infectious materials during collection, handling, and sorting of contaminated textiles through the use of personal protective equipment, proper work practices, containment, labeling, hazard communication, and ergonomics.\nExperts are divided regarding the practice of transporting clothes worn at the workplace to the healthcare worker's home for laundering. Although OSHA regulations prohibit home laundering of items that are considered personal protective apparel or equipment (e.g., laboratory coats), 967 experts disagree about whether this regulation extends to uniforms and scrub suits that are not contaminated with blood or other potentially infectious material. Health-care facility policies on this matter vary and may be inconsistent with recommendations of professional organizations. 1253,1254 Uniforms without blood or body substance contamination presumably do not differ appreciably from street clothes in the degree and microbial nature of soilage. Home laundering would be expected to remove this level of soil adequately. However, if health-care facilities require the use of uniforms, they should either make provisions to launder them or provide information to the employee regarding infection control and cleaning guidelines for the item based on the tasks being performed at the facility. Health-care facilities should address the need to provide this service and should determine the frequency for laundering these items. In a recent study examining the microbial contamination of medical students' white coats, the students perceived the coats as \"clean\" as long as the garments were not visibly contaminated with body substances, even after wearing the coats for several weeks. 1255 The heaviest bacterial load was found on the sleeves and the pockets of these garments; the organisms most frequently isolated were Staphylococcus aureus, diphtheroids, and Acinetobacter spp. 1255 Presumably, the sleeves of the coat may make contact with a patient and potentially serve to transfer environmentally stable microorganisms among patients. In this study, however, surveillance was not conducted among patients to detect new infections or colonizations. The students did, however, report that they would likely replace their coats more frequently and regularly if clean coats were provided. 1255 Apart from this study, which documents the presence of pathogenic bacteria on health-care facility clothing, reports of infections attributed to either the contact with such apparel or with home laundering have been rare. 1256,1257 Laundry services for health-care facilities are provided either in-house (i.e., on-premise laundry [OPL]), co-operatives (i.e., those entities owned and operated by a group of facilities), or by off-site commercial laundries. In the latter, the textiles may be owned by the health-care facility, in which case the processor is paid for laundering only. Alternatively, the textiles may be owned by the processor who is paid for every piece laundered on a \"rental\" fee. The laundry facility in a health-care setting should be designed for efficiency in providing hygienically clean textiles, fabrics, and apparel for patients and staff. Guidelines for laundry construction and operation for health-care facilities, including nursing facilities, have been published. 120,1258 The design and engineering standards for existing facilities are those cited in the AIA edition in effect during the time of the facility's construction. 120 A laundry facility is usually partitioned into two separate areas -a \"dirty\" area for receiving and handling the soiled laundry and a \"clean\" area for processing the washed items. 1259 To minimize the potential for recontaminating cleaned laundry with aerosolized contaminated lint, areas receiving contaminated textiles should be at negative air pressure relative to the clean areas. [1260][1261][1262] Laundry areas should have handwashing facilities readily available to workers. Laundry workers should wear appropriate personal protective equipment (e.g., gloves and protective garments) while sorting soiled fabrics and textiles. 967 Laundry equipment should be used and maintained according to the manufacturer's instructions to prevent microbial contamination of the system. 1250,1263 Damp textiles should not be left in machines overnight. 1250\n# Collecting, Transporting, and Sorting Contaminated Textiles and Fabrics\nThe laundry process starts with the removal of used or contaminated textiles, fabrics, and/or clothing from the areas where such contamination occurred, including but not limited to patients' rooms, surgical/operating areas, and laboratories. Handling contaminated laundry with a minimum of agitation can help prevent the generation of potentially contaminated lint aerosols in patient-care areas. 967,1259 Sorting or rinsing contaminated laundry at the location where contamination occurred is prohibited by OSHA. 967 Contaminated textiles and fabrics are placed into bags or other appropriate containment in this location; these bags are then securely tied or otherwise closed to prevent leakage. 967 Single bags of sufficient tensile strength are adequate for containing laundry, but leak-resistant containment is needed if the laundry is wet and capable of soaking through a cloth bag. 1264 Bags containing contaminated laundry must be clearly identified with labels, color-coding, or other methods so that health-care workers handle these items safely, regardless of whether the laundry is transported within the facility or destined for transport to an off-site laundry service. 967 Typically, contaminated laundry originating in isolation areas of the hospital is segregated and handled with special practices; however, few, if any, cases of health-care associated infection have been linked to this source. 1265 Single-blinded studies have demonstrated that laundry from isolation areas is no more heavily contaminated with microorganisms than laundry from elsewhere in the hospital. 1266 Therefore, adherence to standard precautions when handling contaminated laundry in isolation areas and minimizing agitation of the contaminated items are considered sufficient to prevent the dispersal of potentially infectious aerosols. 6 Contaminated textiles and fabrics in bags can be transported by cart or chute. 1258,1262 Laundry chutes require proper design, maintenance, and use, because the piston-like action of a laundry bag traveling in the chute can propel airborne microbial contaminants throughout the facility. [1267][1268][1269] Laundry chutes should be maintained under negative air pressure to prevent the spread of microorganisms from floor to floor. Loose, contaminated pieces of laundry should not be tossed into chutes, and laundry bags should be closed or otherwise secured to prevent the contents from falling out into the chute. 1270 Health-care facilities should determine the point in the laundry process at which textiles and fabrics should be sorted. Sorting after washing minimizes the exposure of laundry workers to infective material in soiled fabrics, reduces airborne microbial contamination in the laundry area, and helps to prevent potential percutaneous injuries to personnel. 1271 Sorting laundry before washing protects both the machinery and fabrics from hard objects (e.g., needles, syringes, and patients' property) and reduces the potential for recontamination of clean textiles. 1272 Sorting laundry before washing also allows for customization of laundry formulas based on the mix of products in the system and types of soils encountered. Additionally, if work flow allows, increasing the amount of segregation by specific product types will usually yield the greatest amount of work efficiency during inspection, folding, and pack-making operations. 1253 Protective apparel for the workers and appropriate ventilation can minimize these exposures. 967,[1258][1259][1260] Gloves used for the task of sorting laundry should be of sufficient thickness to minimize sharps injuries. 967 Employee safety personnel and industrial hygienists can help to determine the appropriate glove choice.\n# Parameters of the Laundry Process\nFabrics, textiles, and clothing used in health-care settings are disinfected during laundering and generally rendered free of vegetative pathogens (i.e., hygienically clean), but they are not sterile. 1273 Laundering cycles consist of flush, main wash, bleaching, rinsing, and souring. 1274 Cleaned wet textiles, fabrics, and clothing are then dried, pressed as needed, and prepared (e.g., folded and packaged) for distribution back to the facility. Clean linens provided by an off-site laundry must be packaged prior to transport to prevent inadvertent contamination from dust and dirt during loading, delivery, and unloading. Functional packaging of laundry can be achieved in several ways, including a. placing clean linen in a hamper lined with a previously unused liner, which is then closed or covered b. placing clean linen in a properly cleaned cart and covering the cart with disposable material or a properly cleaned reusable textile material that can be secured to the cart; and c. wrapping individual bundles of clean textiles in plastic or other suitable material and sealing or taping the bundles.\nThe antimicrobial action of the laundering process results from a combination of mechanical, thermal, and chemical factors. 1271,1275,1276 Dilution and agitation in water remove substantial quantities of microorganisms. Soaps and detergents function to suspend soils and also exhibit some microbiocidal properties. Hot water provides an effective means of destroying microorganisms. 1277 A temperature of at least 160°F (71°C) for a minimum of 25 minutes is commonly recommended for hot-water washing. 2 Water of this temperature can be provided by steam jet or separate booster heater. 120 The use of chlorine bleach assures an extra margin of safety. 1278, 1279 A total available chlorine residual of 50-150 ppm is usually achieved during the bleach cycle. 1277 Chlorine bleach becomes activated at water temperatures of 135°F-145°F (57.2°C-62.7°C). The last of the series of rinse cycles is the addition of a mild acid (i.e., sour) to neutralize any alkalinity in the water supply, soap, or detergent. The rapid shift in pH from approximately 12 to 5 is an effective means to inactivate some microorganisms. 1247 Effective removal of residual alkali from fabrics is an important measure in reducing the risk for skin reactions among patients.\nChlorine bleach is an economical, broad-spectrum chemical germicide that enhances the effectiveness of the laundering process. Chlorine bleach is not, however, an appropriate laundry additive for all fabrics. Traditionally, bleach was not recommended for laundering flame-retardant fabrics, linens, and clothing because its use diminished the flame-retardant properties of the treated fabric. 1273 However, some modernday flame retardant fabrics can now tolerate chlorine bleach. Flame-retardant fabrics, whether topically treated or inherently flame retardant, should be thoroughly rinsed during the rinse cycles, because detergent residues are capable of supporting combustion. Chlorine alternatives (e.g., activated oxygenbased laundry detergents) provide added benefits for fabric and color safety in addition to antimicrobial activity. Studies comparing the antimicrobial potencies of chlorine bleach and oxygen-based bleach are needed. Oxygen-based bleach and detergents used in health-care settings should be registered by EPA to ensure adequate disinfection of laundry. Health-care workers should note the cleaning instructions of textiles, fabrics, drapes, and clothing to identify special laundering requirements and appropriate hygienic cleaning options. 1278 Although hot-water washing is an effective laundry disinfection method, the cost can be substantial. Laundries are typically the largest users of hot water in hospitals. They consume 50%-75% of the total hot water, 1280 representing an average of 10%-15% of the energy used by a hospital. Several studies have demonstrated that lower water temperatures of 71°F-77°F (22°C-25°C) can reduce microbial contamination when the cycling of the washer, the wash detergent, and the amount of laundry additive are carefully monitored and controlled. 1247,[1281][1282][1283][1284][1285] Low-temperature laundry cycles rely heavily on the presence of chlorine-or oxygen-activated bleach to reduce the levels of microbial contamination. The selection of hot-or cold-water laundry cycles may be dictated by state health-care facility licensing standards or by other regulation. Regardless of whether hot or cold water is used for washing, the temperatures reached in drying and especially during ironing provide additional significant microbiocidal action. 1247 Dryer temperatures and cycle times are dictated by the materials in the fabrics. Man-made fibers (i.e., polyester and polyester blends) require shorter times and lower temperatures.\nAfter washing, cleaned and dried textiles, fabrics, and clothing are pressed, folded, and packaged for transport, distribution, and storage by methods that ensure their cleanliness until use. 2 State regulations and/or accrediting standards may dictate the procedures for this activity. Clean/sterile and contaminated textiles should be transported from the laundry to the health-care facility in vehicles (e.g., trucks, vans, and carts) that allow for separation of clean/sterile and contaminated items. Clean/sterile textiles and contaminated textiles may be transported in the same vehicle, provided that the use of physical barriers and/or space separation can be verified to be effective in protecting the clean/sterile items from contamination. Clean, uncovered/unwrapped textiles stored in a clean location for short periods of time (e.g., uncovered and used within a few hours) have not been demonstrated to contribute to increased levels of health-care acquired infection. Such textiles can be stored in convenient places for use during the provision of care, provided that the textiles can be maintained dry and free from soil and body-substance contamination.\nIn the absence of microbiologic standards for laundered textiles, no rationale exists for routine microbiologic sampling of cleaned health-care textiles and fabrics. 1286 Sampling may be used as part of an outbreak investigation if epidemiologic evidence suggests that textiles, fabrics, or clothing are a suspected vehicle for disease transmission. Sampling techniques include aseptically macerating the fabric into pieces and adding these to broth media or using contact plates (RODAC plates) for direct surface sampling. 1271,1286 When evaluating the disinfecting properties of the laundering process specifically, placing pieces of fabric between two membrane filters may help to minimize the contribution of the physical removal of microorganisms. 1287 Washing machines and dryers in residential-care settings are more likely to be consumer items rather than the commercial, heavy-duty, large volume units typically found in hospitals and other institutional healthcare settings. Although all washing machines and dryers in health-care settings must be properly maintained for performance according to the manufacturer's instructions, questions have been raised\nabout the need to disinfect washers and dryers in residential-care settings. Disinfection of the tubs and tumblers of these machines is unnecessary when proper laundry procedures are followed; these procedures involve a. the physical removal of bulk solids (e.g., feces) before the wash/dry cycle and b. proper use of temperature, detergent, and laundry additives.\nInfection has not been linked to laundry procedures in residential-care facilities, even when consumer versions of detergents and laundry additives are used.\n# Special Laundry Situations\nSome textile items (e.g., surgical drapes and reusable gowns) must be sterilized before use and therefore require steam autoclaving after laundering. 7 Although the American Academy of Pediatrics in previous guidelines recommended autoclaving for linens in neonatal intensive care units (NICUs), studies on the microbial quality of routinely cleaned NICU linen have not identified any increased risk for infection among the neonates receiving care. 1288 Consequently, hygienically clean linens are suitable for use in this setting. 997 The use of sterile linens in burn therapy units remains unresolved.\nCoated or laminated fabrics are often used in the manufacture of PPE. When these items become contaminated with blood or other body substances, the manufacturer's instructions for decontamination and cleaning take into account the compatibility of the rubber backing with the chemical germicides or detergents used in the process. The directions for decontaminating these items should be followed as indicated; the item should be discarded when the backing develops surface cracks.\nDry cleaning, a cleaning process that utilizes organic solvents (e.g., perchloroethylene) for soil removal, is an alternative means of cleaning fabrics that might be damaged in conventional laundering and detergent washing. Several studies, however, have shown that dry cleaning alone is relatively ineffective in reducing the numbers of bacteria and viruses on contaminated linens; 1289, 1290 microbial populations are significantly reduced only when dry-cleaned articles are heat pressed. Dry cleaning should therefore not be considered a routine option for health-care facility laundry and should be reserved for those circumstances in which fabrics can not be safely cleaned with water and detergent. 1291\n# Surgical Gowns, Drapes, and Disposable Fabrics\nAn issue of recent concern involves the use of disposable (i.e., single use) versus reusable (i.e., multiple use) surgical attire and fabrics in health-care settings. 1292 Regardless of the material used to manufacture gowns and drapes, these items must be resistant to liquid and microbial penetration. 7,[1293][1294][1295][1296][1297] Surgical gowns and drapes must be registered with FDA to demonstrate their safety and effectiveness. Repellency and pore size of the fabric contribute to gown performance, but performance capability can be influenced by the item's design and construction. 1298,1299 Reinforced gowns (i.e., gowns with double-layered fabric) generally are more resistant to liquid strike-through. 1300,1301 Reinforced gowns may, however, be less comfortable. Guidelines for selection and use of barrier materials for surgical gowns and drapes have been published. 1302 When selecting a barrier product, repellency level and type of barrier should be compatible for the exposure expected. 967 However, data are limited regarding the association between gown or drape characteristics and risk for surgical site infections. 7,1303 Health-care facilities must ensure optimal protection of patients and health-care workers. Not all fabric items in health care lend themselves to single-use. Facilities exploring options for gowns and drapes should consider the expense of disposable items and the impact on the facility's waste-management costs once these items are discarded. Costs associated with the use of durable goods involve the fabric or textile items; staff expenses to collect, sort, clean, and package the laundry; and energy costs to operate the laundry if on-site or the costs to contract with an outside service. 1304,1305 \n# Antimicrobial-Impregnated Articles and Consumer Items Bearing Antimicrobial Labeling\nManufacturers are increasingly incorporating antibacterial or antimicrobial chemicals into consumer and health-care items. Some consumer products bearing labels that indicate treatment with antimicrobial chemicals have included pens, cutting boards, toys, household cleaners, hand lotions, cat litter, soaps, cotton swabs, toothbrushes, and cosmetics. The \"antibacterial\" label on household cleaning products, in particular, gives consumers the impression that the products perform \"better\" than comparable products without this labeling, when in fact all household cleaners have antibacterial properties.\nIn the health-care setting, treated items may include children's pajamas, mattresses, and bed linens with label claims of antimicrobial properties. These claims require careful evaluation to determine whether they pertain to the use of antimicrobial chemicals as preservatives for the fabric or other components or whether they imply a health claim. 1306,1307 No evidence is available to suggest that use of these products will make consumers and patients healthier or prevent disease. No data support the use of these items as part of a sound infection-control strategy, and therefore, the additional expense of replacing a facility's bedding and sheets with these treated products is unwarranted.\nEPA has reaffirmed its position that manufacturers who make public health claims for articles containing antimicrobial chemicals must provide evidence to support those claims as part of the registration process. 1308 Current EPA regulations outlined in the Treated Articles Exemption of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) require manufacturers to register both the antimicrobial chemical used in or on the product and the finished product itself if a public health claim is maintained for the item. The exemption applies to the use of antimicrobial chemicals for the purpose of preserving the integrity of the product's raw material(s). The U.S. Federal Trade Commission (FTC) is evaluating manufacturer advertising of products with antimicrobial claims. 1309 \n# Standard Mattresses, Pillows, and Air-Fluidized Beds\nStandard mattresses and pillows can become contaminated with body substances during patient care if the integrity of the covers of these items is compromised. The practice of sticking needles into the mattress should be avoided. A mattress cover is generally a fitted, protective material, the purpose of which is to prevent the mattress from becoming contaminated with body fluids and substances. A linen sheet placed on the mattress is not considered a mattress cover. Patches for tears and holes in mattress covers do not provide an impermeable surface over the mattress. Mattress covers should be replaced when torn; the mattress should be replaced if it is visibly stained. Wet mattresses, in particular, can be a substantial environmental source of microorganisms. Infections and colonizations caused by Acinetobacter spp., MRSA, and Pseudomonas aeruginosa have been described, especially among burn patients. [1310][1311][1312][1313][1314][1315] In these reports, the removal of wet mattresses was an effective infection-control measure. Efforts were made to ensure that pads and covers were cleaned and disinfected between patients using disinfectant products compatible with mattress-cover materials to ensure that these covers remained impermeable to fluids. [1310][1311][1312][1313][1314] Pillows and their covers should be easily cleanable, preferably in a hot water laundry cycle. 1315 These should be laundered between patients or if contaminated with body substances.\nAir-fluidized beds are used for the care of patients immobilized for extended periods of time because of therapy or injury (e.g., pain, decubitus ulcers, and burns). 1316 These specialized beds consist of a base unit filled with microsphere beads fluidized by warm, dry air flowing upward from a diffuser located at the bottom of the unit. A porous, polyester filter sheet separates the patient from direct contact with the beads but allows body fluids to pass through to the beads. Moist beads aggregate into clumps which settle to the bottom where they are removed as part of routine bed maintenance.\nBecause the beads become contaminated with the patient's body substances, concerns have been raised about the potential for these beds to serve as an environmental source of pathogens. Certain pathogens (e.g., Enterococcus spp., Serratia marcescens, Staphylococcus aureus, and Streptococcus fecalis) have been recovered either from the microsphere beads or the polyester sheet after cleaning. 1317,1318 Reports of crosscontamination of patients, however, are few. 1318 Nevertheless, routine maintenance and between-patient decontamination procedures can minimize potential risks to patients. Regular removal of bead clumps, coupled with the warm, dry air of the bed, can help to minimize bacterial growth in the unit. [1319][1320][1321] Beads are decontaminated between patients by high heat (113°F-194°F [45°C-90°C], depending on the manufacturer's specifications) for at least 1 hour; this procedure is particularly important for the inactivation of Enterococcus spp. which are relatively resistant to heat. 1322,1323 The polyester filter sheet requires regular changing and thorough cleaning and disinfection, especially between patients. 1317,1318,1322,1323 Microbial contamination of the air space in the immediate vicinity of a properly maintained air-fluidized bed is similar to that found in air around conventional bedding, despite the air flow out of the base unit and around the patient. 1320,1324,1325 An operational air-fluidized bed can, however, interfere with proper pressure differentials, especially in negative-pressure rooms; 1326 the effect varies with the location of the bed relative to the room's configuration and supply and exhaust vent locations. Use of an air-fluidized bed in a negative-pressure room requires consultation with a facility engineer to determine appropriate placement of the bed.\nH. Animals in Health-Care Facilities\n# General Information\nAnimals in health-care facilities traditionally have been limited to laboratories and research areas. However, their presence in patient-care areas is now more frequent, both in acute-care and long-term care settings, prompting consideration for the potential transmission of zoonotic pathogens from animals to humans in these settings.\nAlthough dogs and cats may be commonly encountered in health-care settings, other animals (e.g., fish, birds, non-human primates, rabbits, rodents, and reptiles) also can be present as research, resident, or service animals. These animals can serve as sources of zoonotic pathogens that could potentially infect patients and health-care workers (Table 26). [1327][1328][1329][1330][1331][1332][1333][1334][1335][1336][1337][1338][1339][1340] Animals potentially can serve as reservoirs for antibiotic-resistant microorganisms, which can be introduced to the health-care setting while the animal is present. VRE have been isolated from both farm animals and pets, 1341 and a cat in a geriatric care center was found to be colonized with MRSA. 1342 + Indicates that the pathogen associated with the infection has been isolated from animals and is considered to pose potential risk to humans.\nZoonoses can be transmitted from animals to humans either directly or indirectly via bites, scratches, aerosols, ectoparasites, accidental ingestion, or contact with contaminated soil, food, water, or unpasteurized milk. 1331,1332,[1343][1344][1345] Colonization and hand transferral of pathogens acquired from pets in health-care workers' homes represent potential sources and modes of transmission of zoonotic pathogens in health-care settings. An outbreak of infections caused by a yeast (Malassezia pachydermatis) among newborns was traced to transfer of the yeast from the hands of health-care workers with pet dogs at home. 1346 In addition, an outbreak of ringworm in a NICU caused by Microsporum canis was associated with a nurse and her cat, 1347 and an outbreak of Rhodococcus (Gordona) bronchialis sternal SSIs after coronary-artery bypass surgery was traced to a colonized nurse whose dogs were culture-positive for the organism. 1348 In the latter outbreak, whether the dogs were the sole source of the organism and whether other environmental reservoirs contributed to the outbreak are unknown. Nonetheless, limited data indicate that outbreaks of infectious disease have occurred as a result of contact with animals in areas housing immunocompetent patients. However, the low frequency of outbreaks may result from a. the relatively limited presence of the animals in health-care facilities and b. the immunocompetency of the patients involved in the encounters.\nFormal scientific studies to evaluate potential risks of transmission of zoonoses in health-care settings outside of the laboratory are lacking.\n# Animal-Assisted Activities, Animal-Assisted Therapy, and Resident Animals\nAnimal-Assisted Activities (AAA) are those programs that enhance the patients' quality of life. These programs allow patients to visit animals in either a common, central location in the facility or in individual patient rooms. A group session with the animals enhances opportunities for ambulatory patients and facility residents to interact with caregivers, family members, and volunteers. [1349][1350][1351] Alternatively, allowing the animals access to individual rooms provides the same opportunity to nonambulatory patients and patients for whom privacy or dignity issues are a consideration. The decision to allow this access to patients' rooms should be made on a case-by-case basis, with the consultation and consent of the attending physician and nursing staff.\nAnimal-Assisted Therapy (AAT) is a goal-directed intervention that incorporates an animal into the treatment process provided by a credentialed therapist. 1330,1331 The concept for AAT arose from the observation that some patients with pets at home recover from surgical and medical procedures more rapidly than patients without pets. 1352,1353 Contact with animals is considered beneficial for enhancing wellness in certain patient populations (e.g., children, the elderly, and extended-care hospitalized patients). 1349,[1354][1355][1356][1357] However, evidence supporting this benefit is largely derived from anecdotal reports and observations of patient/animal interactions. [1357][1358][1359] Guidelines for establishing AAT programs are available for facilities considering this option. 1360 The incorporation of non-human primates into an AAA or AAT program is not encouraged because of concerns regarding potential disease transmission from and unpredictable behavior of these animals. 1361,1362 Animals participating in either AAA or AAT sessions should be in good health and up-to-date with recommended immunizations and prophylactic medications (e.g., heartworm prevention) as determined by a licensed veterinarian based on local needs and recommendations. Regular re-evaluation of the animal's health and behavior status is essential. 1360 Animals should be routinely screened for enteric parasites and/or have evidence of a recently completed antihelminthic regimen. 1363 They should also be free of ectoparasites (e.g., fleas and ticks) and should have no sutures, open wounds, or obvious dermatologic lesions that could be associated with bacterial, fungal, or viral infections or parasitic infestations. Incorporating young animals (i.e., those aged <1 year) into these programs is not encouraged because of issues regarding unpredictable behavior and elimination control. Additionally, health of these animals at risk. Animals should be clean and well-groomed. The visits must be supervised by persons who know the animals and their behavior. Animal handlers should be trained in these activities and receive site-specific orientation to ensure that they work efficiently with the staff in the specific healthcare environment. 1360 Additionally, animal handlers should be in good health. 1360 The most important infection-control measure to prevent potential disease transmission is strict enforcement of hand-hygiene measures (e.g., using either soap and water or an alcohol-based hand rub) for all patients, staff, and residents after handling the animals. 1355,1364 Care should also be taken to avoid direct contact with animal urine or feces. Clean-up of these substances from environmental surfaces requires gloves and the use of leak-resistant plastic bags to discard absorbent material used in the process. 2 The area must be cleaned after visits according to standard cleaning procedures.\nThe American Academy of Allergy, Asthma, and Immunology estimates that dog or cat allergies occur in approximately 15% of the population. 1365 Minimizing contact with animal saliva, dander, and/or urine helps to mitigate allergic responses. 1365-1367 Some facilities may not allow animal visitation for patients with a. underlying asthma, b. known allergies to cat or dog hair, c. respiratory allergies of unknown etiology, and d. immunosuppressive disorders.\nHair shedding can be minimized by processes that remove dead hair (e.g., grooming) and that prevent the shedding of dead hair (e.g., therapy capes for dogs). Allergens can be minimized by bathing therapy animals within 24 hours of a visit. 1333,1368 Animal therapists and handlers must take precautions to prevent animal bites. Common pathogens associated with animal bites include Capnocytophaga canimorsus, Pasteurella spp., Staphylococcus spp., and Streptococcus spp. Selecting well-behaved and well-trained animals for these programs greatly decreases the incidence of bites. Rodents, exotic species, wild/domestic animals (i.e., wolf-dog hybrids), and wild animals whose behavior is unpredictable should be excluded from AAA or AAT programs. A well-trained animal handler should be able to recognize stress in the animal and to determine when to terminate a session to minimize risk. When an animal bites a person during AAA or AAT, the animal is to be permanently removed from the program. If a bite does occur, the wound must be cleansed immediately and monitored for subsequent infection. Most infections can be treated with antibiotics, and antibiotics often are prescribed prophylactically in these situations.\nThe health-care facility's infection-control staff should participate actively in planning for and coordinating AAA and AAT sessions. Many facilities do not offer AAA or AAT programs for severely immunocompromised patients (e.g., HSCT patients and patients on corticosteroid therapy). 1339 The question of whether family pets or companion animals can visit terminally-ill HSCT patients or other severely immunosuppressed patients is best handled on a case-by-case basis, although animals should not be brought into the HSCT unit or any other unit housing severely immunosuppressed patients. An indepth discussion of this issue is presented elsewhere. 1366 Immunocompromised patients who have been discharged from a health-care facility may be at higher risk for acquiring some pet-related zoonoses. Although guidelines have been developed to minimize the risk of disease transmission to HIV-infected patients, 8 these recommendations may be applicable for patients with other immunosuppressive disorders. In addition to handwashing or hand hygiene, these recommendations include avoiding contact with a. animal feces and soiled litter box materials, b. animals with diarrhea, c. very young animals (i.e., dogs <6 months of age and cats <1 year of age), and d. exotic animals and reptiles. 8 Pets or companion animals with diarrhea should receive veterinary care to resolve their condition.\nMany health-care facilities are adopting more home-like environments for residential-care or extendedstay patients in acute-care settings, and resident animals are one element of this approach. 1369 One concept, the \"Eden Alternative,\" incorporates children, plants, and animals (e.g., dogs, cats, fish, birds, rabbits, and rodents) into the daily care setting. 1370,1371 The concept of working with resident animals has not been scientifically evaluated. Several issues beyond the benefits of therapy must be considered before embarking on such a program, including a. whether the animals will come into direct contact with patients and/or be allowed to roam freely in the facility b. how the staff will provide care for the animals; c. the management of patients' or residents' allergies, asthma, and phobias; d. precautionary measures to prevent bites and scratches; and e. measures to properly manage the disposal of animal feces and urine, thereby preventing environmental contamination by zoonotic microorganisms (e.g., Toxoplasma spp., Toxocara spp., and Ancylostoma spp.). 1372,1373 Few data document a link between health-care acquired infection rates and frequency of cleaning fish tanks or rodent cages. Skin infections caused by Mycobacterium marinum have been described among persons who have fish aquariums at home. 1374,1375 Nevertheless, immunocompromised patients should avoid direct contact with fish tanks and cages and the aerosols that these items produce. Further, fish tanks should be kept clean on a regular basis as determined by facility policy, and this task should be performed by gloved staff members who are not responsible for patient care. The use of the infectioncontrol risk assessment can help determine whether a fish tank poses a risk for patient or resident safety and health in these situations. No evidence, however, links the incidence of health-care acquired infections among immunocompetent patients or residents with the presence of a properly cleaned and maintained fish tank, even in dining areas. As a general preventive measure, resident animal programs are advised to restrict animals from a. food preparation kitchens, b. laundries, c. central sterile supply and any storage areas for clean supplies, and d. medication preparation areas.\nResident-animal programs in acute-care facilities should not allow the animals into the isolation areas, protective environments, ORs, or any area where immunocompromised patients are housed. Patients and staff routinely should wash their hands or use waterless, alcohol-based hand-hygiene products after contact with animals.\n# Service Animals\nAlthough this section provides an overview about service animals in health-care settings, it cannot address every situation or question that may arise (see Appendix E -Information Resources). A service animal is any animal individually trained to do work or perform tasks for the benefit of a person with a disability. 1366, 1376 A service animal is not considered a pet but rather an animal trained to provide assistance to a person because of a disability. Title III of the \"Americans with Disabilities Act\" (ADA) of 1990 mandates that persons with disabilities accompanied by service animals be allowed access with their service animals into places of public accommodation, including restaurants, public transportation, schools, and health-care facilities. 1366,1376 In health-care facilities, a person with a disability requiring a service animal may be an employee, a visitor, or a patient.\nAn overview of the subject of service animals and their presence in health-care facilities has been published. 1366 No evidence suggests that animals pose a more significant risk of transmitting infection than people; therefore, service animals should not be excluded from such areas, unless an individual patient's situation or a particular animal poses greater risk that cannot be mitigated through reasonable measures. If health-care personnel, visitors, and patients are permitted to enter care areas (e.g., inpatient rooms, some ICUs, and public areas) without taking additional precautions to prevent transmission of infectious agents (e.g., donning gloves, gowns, or masks), a clean, healthy, well-behaved service animal should be allowed access with its handler. 1366 Similarly, if immunocompromised patients are able to receive visitors without using protective garments or equipment, an exclusion of service animals from this area would not be justified. 1366 Because health-care facilities are covered by the ADA or the Rehabilitation Act, a person with a disability may be accompanied by a service animal within the facility unless the animal's presence or behavior creates a fundamental alteration in the nature of a facility's services in a particular area or a direct threat to other persons in a particular area. 1366 A \"direct threat\" is defined as a significant risk to the health or safety of others that cannot be mitigated or eliminated by modifying policies, practices, or procedures. 1376 The determination that a service animal poses a direct threat in any particular healthcare setting must be based on an individualized assessment of the service animal, the patient, and the health-care situation.\nWhen evaluating risk in such situations, health-care personnel should consider the nature of the risk (including duration and severity); the probability that injury will occur; and whether reasonable modifications of policies, practices, or procedures will mitigate the risk (J. Wodatch, U.S. Department of Justice, 2000). The person with a disability should contribute to the risk-assessment process as part of a pre-procedure health-care provider/patient conference.\nExcluding a service animal from an OR or similar special care areas (e.g., burn units, some ICUs, PE units, and any other area containing equipment critical for life support) is appropriate if these areas are considered to have \"restricted access\" with regards to the general public. General infection-control measures that dictate such limited access include a. the area is required to meet environmental criteria to minimize the risk of disease transmission, b. strict attention to hand hygiene and absence of dermatologic conditions, and c. barrier protective measures [e.g., using gloves, wearing gowns and masks] are indicated for persons in the affected space.\nNo infection-control measures regarding the use of barrier precautions could be reasonably imposed on the service animal. Excluding a service animal that becomes threatening because of a perceived danger to its handler during treatment also is appropriate; however, exclusion of such an animal must be based on the actual behavior of the particular animal, not on speculation about how the animal might behave.\nAnother issue regarding service animals is whether to permit persons with disabilities to be accompanied by their service animals during all phases of their stay in the health-care facility. Healthcare personnel should discuss all aspects of anticipatory care with the patient who uses a service animal. Health-care personnel may not exclude a service animal because health-care staff may be able to perform the same services that the service animal does (e.g., retrieving dropped items and guiding an otherwise ambulatory person to the restroom). Similarly, health-care personnel can not exclude service animals because the health-care staff perceive a lack of need for the service animal during the person's stay in the health-care facility. A person with a disability is entitled to independent access (i.e., to be accompanied by a service animal unless the animal poses a direct threat or a fundamental alteration in the nature of services); \"need\" for the animal is not a valid factor in either analysis. For some forms of care (e.g., ambulation as physical therapy following total hip replacement or knee replacement), the service animal should not be used in place of a credentialed health-care worker who directly provides therapy. However, service animals need not be restricted from being in the presence of its handler during this time; in addition, rehabilitation and discharge planning should incorporate the patient's future use of the animal. The health-care personnel and the patient with a disability should discuss both the possible need for the service animal to be separated from its handler for a period of time during non-emergency care and an alternate plan of care for the service animal in the event the patient is unable or unwilling to provide that care. This plan might include family members taking the animal out of the facility several times a day for exercise and elimination, the animal staying with relatives, or boarding off-site. Care of the service animal, however, remains the obligation of the person with the disability, not the health-care staff.\nAlthough animals potentially carry zoonotic pathogens transmissible to man, the risk is minimal with a healthy, clean, vaccinated, well-behaved, and well-trained service animal, the most common of which are dogs and cats. No reports have been published regarding infectious disease that affects humans originating in service dogs. Standard cleaning procedures are sufficient following occupation of an area by a service animal. 1366 Clean-up of spills of animal urine, feces, or other body substances can be accomplished with blood/body substance procedures outlined in the Environmental Services section of this guideline. No special bathing procedures are required prior to a service animal accompanying its handler into a health-care facility.\nProviding access to exotic animals (e.g., reptiles and non-human primates) that are used as service animals is problematic. Concerns about these animals are discussed in two published reviews. 1331,1366 Because some of these animals exhibit high-risk behaviors that may increase the potential for zoonotic disease transmission (e.g., herpes B infection), providing health-care facility access to nonhuman primates used as service animals is discouraged, especially if these animals might come into contact with the general public. 1361,1362 Health-care administrators should consult the Americans with Disabilities Act for guidance when developing policies about service animals in their facilities. 1366,1376 Requiring documentation for access of a service animal to an area generally accessible to the public would impose a burden on a person with a disability. When health-care workers are not certain that an animal is a service animal, they may ask the person who has the animal if it is a service animal required because of a disability; however, no certification or other documentation of service animal status can be required. 1377 \n# Animals as Patients in Human Health-Care Facilities\nThe potential for direct and indirect transmission of zoonoses must be considered when rooms and equipment in human health-care facilities are used for the medical or surgical treatment or diagnosis of animals. 1378 Inquiries should be made to veterinary medical professionals to determine an appropriate facility and equipment to care for an animal.\nThe central issue associated with providing medical or surgical care to animals in human health-care facilities is whether cross-contamination occurs between the animal patient and the human health-care workers and/or human patients. The fundamental principles of infection control and aseptic practice should differ only minimally, if at all, between veterinary medicine and human medicine. Health-careassociated infections can and have occurred in both patients and workers in veterinary medical facilities when lapses in infection-control procedures are evident. [1379][1380][1381][1382][1383][1384] Further, veterinary patients can be at risk for acquiring infection from veterinary health-care workers if proper precautions are not taken. 1385 The issue of providing care to veterinary patients in human health-care facilities can be divided into the following three areas of infection-control concerns: a. whether the room/area used for animal care can be made safe for human patients, b. whether the medical/surgical instruments used on animals can be subsequently used on human patients, and c. which disinfecting or sterilizing procedures need to be done for these purposes.\nStudies addressing these concerns are lacking. However, with respect to disinfection or sterilization in veterinary settings, only minimal evidence suggests that zoonotic microbial pathogens are unusually resistant to inactivation by chemical or physical agents (with the exception of prions). Ample evidence supports the contrary observation (i.e., that pathogens from human-and animal sources are similar in their relative instrinsic resistance to inactivation). [1386][1387][1388][1389][1390][1391] Further, no evidence suggests that zoonotic pathogens behave differently from human pathogens with respect to ventilation. Despite this knowledge, an aesthetic and sociologic perception that animal care must remain separate from human care persists. Health-care facilities, however, are increasingly faced with requests from the veterinary medical community for access to human health-care facilities for reasons that are largely economical (e.g., costs of acquiring sophisticated diagnostic technology and complex medical instruments). If hospital guidelines allow treatment of animals, alternate veterinary resources (including veterinary hospitals, clinics, and universities) should be exhausted before using human health-care settings. Additionally, the hospital's public/media relations should be notified of the situation. The goal is to develop policies and procedures to proactively and positively discuss and disclose this activity to the general public.\nAn infection-control risk assessment (ICRA) must be undertaken to evaluate the circumstances specific to providing care to animals in a human health-care facility. Individual hospital policies and guidelines should be reviewed before any animal treatment is considered in such facilities. Animals treated in human health-care facilities should be under the direct care and supervision of a licensed veterinarian; they also should be free of known infectious diseases, ectoparasites, and other external contaminants (e.g., soil, urine, and feces). Measures should be taken to avoid treating animals with a known or suspected zoonotic disease in a human health-care setting (e.g., lambs being treated for Q fever).\nIf human health-care facilities must be used for animal treatment or diagnostics, the following general infection-control actions are suggested: a. whenever possible, the use of ORs or other rooms used for invasive procedures should be avoided [e.g., cardiac catheterization labs and invasive nuclear medicine areas] b. when all other space options are exhausted and use of the aforementioned rooms is unavoidable, the procedure should be scheduled late in the day as the last procedure for that particular area such that patients are not present in the department/unit/area; c. environmental surfaces should be thoroughly cleaned and disinfected using procedures discussed in the Environmental Services portion of this guideline after the animal is removed from the care area; d. sufficient time should be allowed for ACH to help prevent allergic reactions by human patients [Table B.1. in Appendix B]; e. only disposable equipment or equipment that can be thoroughly and easily cleaned, disinfected, or sterilized should be used; f. when medical or surgical instruments, especially those invasive instruments that are difficult to clean [e.g., endoscopes], are used on animals, these instruments should be reserved for future use only on animals; and g) standard precautions should be followed.\n# Research Animals in Health-Care Facilities\nThe risk of acquiring a zoonotic infection from research animals has decreased in recent years because many small laboratory animals (e.g., mice, rats, and rabbits) come from quality stock and have defined microbiologic profiles. 1392 Larger animals (e.g., nonhuman primates) are still obtained frequently from the wild and may harbor pathogens transmissible to humans. Primates, in particular, benefit from vaccinations to protect their health during the research period provided the vaccination does not interfere with the study of the particular agent. Animals serving as models for human disease studies pose some risk for transmission of infection to laboratory or health-care workers from percutaneous or mucosal exposure. Exposures can occur either through a. direct contact with an infected animal or its body substances and secretions or b. indirect contact with infectious material on equipment, instruments, surfaces, or supplies. 1392 Uncontained aerosols generated during laboratory procedures can also transmit infection.\nInfection-control measures to prevent transmission of zoonotic infections from research animals are largely derived from the following basic laboratory safety principles: a. purchasing pathogen-free animals, b. quarantining incoming animals to detect any zoonotic pathogens, c. treating infected animals or removing them from the facility, d. vaccinating animal carriers and high-risk contacts if possible, e. using specialized containment caging or facilities, and f. using protective clothing and equipment [e.g., gloves, face shields, gowns, and masks]. 1392 An excellent resource for detailed discussion of these safety measures has been published. 1013 The animal research unit within a health-care facility should be engineered to provide a. adequate containment of animals and pathogens; b. daily decontamination and transport of equipment and waste; c. proper ventilation and air filtration, which prevents recirculation of the air in the unit to other areas of the facility; and d. negative air pressure in the animal rooms relative to the corridors.\nTo ensure adequate security and containment, no through traffic to other areas of the health-care facility should flow through this unit; access should be restricted to animal-care staff, researchers, environmental services, maintenance, and security personnel.\nOccupational health programs for animal-care staff, researchers, and maintenance staff should take into consideration the animals' natural pathogens and research pathogens. Components of such programs include a. prophylactic vaccines, b. TB skin testing when primates are used, c. baseline serums, and d. hearing and respiratory testing.\nWork practices, PPE, and engineering controls specific for each of the four animal biosafety levels have been published. 1013,1393 The facility's occupational or employee health clinic should be aware of the appropriate post-exposure procedures involving zoonoses and have available the appropriate postexposure biologicals and medications.\nAnimal-research-area staff should also develop standard operating procedures for a. daily animal husbandry [e.g., protection of the employee while facilitating animal welfare] b. pathogen containment and decontamination; c. management, cleaning, disinfecting and/or sterilizing equipment and instruments; and d. employee training for laboratory safety and safety procedures specific to animal research worksites. 1013 The federal Animal Welfare Act of 1966 and its amendments serve as the regulatory basis for ensuring animal welfare in research. 1394,1395 I. Regulated Medical Waste\n# Epidemiology\nNo epidemiologic evidence suggests that most of the solid-or liquid wastes from hospitals, other healthcare facilities, or clinical/research laboratories is any more infective than residential waste. Several studies have compared the microbial load and the diversity of microorganisms in residential wastes and wastes obtained from a variety of health-care settings. [1399][1400][1401][1402] Although hospital wastes had a greater number of different bacterial species compared with residential waste, wastes from residences were more heavily contaminated. 1397,1398 Moreover, no epidemiologic evidence suggests that traditional wastedisposal practices of health-care facilities (whereby clinical and microbiological wastes were decontaminated on site before leaving the facility) have caused disease in either the health-care setting or the general community. 1400,1401 This statement excludes, however, sharps injuries sustained during or immediately after the delivery of patient care before the sharp is \"discarded.\" Therefore, identifying wastes for which handling and disposal precautions are indicated is largely a matter of judgment about the relative risk of disease transmission, because no reasonable standards on which to base these determinations have been developed. Aesthetic and emotional considerations (originating during the early years of the HIV epidemic) have, however, figured into the development of treatment and disposal policies, particularly for pathology and anatomy wastes and sharps. [1402][1403][1404][1405] Public concerns have resulted in the promulgation of federal, state, and local rules and regulations regarding medical waste management and disposal. [1406][1407][1408][1409][1410][1411][1412][1413][1414] \n# Categories of Medical Waste\nPrecisely defining medical waste on the basis of quantity and type of etiologic agents present is virtually impossible. The most practical approach to medical waste management is to identify wastes that represent a sufficient potential risk of causing infection during handling and disposal and for which some precautions likely are prudent. 2 Health-care facility medical wastes targeted for handling and disposal precautions include microbiology laboratory waste (e.g., microbiologic cultures and stocks of microorganisms), pathology and anatomy waste, blood specimens from clinics and laboratories, blood products, and other body-fluid specimens. 2 Moreover, the risk of either injury or infection from certain sharp items (e.g., needles and scalpel blades) contaminated with blood also must be considered. Although any item that has had contact with blood, exudates, or secretions may be potentially infective, treating all such waste as infective is neither practical nor necessary. Federal, state, and local guidelines and regulations specify the categories of medical waste that are subject to regulation and outline the requirements associated with treatment and disposal. The categorization of these wastes has generated the term \"regulated medical waste.\" This term emphasizes the role of regulation in defining the actual material and as an alternative to \"infectious waste,\" given the lack of evidence of this type of waste's infectivity. State regulations also address the degree or amount of contamination (e.g., blood-soaked gauze) that defines the discarded item as a regulated medical waste. The EPA's Manual for Infectious Waste Management identifies and categorizes other specific types of waste generated in health-care facilities with research laboratories that also require handling precautions. 1406 \n# Management of Regulated Medical Waste in Health-Care Facilities\nMedical wastes require careful disposal and containment before collection and consolidation for treatment. OSHA has dictated initial measures for discarding regulated medical-waste items. These measures are designed to protect the workers who generate medical wastes and who manage the wastes from point of generation to disposal. 967 A single, leak-resistant biohazard bag is usually adequate for containment of regulated medical wastes, provided the bag is sturdy and the waste can be discarded without contaminating the bag's exterior. The contamination or puncturing of the bag requires placement into a second biohazard bag. All bags should be securely closed for disposal. Puncture-resistant containers located at the point of use (e.g., sharps containers) are used as containment for discarded slides or tubes with small amounts of blood, scalpel blades, needles and syringes, and unused sterile sharps. 967 To prevent needlestick injuries, needles and other contaminated sharps should not be recapped, purposefully bent, or broken by hand. CDC has published general guidelines for handling sharps. 6,1415 Health-care facilities may need additional precautions to prevent the production of aerosols during the handling of blood-contaminated items for certain rare diseases or conditions (e.g., Lassa fever and Ebola virus infection). 203 Transporting and storing regulated medical wastes within the health-care facility prior to terminal treatment is often necessary. Both federal and state regulations address the safe transport and storage of on-and off-site regulated medical wastes. [1406][1407][1408] Health-care facilities are instructed to dispose medical wastes regularly to avoid accumulation. Medical wastes requiring storage should be kept in labeled, leakproof, puncture-resistant containers under conditions that minimize or prevent foul odors. The storage area should be well ventilated and be inaccessible to pests. Any facility that generates regulated medical wastes should have a regulated medical waste management plan to ensure health and environmental safety as per federal, state, and local regulations.\n# Treatment of Regulated Medical Waste\nRegulated medical wastes are treated or decontaminated to reduce the microbial load in or on the waste and to render the by-products safe for further handling and disposal. From a microbiologic standpoint, waste need not be rendered \"sterile\" because the treated waste will not be deposited in a sterile site. In addition, waste need not be subjected to the same reprocessing standards as are surgical instruments. Historically, treatment methods involved steam-sterilization (i.e., autoclaving), incineration, or interment (for anatomy wastes). Alternative treatment methods developed in recent years include chemical disinfection, grinding/shredding/disinfection methods, energy-based technologies (e.g., microwave or radiowave treatments), and disinfection/encapsulation methods. 1409 State medical waste regulations specify appropriate treatment methods for each category of regulated medical waste.\nOf all the categories comprising regulated medical waste, microbiologic wastes (e.g., untreated cultures, stocks, and amplified microbial populations) pose the greatest potential for infectious disease transmission, and sharps pose the greatest risk for injuries. Untreated stocks and cultures of microorganisms are subsets of the clinical laboratory or microbiologic waste stream. If the microorganism must be grown and amplified in culture to high concentration to permit work with the specimen, this item should be considered for on-site decontamination, preferably within the laboratory unit. Historically, this was accomplished effectively by either autoclaving (steam sterilization) or incineration. If steam sterilization in the health-care facility is used for waste treatment, exposure of the waste for up to 90 minutes at 250°F (121°C) in a autoclave (depending on the size of the load and type container) may be necessary to ensure an adequate decontamination cycle. [1416][1417][1418] After steam sterilization, the residue can be safely handled and discarded with all other nonhazardous solid waste in accordance with state solidwaste disposal regulations. On-site incineration is another treatment option for microbiologic, pathologic, and anatomic waste, provided the incinerator is engineered to burn these wastes completely and stay within EPA emissions standards. 1410 Improper incineration of waste with high moisture and low energy content (e.g., pathology waste) can lead to emission problems. State medical-waste regulatory programs identify acceptable methods for inactivating amplified stocks and cultures of microorganisms, some of which may employ technology rather than steam sterilization or incineration.\nConcerns have been raised about the ability of modern health-care facilities to inactivate microbiologic wastes on-site, given that many of these institutions have decommissioned their laboratory autoclaves. Current laboratory guidelines for working with infectious microorganisms at biosafety level (BSL) 3 recommend that all laboratory waste be decontaminated before disposal by an approved method, preferably within the laboratory. 1013 These same guidelines recommend that all materials removed from a BSL 4 laboratory (unless they are biological materials that are to remain viable) are to be decontaminated before they leave the laboratory. 1013 Recent federal regulations for laboratories that handle certain biological agents known as \"select agents\" (i.e., those that have the potential to pose a severe threat to public health and safety) require these agents (and those obtained from a clinical specimen intended for diagnostic, reference, or verification purposes) to be destroyed on-site before disposal. 1412 Although recommendations for laboratory waste disposal from BSL 1 or 2 laboratories (e.g., most health-care clinical and diagnostic laboratories) allow for these materials to be decontaminated off-site before disposal, on-site decontamination by a known effective method is preferred to reduce the potential of exposure during the handling of infectious material.\nA recent outbreak of TB among workers in a regional medical-waste treatment facility in the United States demonstrated the hazards associated with aerosolized microbiologic wastes. 1419,1420 The facility received diagnostic cultures of Mycobacterium tuberculosis from several different health-care facilities before these cultures were chemically disinfected; this facility treated this waste with a grinding/shredding process that generated aerosols from the material. 1419,1420 Several operational deficiencies facilitated the release of aerosols and exposed workers to airborne M. tuberculosis. Among the suggested control measures was that health-care facilities perform on-site decontamination of laboratory waste containing live cultures of microorganisms before release of the waste to a waste management company. 1419,1420 This measure is supported by recommendations found in the CDC/NIH guideline for laboratory workers. 1013 This outbreak demonstrates the need to avoid the use of any medical-waste treatment method or technology that can aerosolize pathogens from live cultures and stocks (especially those of airborne microorganisms) unless aerosols can be effectively contained and workers can be equipped with proper PPE. [1419][1420][1421] Safe laboratory practices, including those addressing waste management, have been published. 1013,1422 In an era when local, state, and federal health-care facilities and laboratories are developing bioterrorism response strategies and capabilities, the need to reinstate in-laboratory capacity to destroy cultures and stocks of microorganisms becomes a relevant issue. 1423 Recent federal regulations require health-care facility laboratories to maintain the capability of destroying discarded cultures and stocks on-site if these laboratories isolate from a clinical specimen any microorganism or toxin identified as a \"select agent\" from a clinical specimen (Table 27). 1412,1413 As an alternative, isolated cultures of select agents can be transferred to a facility registered to accept these agents in accordance with federal regulations. 1412 State medical waste regulations can, however, complicate or completely prevent this transfer if these cultures are determined to be medical waste, because most states regulate the inter-facility transfer of untreated medical wastes. \n# Discharging Blood, Fluids to Sanitary Sewers or Septic Tanks\nThe contents of all vessels that contain more than a few milliliters of blood remaining after laboratory procedures, suction fluids, or bulk blood can either be inactivated in accordance with state-approved treatment technologies or carefully poured down a utility sink drain or toilet. 1414 State regulations may dictate the maximum volume allowable for discharge of blood/body fluids to the sanitary sewer. No evidence indicates that bloodborne diseases have been transmitted from contact with raw or treated sewage. Many bloodborne pathogens, particularly bloodborne viruses, are not stable in the environment for long periods of time; 1425,1426 therefore, the discharge of small quantities of blood and other body fluids to the sanitary sewer is considered a safe method of disposing of these waste materials. 1414 The following factors increase the likelihood that bloodborne pathogens will be inactivated in the disposal process: a. dilution of the discharged materials with water b. inactivation of pathogens resulting from exposure to cleaning chemicals, disinfectants, and other chemicals in raw sewage; and c. effectiveness of sewage treatment in inactivating any residual bloodborne pathogens that reach the treatment facility.\nSmall amounts of blood and other body fluids should not affect the functioning of a municipal sewer system. However, large quantities of these fluids, with their high protein content, might interfere with the biological oxygen demand (BOD) of the system. Local municipal sewage treatment restrictions may dictate that an alternative method of bulk fluid disposal be selected. State regulations may dictate what quantity constitutes a small amount of blood or body fluids.\nAlthough concerns have been raised about the discharge of blood and other body fluids to a septic tank system, no evidence suggests that septic tanks have transmitted bloodborne infections. A properly functioning septic system is adequate for inactivating bloodborne pathogens. System manufacturers' instructions specify what materials may be discharged to the septic tank without jeopardizing its proper operation.\n# Medical Waste and CJD\nConcerns also have been raised about the need for special handling and treatment procedures for wastes generated during the care of patients with CJD or other transmissible spongiform encephalopathies (TSEs). Prions, the agents that cause TSEs, have significant resistance to inactivation by a variety of physical, chemical, or gaseous methods. 1427 No epidemiologic evidence, however, links acquisition of CJD with medical-waste disposal practices. Although handling neurologic tissue for pathologic examination and autopsy materials with care, using barrier precautions, and following specific procedures for the autopsy are prudent measures, 1197 employing extraordinary measures once the materials are discarded is unnecessary. Regulated medical wastes generated during the care of the CJD patient can be managed using the same strategies as wastes generated during the care of other patients. After decontamination, these wastes may then be disposed in a sanitary landfill or discharged to the sanitary sewer, as appropriate.\n# Part II. Recommendations for Environmental Infection Control in Health-Care Facilities\n\n# A. Rationale for Recommendations\nAs in previous CDC guidelines, each recommendation is categorized on the basis of existing scientific data, theoretic rationale, applicability, and possible economic benefit. The recommendations are evidence-based wherever possible. However, certain recommendations are derived from empiric infection-control or engineering principles, theoretic rationale, or from experience gained from events that cannot be readily studied (e.g., floods).\nThe HICPAC system for categorizing recommendations has been modified to include a category for engineering standards and actions required by state or federal regulations. Guidelines and standards published by the American Institute of Architects (AIA), American Society of Heating, Refrigeration, and Air-Conditioning Engineers (ASHRAE), and the Association for the Advancement in Medical Instrumentation (AAMI) form the basis of certain recommendations. These standards reflect a consensus of expert opinions and extensive consultation with agencies of the U.S. Department of Health and Human Services. Compliance with these standards is usually voluntary. However, state and federal governments often adopt these standards as regulations. For example, the standards from AIA regarding construction and design of new or renovated health-care facilities, have been adopted by reference by >40 states. Certain recommendations have two category ratings (e.g., Categories IA and IC or Categories IB and IC), indicating the recommendation is evidence-based as well as a standard or regulation.\n# B. Rating Categories\nRecommendations are rated according to the following categories: • * Develop and implement a maintenance schedule for ACH, pressure differentials, and filtration efficiencies using facility-specific data as part of the multidisciplinary risk assessment. Take into account the age and reliability of the system. • * Document these parameters, especially the pressure differentials. 3. Engineer humidity controls into the HVAC system and monitor the controls to ensure proper moisture removal. 120 Category IC (AIA: 7.31.D9)\n•\n• * Locate duct humidifiers upstream from the final filters.\n• * Incorporate a water-removal mechanism into the system.\n• * Locate all duct takeoffs sufficiently down-stream from the humidifier so that moisture is completely absorbed. 4. Incorporate steam humidifiers, if possible, to reduce potential for microbial proliferation within the system, and avoid use of cool mist humidifiers. Category II 5. Ensure that air intakes and exhaust outlets are located properly in construction of new facilities and renovation of existing facilities. • * Locate exhaust outlets from contaminated areas above roof level to minimize recirculation of exhausted air. 6. Maintain air intakes and inspect filters periodically to ensure proper operation. 3,120,249,250,[273][274][275]277 Category IC (AIA: 7.31.D8) 7. Bag dust-filled filters immediately upon removal to prevent dispersion of dust and fungal spores during transport within the facility. 106, 221 Category IB • * Seal or close the bag containing the discarded filter.\n• * Discard spent filters as regular solid waste, regardless of the area from which they were removed. 221 8. Remove bird roosts and nests near air intakes to prevent mites and fungal spores from entering the ventilation system. 3,98,119 Category IB 9. Prevent dust accumulation by cleaning air-duct grilles in accordance with facility-specific procedures and schedules when rooms are not occupied by patients. 21,120,249,250,[273][274][275]277 Category IC, II (AIA: 7.31.D10) 10. Periodically measure output to monitor system function; clean ventilation ducts as part of routine HVAC maintenance to ensure optimum performance. 120,263,264 Category II (AIA: 7.31.D10) C. Use portable, industrial-grade HEPA filter units capable of filtration rates in the range of 300-800 ft 3 /min. to augment removal of respirable particles as needed. 219 Category II M. Whenever feasible, design and install fixed backup ventilation systems for new or renovated construction for PE rooms, AII rooms, operating rooms, and other critical care areas identified by ICRA. 120 A. Establish a multidisciplinary team that includes infection-control staff to coordinate demolition, construction, and renovation projects and consider proactive preventive measures at the inception; produce and maintain summary statements of the team's activities. 17,19,20,97,109,120,249,250,[273][274][275][276][277] Category IB, IC (AIA: 5.1) B. Educate both the construction team and the health-care staff in immunocompromised patient-care areas regarding the airborne infection risks associated with construction projects, dispersal of fungal spores during such activities, and methods to control the dissemination of fungal spores. 3, 249, 250, 273-277, 1428-1432 Category IB C. Incorporate mandatory adherence agreements for infection control into construction contracts, with penalties for noncompliance and mechanisms to ensure timely correction of problems. 3,120,249,[273][274][275][276][277] Category IC (AIA: 5.1) D. Establish and maintain surveillance for airborne environmental disease (e.g., aspergillosis) as appropriate during construction, renovation, repair, and demolition activities to ensure the health and safety of immunocompromised patients. 3,64,65,79 Category IB 1. Using active surveillance, monitor for airborne fungal infections in immunocompromised patients. 3,9,64,65 Category IB 2. Periodically review the facility's microbiologic, histopathologic, and postmortem data to identify additional cases. 3,9,64,65 Category IB 3. If cases of aspergillosis or other health-care associated airborne fungal infections occur, aggressively pursue the diagnosis with tissue biopsies and cultures as feasible. 3,64,65,79,249,[273][274][275][276][277] Category IB E. Implement infection-control measures relevant to construction, renovation, maintenance, demolition, and repair. 96,97,120,276,277 Category IB, IC (AIA: 5.1, 5.2) 1. Before the project gets underway, perform an ICRA to define the scope of the project and the need for barrier measures. 96,97,120,249,[273][274][275][276][277] • * Determine if immunocompromised patients may be at risk for exposure to fungal spores from dust generated during the project. 20, 109, 273-275, 277 • * Develop a contingency plan to prevent such exposures. 20,109,[273][274][275]277 Category IB, IC (AIA: 5.1) 2. Implement infection-control measures for external demolition and construction activities. 50,249,[273][274][275][276][277]283 • * Determine if the facility can operate temporarily on recirculated air; if feasible, seal off adjacent air intakes. • * If this is not possible or practical, check the low-efficiency (roughing) filter banks frequently and replace as needed to avoid buildup of particulates. • * Seal windows and reduce wherever possible other sources of outside air intrusion (e.g., open doors in stairwells and corridors), especially in PE areas. Category IB 3. Avoid damaging the underground water distribution system (i.e., buried pipes) to prevent soil and dust contamination of the water. 120,305 Category IB, IC (AIA: 5.1) 121 4. Implement infection-control measures for internal construction activities. 20,49,97,120,249,[273][274][275][276][277] • * Construct barriers to prevent dust from construction areas from entering patient-care areas; ensure that barriers are impermeable to fungal spores and in compliance with local fire codes. 20,49,97,120,284,312,713,1431 • * Block and seal off return air vents if rigid barriers are used for containment. 120,276,277 • * Implement dust control measures on surfaces and by diverting pedestrian traffic away from work zones. 20, 49, 97, 120 • * Relocate patients whose rooms are adjacent to work zones, depending upon their immune status, the scope of the project, the potential for generation of dust or water aerosols, and the methods used to control these aerosols. 49,120,281 120,249,[273][274][275][276][277] ~ Category IB h. Clean work zones and their entrances daily by\n• wet-wiping tools and tool carts before their removal from the work zone;\n• placing mats with tacky surfaces inside the entrance; and\n• covering debris and securing this covering before removing debris from the work zone. 120,249,[273][274][275][276][277] ~ Category IB i. In patient-care areas, for major repairs that include removal of ceiling tiles and disruption of the space above the false ceiling, use plastic sheets or prefabricated plastic units to contain dust; use a negative pressure system within this enclosure to remove dust; and either pass air through an industrial grade, portable HEPA filter capable of filtration rates ranging from 300-800 ft 3 /min., or exhaust air directly to the outside. 49,276,277,281,309 • * properly constructing windows, doors, and intake and exhaust ports;\n• * maintaining ceilings that are smooth and free of fissures, open joints, and crevices;\n• * sealing walls above and below the ceiling, and\n• * monitoring for leakage and making necessary repairs. 3,111,120,317,318 Category IB, IC (AIA: 7.2.D3) 3. Ventilate the room to maintain ≥12 ACH. 3,9,120,241,317,318 Category IC (AIA: 7.2.D) 4. Locate air supply and exhaust grilles so that clean, filtered air enters from one side of the room, flows across the patient's bed, and exits from the opposite side of the room. 3,120,317,318 Category IC (AIA: 7.31.D1) 5. Maintain positive room air pressure (≥2.5 Pa [0.01-inch water gauge]) in relation to the corridor. 3,35,120,317,318 Category IB, IC (AIA: Table 7.2) 6. Maintain airflow patterns and monitor these on a daily basis by using permanently installed visual means of detecting airflow in new or renovated construction, or using other visual methods (e.g., flutter strips, or smoke tubes) in existing PE units. Document the monitoring results. 120,273 Category IC (AIA: 7.2.D6) 7. Install self-closing devices on all room exit doors in protective environments. 120 3. Place smallpox patients in negative pressure rooms at the onset of their illness, preferably using a room with an anteroom if available. 6 Category II D. No recommendation is offered regarding negative pressure or isolation rooms for patients with Pneumocystis carinii pneumonia. 126,131,132 Unresolved issue E. Maintain back-up ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for AII rooms and take immediate steps to restore the fixed ventilation system function. 4,120,278 Category IC (AIA: 5.1)\n# C.V. Infection-Control and Ventilation Requirements for Operating Rooms\nA. Implement environmental infection-control and ventilation measures for operating rooms. 1. Maintain positive-pressure ventilation with respect to corridors and adjacent areas. 7,120,356 Category IB, IC (AIA: Table 7.2) 2. Maintain ≥15 ACH, of which ≥3 ACH should be fresh air. 120,357,358 Category IC (AIA: Table 7.2) 3. Filter all recirculated and fresh air through the appropriate filters, providing 90% efficiency (dust-spot testing) at a minimum. 120,362 Category IC (AIA: Table 7.3) 4. In rooms not engineered for horizontal laminar airflow, introduce air at the ceiling and exhaust air near the floor. 120,357,359 B.1) because extubation is a coughproducing procedure. 4,358 Category IB C. Use portable, industrial-grade HEPA filters temporarily for supplemental air cleaning during intubation and extubation for infectious TB patients who require surgery. 4,219,358 Category II 1. Position the units appropriately so that all room air passes through the filter; obtain engineering consultation to determine the appropriate placement of the unit. 4 Category II 2. Switch the portable unit off during the surgical procedure. Category II 3. Provide fresh air as per ventilation standards for operating rooms; portable units do not meet the requirements for the number of fresh ACH. 120,215,219 Category II D. If possible, schedule infectious TB patients as the last surgical cases of the day to maximize the time available for removal of airborne contamination. Category II E. No recommendation is offered for performing orthopedic implant operations in rooms supplied with laminar airflow. 362,364 Unresolved issue F. Maintain backup ventilation equipment (e.g., portable units for fans or filters) for emergency provision of ventilation requirements for operating rooms, and take immediate steps to restore the fixed ventilation system function. 68,120,278,372 Category IB, IC (AIA: 5.1)\n# C.VI. Other Potential Infectious Aerosol Hazards in Health-Care Facilities\nA. In settings where surgical lasers are used, wear appropriate personal protective equipment, including N95 or N100 respirators, to minimize exposure to laser plumes. 347, 378, 389 Category IC (OSHA; 29 CFR 1910.134,139) B. Use central wall suction units with in-line filters to evacuate minimal laser plumes. 378,382,386,389 Category II C. Use a mechanical smoke evacuation system with a high-efficiency filter to manage the generation of large amounts of laser plume, when ablating tissue infected with human papilloma virus (HPV) or performing procedures on a patient with extrapulmonary TB. 4,382,[389][390][391][392] Category II\n# D. Recommendations-Water\n\n# D.I. Controlling the Spread of Waterborne Microoganisms\nA. Practice hand hygiene to prevent the hand transfer of waterborne pathogens, and use barrier precautions (e.g., gloves) as defined by other guidelines. 6,464,577,586,592,1364 • * Flush each outlet until chlorine odor is detected.\n• * Maintain the elevated chlorine concentration in the system for ≥2 hrs (but ≤24 hrs). 4. Use a very thorough flushing of the water system instead of chlorination if a highly chlorineresistant microorganism (e.g., Cryptosporidium spp.) is suspected as the water contaminant. Category II F. Flush and restart equipment and fixtures according to manufacturers' instructions. Category II G. Change the pretreatment filter and disinfect the dialysis water system with an EPA-registered product to prevent colonization of the reverse osmosis membrane and downstream microbial contamination. 721 Category II H. Run water softeners through a regeneration cycle to restore their capacity and function. Category II I. If the facility has a water-holding reservoir or water-storage tank, consult the facility engineer or local health department to determine whether this equipment needs to be drained, disinfected with an EPA-registered product, and refilled. Category II J. Implement facility management procedures to manage a sewage system failure or flooding (e.g., arranging with other health-care facilities for temporary transfer of patients or provision of services), and establish communications with the local municipal water utility and the local health department to ensure that advisories are received in a timely manner upon release. 713 These recommendations refer to the spraying or fogging of chemicals (e.g., formaldehyde, phenolbased agents, or quaternary ammonium compounds) as a way to decontaminate environmental surfaces or disinfect the air in patient rooms. The recommendation against fogging was based on studies in the 1970's that reported a lack of microbicidal efficacy (e.g., use of quaternary ammonium compounds in mist applications) but also adverse effects on healthcare workers and others in facilities where these methods were utilized. Furthermore, some of these chemicals are not EPA-registered for use in fogging-type applications. The 2003 recommendations still apply; however, CDC does not yet make a recommendation regarding these newer technologies. This issue will be revisited as additional evidence becomes available.\nG. Avoid large-surface cleaning methods that produce mists or aerosols or disperse dust in patient-care areas. 9,20,109,272 \n# H.II. Animal-Assisted Activities, Animal-Assisted Therapy, and Resident Animal Programs\nA. Avoid selection of nonhuman primates and reptiles in animal-assisted activities, animal-assisted therapy, or resident animal programs. 1360-1362 Category IB B. Enroll animals that are fully vaccinated for zoonotic diseases and that are healthy, clean, wellgroomed, and negative for enteric parasites or otherwise have completed recent antihelminthic treatment under the regular care of a veterinarian. 1349, 1360 Category II C. Enroll animals that are trained with the assistance or under the direction of individuals who are experienced in this field. 1360 Category II D. Ensure that animals are handled by persons trained in providing activities or therapies safely, and who know the animals' health status and behavior traits. 1349,1360 Category II E. Take prompt action when an incident of biting or scratching by an animal occurs during an animalassisted activity or therapy. 1. Remove the animal permanently from these programs. 1360 Category II 2. Report the incident promptly to appropriate authorities (e.g., infection-control staff, animal program coordinator, or local animal control). 1360 Category II 3. Promptly clean and treat scratches, bites, or other accidental breaks in the skin. Category II F. Perform an ICRA and work actively with the animal handler prior to conducting an animal-assisted activity or therapy to determine if the session should be held in a public area of the facility or in individual patient rooms. 1349,1360 Category II G. Take precautions to mitigate allergic responses to animals. Category II 1. Minimize shedding of animal dander by bathing animals <24 hours before a visit. 1360 Category II 2. Groom animals to remove loose hair before a visit, or using a therapy animal cape. 1358 Category II H. Use routine cleaning protocols for housekeeping surfaces after therapy sessions. Category II I. Restrict resident animals, including fish in fish tanks, from access to or placement in patient-care areas, food preparation areas, dining areas, laundry, central sterile supply areas, sterile and clean supply storage areas, medication preparation areas, operating rooms, isolation areas, and PE areas. Category II J. Establish a facility policy for regular cleaning of fish tanks, rodent cages, bird cages, and any other animal dwellings and assign this cleaning task to a nonpatient-care staff member; avoid splashing tank water or contaminating environmental surfaces with animal bedding. Category II\n# H.III. Protective Measures for Immunocompromised Patients\nA. Advise patients to avoid contact with animal feces and body fluids such as saliva, urine, or solid litter box material. 8 Category II B. Promptly clean and treat scratches, bites, or other wounds that break the skin. 8 Category II C. Advise patients to avoid direct or indirect contact with reptiles. 1340 Category IB D. Conduct a case-by-case assessment to determine if animal-assisted activities or animal-assisted therapy programs are appropriate for immunocompromised patients. 1349 Category II E. No recommendation is offered regarding permitting pet visits to terminally ill immunosuppressed patients outside their PE units. Unresolved issue\n# H.IV. Service Animals\nEdit [February 2017]: An * indicates recommendations that were renumbered for clarity. The renumbering does not constitute change to the intent of the recommendations.\nA. Avoid providing access to nonhuman primates and reptiles as service animals. 1340, 1362 Category IB B. Allow service animals access to the facility in accordance with the Americans with Disabilities Act of 1990, unless the presence of the animal creates a direct threat to other persons or a fundamental alteration in the nature of services. 1366,1376 Category IC (U.S. Department of Justice: 28 CFR § 36.302) C. When a decision must be made regarding a service animal's access to any particular area of the health-care facility, evaluate the service animal, the patient, and the health-care situation on a caseby-case basis to determine whether significant risk of harm exists and whether reasonable modifications in policies and procedures will mitigate this risk. 1376 Category IC (Justice: 28 CFR § 36.208 and App.B) D. If a patient must be separated from his or her service animal while in the health-care facility\n• * ascertain from the person what arrangements have been made for supervision or care of the animal during this period of separation; and • * make appropriate arrangements to address the patient's needs in the absence of the service animal. Category II\n# H.V. Animals as Patients in Human Health-Care Facilities\nA. Develop health-care facility policies to address the treatment of animals in human healthcare facilities.\n1. Use the multidisciplinary team approach to policy development, including public media relations in order to disclose and discuss these activities. Category II 2. Exhaust all veterinary facility, equipment, and instrument options before undertaking the procedure. Category II 3. Ensure that the care of the animal is supervised by a licensed veterinarian. Category II B. When animals are treated in human health-care facilities, avoid treating animals in operating rooms or other patient-care areas where invasive procedures are performed (e.g., cardiac catheterization laboratories, or invasive nuclear medicine areas). Category II C. Schedule the animal procedure for the last case of the day for the area, at a time when human patients are not scheduled to be in the vicinity. Category II D. Adhere strictly to standard precautions. Category II E. Clean and disinfect environmental surfaces thoroughly using an EPA-registered product in the room after the animal is removed. Category II F. Allow sufficient ACH to clean the air and help remove airborne dander, microorganisms, and allergens [Appendix B, \n# Part III. References\nNote: The bold item in parentheses indicated the citation number or the location of this reference listed in the MMWR version of this guideline.\nmicrobiological agents they work with. There are four biosafety levels based on the hazards associated with the various microbiological agents. BOD5: the amount of dissolved oxygen consumed in five days by biological processes breaking down organic matter. Bonneting: a floor cleaning method for either carpeted or hard surface floors that uses a circular motion of a large fibrous disc to lift and remove soil and dust from the surface. Capped spur: a pipe leading from the water recirculating system to an outlet that has been closed off (\"capped\"). A capped spur cannot be flushed, and it might not be noticed unless the surrounding wall is removed. CFU/m 3 : colony forming units per cubic meter (of air). Chlamydospores: thick-walled, typically spherical or ovoid resting spores asexually produced by certain types of fungi from cells of the somatic hyphae. Chloramines: compounds containing nitrogen, hydrogen, and chlorine. These are formed by the reaction between hypochlorous acid (HOCl) and ammonia (NH3) and/or organic amines in water. The formation of chloramines in drinking water treatment extends the disinfecting power of chlorine. The term is also referred to as Combined Available Chlorine.\nCleaning: the removal of visible soil and organic contamination from a device or surface, using either the physical action of scrubbing with a surfactant or detergent and water, or an energy-based process (e.g., ultrasonic cleaners) with appropriate chemical agents. Coagulation-flocculation: coagulation is the clumping of particles that results in the settling of impurities. It may be induced by coagulants (e.g., lime, alum, and iron salts). Flocculation in water and wastewater treatment is the agglomeration or clustering of colloidal and finely-divided suspended matter after coagulation by gentle stirring by either mechanical or hydraulic means, such that they can be separated from water or sewage. Commissioning (a room): testing a system or device to ensure that it meets the pre-use specifications as indicated by the manufacturer or predetermined standard, or air sampling in a room to establish a preoccupancy baseline standard of microbial or particulate contamination. The term is also referred to as benchmarking at 77°F (25°C).\nCompletely packaged: functionally packaged, as for laundry.\nConidia: asexual spores of fungi borne externally.\nConidiophores: specialized hyphae that bear conidia in fungi. Conditioned space: that part of a building that is heated or cooled, or both, for the comfort of the occupants. Contaminant: an unwanted airborne constituent that may reduce the acceptibility of air. Convection: the transfer of heat or other atmospheric properties within the atmosphere or in the airspace of an enclosure by the circulation of currents from one region to another, especially by such motion directed upward.\nCooling tower: a structure engineered to receive accumulated heat from ventilation systems and equipment and transfer this heat to water, which then releases the stored heat to the atmosphere through evaporative cooling.\nCritical item (medical instrument): a medical instrument or device that contacts normally sterile areas of the body or enters the vascular system. There is a high risk of infection from such devices if they are microbiologically contaminated prior to use. These devices must be sterilized before use. Dead legs: areas in the water system where water stagnates. A dead leg is a pipe or spur, leading from the water recirculating system to an outlet that is used infrequently, resulting in inadequate flow of water from the recirculating system to the outlet. This inadequate flow reduces the perfusion of heat or chlorine into this part of the water distribution system, thereby adversely affecting the disinfection of the water system in that area. Deionization: removal of ions from water by exchange with other ions associated with fixed charges on a resin bed. Cations are usually removed and H + ions are exchanged; OHions are exchanged for anions. Detritis: particulate matter produced by or remaining after the wearing away or disintegration of a substance or tissue. Dew point: the temperature at which a gas or vapor condenses to form a liquid; the point at which moisture begins to condense out of the air. At dew point, air is cooled to the point where it is at 100% relative humidity or saturation.\nDialysate: the aqueous electrolyte solution, usually containing dextrose, used to make a concentration gradient between the solution and blood in the hemodialyzer (dialyzer). Dialyzer: a device that consists of two compartments (blood and dialysate) separated by a semipermeable membrane. A dialyzer is usually referred to as an artificial kidney. Diffuser: the grille plate that disperses the air stream coming into the conditioned air space. Direct transmission: involves direct body surface-to-body surface contact and physical transfer of microorganisms between a susceptible host and an infected/colonized person, or exposure to cloud of infectious particles within 3 feet of the source; the aerosolized particles are >5 μm in size. Disability: as defined by the Americans with Disabilities Act, a disability is any physical or mental impairment that substantially limits one or more major life activities, including but not limited to walking, talking, seeing, breathing, hearing, or caring for oneself. Disinfection: a generally less lethal process of microbial inactivation (compared to sterilization) that eliminates virtually all recognized pathogenic microorganisms but not necessarily all microbial forms (e.g., bacterial spores). Drain pans: pans that collect water within the HVAC system and remove it from the system. Condensation results when air and steam come together. Drift: circulating water lost from the cooling tower in the form as liquid droplets entrained in the exhaust air stream (i.e., exhaust aerosols from a cooling tower). Drift eliminators: an assembly of baffles or labyrinth passages through which the air passes prior to its exit from the cooling tower. The purpose of a drift eliminator is to remove entrained water droplets from the exhaust air. Droplets: particles of moisture, such as are generated when a person coughs or sneezes, or when water is converted to a fine mist by a device such as an aerator or shower head. These particles may contain infectious microorganisms. Intermediate in size between drops and droplet nuclei, these particles tend to quickly settle out from the air so that any risk of disease transmission is generally limited to persons in close proximity to the droplet source. Droplet nuclei: sufficiently small particles (1-5 μm in diameter) that can remain airborne indefinitely and cause infection when a susceptible person is exposed at or beyond 3 feet of the source of these particles.\nDual duct system: an HVAC system that consists of parallel ducts that produce a cold air stream in one and a hot air stream in the other.\nDust: an air suspension of particles (aerosol) of any solid material, usually with particle sizes ≤100 μm in diameter.\nDust-spot test: a procedure that uses atmospheric air or a defined dust to measure a filter's ability to remove particles. A photometer is used to measure air samples on either side of the filter, and the difference is expressed as a percentage of particles removed. Effective leakage area: the area through which air can enter or leave the room. This does not include supply, return, or exhaust ducts. The smaller the effective leakage area, the better isolated the room. Endotoxin: the lipopolysaccharides of gram-negative bacteria, the toxic character of which resides in the lipid portion. Endotoxins generally produce pyrogenic reactions in persons exposed to these bacterial components.\nEnveloped virus: a virus whose outer surface is derived from a membrane of the host cell (either nuclear or the cell's outer membrane) during the budding phase of the maturation process. This membrane-derived material contains lipid, a component that makes these viruses sensitive to the action of chemical germicides. Evaporative condenser: a wet-type, heat-rejection unit that produces large volumes of aerosols during the process of removing heat from conditioned space air. Exhaust air: air removed from a space and not reused therein. Exposure: the condition of being subjected to something (e.g., infectious agents) that could have a harmful effect.\nFastidious: having complex nutritional requirements for growth, as in microorganisms.\nFill: that portion of a cooling tower which makes up its primary heat transfer surface. Fill is alternatively known as \"packing.\" Finished water: treated, or potable water. Fixed room-air HEPA recirculation systems: nonmobile devices or systems that remove airborne contaminants by recirculating air through a HEPA filter. These may be built into the room and permanently\n# Air Sampling for Aerosols Containing Legionellae\nAir sampling is an insensitive means of detecting Legionella pneumophila, and is of limited practical value in environmental sampling for this pathogen. In certain instances, however, it can be used to a. demonstrate the presence of legionellae in aerosol droplets associated with suspected bacterial reservoirs b. define the role of certain devices [e.g., showers, faucets, decorative fountains, or evaporate condensers] in disease transmission; and c. quantitate and determine the size of the droplets containing legionellae. 1436 Stringent controls and calibration are necessary when sampling is used to determine particle size and numbers of viable bacteria. 1437 Samplers should be placed in locations where human exposure to aerosols is anticipated, and investigators should wear a NIOSH-approved respirator (e.g., N95 respirator) if sampling involves exposure to potentially infectious aerosols.\nMethods used to sample air for legionellae include impingement in liquid, impaction on solid medium, and sedimentation using settle plates. 1436 The Chemical Corps.-type all-glass impingers (AGI) with the stem 30 mm from the bottom of the flask have been used successfully to sample for legionellae. 1436 Because of the velocity at which air samples are collected, clumps tend to become fragmented, leading to a more accurate count of bacteria present in the air. The disadvantages of this method are a. the velocity of collection tends to destroy some vegetative cells b. the method does not differentiate particle sizes; and c. AGIs are easily broken in the field.\nYeast extract broth (0.25%) is the recommended liquid medium for AGI sampling of legionellae; 1437 standard methods for water samples can be used to culture these samples.\nAndersen samplers are viable particle samplers in which particles pass through jet orifices of decreasing size in cascade fashion until they impact on an agar surface. 1218 The agar plates are then removed and incubated. The stage distribution of the legionellae should indicate the extent to which the bacteria would have penetrated the respiratory system. The advantages of this sampling method are a. the equipment is more durable during use b. the sampler can cetermine the number and size of droplets containing legionellae; c. the agar plates can be placed directly in an incubator with no further manipulations; and d. both selective and nonselective BCYE agar can be used. If the samples must be shipped to a laboratory, they should be packed and shipped without refrigeration as soon as possible.\n# Calculation of Air Sampling Results\nAssuming that each colony on the agar plate is the growth from a single bacteria-carrying particle, the contamination of the air being sampled is determined from the number of colonies counted. The airborne microorganisms may be reported in terms of the number per cubic foot of air sampled. The following formulas can be applied to convert colony counts to organisms per cubic foot of air sampled. 1218 For solid agar impactor samplers: C / (R H P) = N where N = number of organisms collected per cubic foot of air sampled C = total plate count R = airflow rate in cubic feet per minute P = duration of sampling period in minutes For liquid impingers: (C H V) / (Q H P H R) = N where C = total number of colonies from all aliquots plated V = final volume in mL of collecting media Q = total number of mL plated P, R, and N are defined as above 3. To satisfy exhaust needs, replacement air from outside is necessary. Table B.3 does not attempt to describe specific amounts of outside air to be supplied to individual spaces except for certain areas such as those listed. Distribution of the outside air, added to the system to balance required exhaust, shall be as required by good engineering practice.\n4. Number of air changes may be reduced when the room is unoccupied if provisions are made to ensure that the number of air changes indicated is reestablished any time the space is being utilized. Adjustments shall include provisions so that the direction of air movement shall remain the same when the number of air changes is reduced. Areas not indicated as having continuous directional control may have ventilation systems shut down when space is unoccupied and ventilation is not otherwise needed.\n5. Air from areas with contamination and/or odor problems shall be exhausted to the outside and not recirculated to other areas. Note that individual circumstances may require special consideration for air exhaust to outside.\n6. Because of cleaning difficulty and potential for buildup of contamination, recirculating room units shall not be used in areas marked \"No.\" Isolation rooms may be ventilated by reheat induction units in which only the primary air supplied from a central system passes through the reheat unit. Gravitytype heating or cooling units such as radiators or convectors shall not be used in special care areas.\n7. The ranges listed are the minimum and maximum limits where control is specifically needed. See A8.31.D in the AIA guideline (reference 120) for additional information.\n8. Where temperature ranges are indicated, the systems shall be capable of maintaining the rooms at any point within the range. A single figure indicates a heating or cooling capacity of at least the indicated temperature. This is usually applicable where residents may be undressed and require a warmer environment. Nothing in these guidelines shall be construed as precluding the use of temperatures lower than those noted when the residents' comfort and medical conditions make lower temperatures desirable. Unoccupied areas such as storage rooms shall have temperatures appropriate for the function intended.\n9. See A8.31.D1 in the AIA guideline (reference 120).\n10. Food preparation facilities shall have ventilation systems whose air supply mechanisms are interfaced appropriately with exhaust hood controls or relief vents so that exfiltration or infiltration to or from exit corridors does not compromise the exit corridor restrictions of NFPA 90A, the pressure requirements of NFPA 96, or the maximum defined in the table. The number of air changes may be reduced or varied to any extent required for odor control when the space is not in use. heterotrophic plate count would suggest a greater rate and extent of biofilm formation in a health-care facility water system. The water supplied to the facility should also contain <1 coliform bacteria/100 mL. Coliform bacteria are organisms whose presence in the distribution system could indicate fecal contamination. It has been shown that coliform bacteria can colonize biofilms within drinking water systems. Intermittant contamination of a water system with these organisms could lead to colonization of the system.\nWater samples can be collected from throughout the health-care facility system, including both hot and cold water sources; samples should be cultured by standard methods. 945 If heterotrophic plate counts in samples from the facility water system are higher than those from samples collected at the point of water entry to the building, it can be concluded that the facility water quality has diminished. If biofilms are detected in the facility water system and determined by an epidemiologic and environmental investigation to be a reservoir for health-care associated pathogens, the municipal water supplier could be contacted with a request to provide higher chlorine residuals in the distribution system, or the health-care facility could consider installing a supplemental chlorination system.\nSample collection sites for biofilm in health-care facilities include a. hot water tanks b. shower heads; and c. faucet aerators, especially in immunocompromised patient-care areas.\nSwabs should be placed into tubes containing phosphate buffered water, pH 7.2 or phosphate buffered saline, shipped to the laboratory under refrigeration and processed within 24 hrs. of collection. Samples are suspended by vortexing with sterile glass beads and plated onto a nonselective medium (e.g., Plate Count Agar or R2A medium) and selective media (e.g., media for Legionella spp. isolation) after serial dilution. If the plate counts are elevated above levels in the water (i.e. comparing the plate count per square centimeter of swabbed surface to the plate count per milliliter of water), then biofilm formation can be suspected. In the case of an outbreak, it would be advisable to isolate organisms from these plates to determine whether the suspect organisms are present in the biofilm or water samples and compare them to the organisms isolated from patient specimens.\n# Water and Dialysate Sampling Strategies in Dialysis\nIn order to detect the low, total viable heterotrophic plate counts outlined by the current AAMI standards for water and dialysate in dialysis settings, it is necessary to use standard quantitative culture techniques with appropriate sensitivity levels. 792,832,833 The membrane filter technique is particularly suited for this application because it permits large volumes of water to be assayed. 792,834 Since the membrane filter technique may not be readily available in clinical laboratories, the spread plate assay can be used as an alternative. 834 If the spread plate assay is used, however, the standard prohibits the use of a calibrated loop when applying sample to the plate. 792 The prohibition is based on the low sensitivity of the calibrated loop. A standard calibrated loop transfers 0.001 mL of sample to the culture medium, so that the minimum sensitivity of the assay is 1,000 CFU/mL. This level of sensitivity is unacceptable when the maximum allowable limit for microorganisms is 200 CFU/mL. Therefore, when the spread plate method is used, a pipette must be used to place 0.1-0.5 mL of water on the culture medium.\nThe current AAMI standard specifically prohibits the use of nutrient-rich media (e.g., blood agar, and chocolate agar) in dialysis water and dialysate assays because these culture media are too rich for growth of the naturally occurring organisms found in water. 792 Debate continues within AAMI, however, as to the most appropriate culture medium and incubation conditions to be used. The original clinical observations on which the microbiological requirements of this standard were based used Standard Methods Agar (SMA), a medium containing relatively few nutrients. 666 The use of tryptic soy agar (TSA), a general purpose medium for isolating and cultivating microorganisms was recommended in later versions of the standard because it was thought to be more appropriate for culturing bicarbonate-containing dialysate. 788,789,835 Moreover, culturing systems based on TSA are readily available from commercial sources. Several studies, however, have shown that the use of nutrient-poor media, such as R2A, results in an increased recovery of bacteria from water. 1451,1452 The original standard also specified incubation for 48 hours at 95°F-98.6°F (35°C-37°C) before enumeration of bacterial colonies. Extending the culturing time up to 168 hours, or 7 days and using incubation temperatures of 73.4°F-82.4°F (23°C-28°C) have also been shown to increase the recovery of bacteria. 1451,1452 Other investigators, however, have not found such clear cut differences between culturing techniques. 835,1453 After considerable discussion, the AAMI Committee has not reached a consensus regarding changes in the assay technique, and the use of TSA or its equivalent for 48 hours at 95°F-98.6°F (35°C-37°C) remains the recommended method. It should be recognized, however, that these culturing conditions may underestimate the bacterial burden in the water and fail to identify the presence of some organisms. Specifically, the recommended method may not detect the presence of various NTM that have been associated with several outbreaks of infection in dialysis units. 31,32 In these instances, however, the high numbers of mycobacteria in the water were related to the total heterotrophic plate counts, each of which was significantly greater than that allowable by the AAMI standard. Additionally, the recommended method will not detect fungi and yeast, which have been shown to contaminate water used for hemodialysis applications. 1454 Biofilm on the surface of the pipes may hide viable bacterial colonies, even though no viable colonies are detected in the water using sensitive culturing techniques. 1455 Many disinfection processes remove biofilm poorly, and a rapid increase in the level of bacteria in the water following disinfection may indicate significant biofilm formation. Therefore, although the results of microbiological surveillance obtained using the test methods outlined above may be useful in guiding disinfection schedules and in demonstrating compliance with AAMI standards, they should not be taken as an indication of the absolute microbiological purity of the water. 792 Endotoxin can be tested by one of two types of assays a. a kinetic test method [e.g., colorimetric or turbidimetric] or b. a gel-clot assay.\nEndotoxin units are assayed by the Limulus Amebocyte Lysate (LAL) method. Because endotoxins differ in their activity on a mass basis, their activity is referred to a standard Escherichia coli endotoxin. The current standard (EC-6) is prepared from E. coli O113:H10. The relationship between mass of endotoxin and its activity varies with both the lot of LAL and the lot of control standard endotoxin used. Since standards for endotoxin were harmonized in 1983 with the introduction of EC-5, the relationship between mass and activity of endotoxin has been approximately 5-10 EU/ng. Studies to harmonize standards have led to the measurement of endotoxin units (EU) where 5 EU is equivalent to 1 ng E. coli O55:B5 endotoxin. 1456 In summary, water used to prepare dialysate and to reprocess hemodialyzers should not contain a total microbial count >200 CFU/mL as determined by assay on TSA agar for 48 hrs. at 96.8°F (36°C), and ≤2 endotoxin units (EU) per mL. The dialysate at the end of a dialysis treatment should not contain >2,000 CFU/mL. 31, 32, 668, 789, 792\n# Water Sampling Strategies and Culture Techniques for Detecting Legionellae\nLegionella spp. are ubiquitous and can be isolated from 20%-40% of freshwater environments, including man-made water systems. 1457,1458 In health-care facilities, where legionellae in potable water rarely result in disease among immunocompromised patients, courses of remedial action are unclear.\nScheduled microbiologic monitoring for legionellae remains controversial because the presence of legionellae is not necessarily evidence of a potential for causing disease. 1459 CDC recommends aggressive disinfection measures for cleaning and maintaining devices known to transmit legionellae, but does not recommend regularly scheduled microbiologic assays for the bacteria. 396 However, scheduled monitoring of potable water within a hospital might be considered in certain settings where persons are highly susceptible to illness and mortality from Legionella infection (e.g., hematopoietic stem cell transplantation units and solid organ transplant units). 9 Also, after an outbreak of legionellosis, health officials agree monitoring is necessary to identify the source and to evaluate the efficacy of biocides or other prevention measures.\nExamination of water samples is the most efficient microbiologic method for identifying sources of legionellae and is an integral part of an epidemiologic investigation into health-care associated Legionnaires disease. Because of the diversity of plumbing and HVAC systems in health-care facilities, the number and types of sites to be tested must be determined before collection of water samples. One environmental sampling protocol that addresses sampling site selection in hospitals might serve as a prototype for sampling in other institutions. 1209 Any water source that might be aerosolized should be considered a potential source for transmission of legionellae. The bacteria are rarely found in municipal water supplies and tend to colonize plumbing systems and point-of-use devices. To colonize, legionellae usually require a temperature range of 77°F-108°F (25°C-42.2°C) and are most commonly located in hot water systems. 1460 Legionellae do not survive drying. Therefore, air-conditioning equipment condensate, which frequently evaporates, is not a likely source. 1461 Water samples and swabs from point-of-use devices or system surfaces should be collected when sampling for legionellae (Box C.1). 1437 Swabs of system surfaces allow sampling of biofilms, which frequently contain legionellae. When culturing faucet aerators and shower heads, swabs of surface areas should be collected first; water samples are collected after aerators or shower heads are removed from their pipes. Collection and culture techniques are outlined (Box C.2). Swabs can be streaked directly onto buffered charcoal yeast extract agar (BCYE) plates if the pates are available at the collection site. If the swabs and water samples must be transported back to a laboratory for processing, immersing individual swabs in sample water minimizes drying during transit. Place swabs and water samples in insulated coolers to protect specimens from temperature extremes.\nBox C.1. Potential sampling sites for Legionella spp. in health-care facilities*\n• Potable water systems incoming water main, water softener unit, holding tanks, cisterns, water heater tanks (at the inflows and outflows)\n• Potable water outlets, especially those in or near patient rooms faucets or taps, showers\n• Cooling towers and evaporative condensers makeup water (e.g., added to replace water lost because of evaporation, drift, or leakage), basin (i.e., area under the tower for collection of cooled water), sump (i.e., section of basin from which cooled water returns to heat source), heat sources (e.g., chillers)\n• Humidfiers (e.g., nebullizers) bubblers for oxygen, water used for respiratory therapy equipment 2. Collect culture swabs of internal surfaces of faucets, aerators, and shower heads in a sterile, screw-top container (e.g., 50 mL plastic centrifuge tube). Submerge each swab in 5-10 mL of sample water taken from the same device from which the sample was obtained. 3. Transport samples and process in a laboratory proficient at culturing water specimens for Legionella spp. as soon as possible after collection. (Samples may be transported at room temperature but must be protected from temperature extremes. Samples not processed within 24 hours of collection should be refrigerated.) 4. Test samples for the presence of Legionella spp. by using semiselective culture media using procedures specific to the cultivation and detection of Legionella spp.\no Detection of Legionella spp. antigen by the direct fluorescent antibody technique is not suitable for environmental samples. o Use of polymerase chain reaction for identification of Legionella spp. is not recommended until more data regading the sensitivity and specificity of this procedure are available. \n# Procedure for Cleaning Cooling Towers and Related Equipment I. Perform these steps prior to chemical disinfection and mechanical cleaning.\nA. Provide protective equipment to workers who perform the disinfection, to prevent their exposure to chemicals used for disinfection and aerosolized water containing Legionella spp. Protective equipment may include full-length protective clothing, boots, gloves, goggles, and a full-or halfface mask that combines a HEPA filter and chemical cartridges to protect against airborne chlorine levels of up to 10 mg/L. B. Shut off cooling tower.\n1. Shut off the heat source, if possible. 2. Shut off fans, if present, on the cooling tower/evaporative condenser (CT/EC).\n3. Shut off the system blowdown (i.e., purge) valve. 4. Shut off the automated blowdown controller, if present, and set the system controller to manual. 5. Keep make-up water valves open. 6. Close building air-intake vents within at least 30 meters of the CT/EC until after the cleaning procedure is complete. 7. Continue operating pumps for water circulation through the CT/EC.\n# II. Perform these chemical disinfection procedures.\nA. Add fast-release, chlorine-containing disinfectant in pellet, granular, or liquid form, and follow safety instructions on the product label. Use EPA-registered products, if available. Examples of disinfectants include sodium hypochlorite (NaOCl) or calcium hypochlorite (Ca[OCl]2), calculated to achieve initial free residual chlorine (FRC) of 50 mg/L: either a. Monitor the FRC by using an FRC-measuring device with the DPD method (e.g., a swimmingpool test kit), and measure the pH with a pH meter every 15 minutes for 2 hours. Add chlorine as needed to maintain the FRC at ≥10 mg/L. Because the biocidal effect of chlorine is reduced at a higher pH, adjust the pH to 7.5-8.0. The pH may be lowered by using any acid (e.g., nuriatic acid or sulfuric acid used for maintenance of swimming pools) that is compatible with the treatment chemicals. E. Two hours after adding disinfectant and dispersant or after the FRC level is stable at ≥10 mg/L, monitor at 2-hour intervals and maintain the FRC at ≥10 mg/L for 24 hours. F. After the FRC level has been maintained at ≥10 mg/L for 24 hours, drain the system. CT/EC water may be drained safely into the sanitary sewer. Municipal water and sewerage authorities should be contacted regarding local regulations. If a sanitary sewer is not available, consult local or state authorities (e.g., a department of natural resources or environmental protection) regarding disposal of water. If necessary, the drain-off may be dechlorinated by dissipation or chemical neutralization with sodium bisulfite.\n# \n• * sharps [e.g., needles and scalpels]. 2 Category II B. Consult federal, state, and local regulations to determine if other waste items are considered regulated medical wastes. 967,1407,1408 \n# I.II. Disposal Plan for Regulated Medical Wastes\nA. Develop a plan for the collection, handling, predisposal treatment, and terminal disposal of regulated medical wastes. 967 \n# I.III. Handling, Transporting, and Storing Regulated Medical Wastes\nA. Inform personnel involved in the handling and disposal of potentially infective waste of the possible health and safety hazards; ensure that they are trained in appropriate handling and disposal methods. 967 Category IC (OSHA: 29 CFR 1910.1030 § g.2.i) B. Manage the handling and disposal of regulated medical wastes generated in isolation areas by using the same methods as for regulated medical wastes from other patient-care areas. 2 Category II C. Use proper sharps disposal strategies. 967 Category IC (OSHA: 29 CFR 191029 CFR .1030.iii.A)\n1. Use a sharps container capable of maintaining its impermeability after waste treatment to avoid subsequent physical injuries during final disposal. 967 Category IC (OSHA: 29 CFR 191029 CFR .1030.iii.A) 2. Place disposable syringes with needles, including sterile sharps that are being discarded, scalpel blades, and other sharp items into puncture-resistant containers located as close as practical to the point of use. 967 Category IC (OSHA: 29 CFR 191029 CFR .1030.iii.A) 3. Do not bend, recap, or break used syringe needles before discarding them into a container. 6,967,1415 Category IC (OSHA: 29 CFR 1910.1030 § d.2.vii and § d.2.vii.A) D. Store regulated medical wastes awaiting treatment in a properly ventilated area that is inaccessible to vertebrate pests; use waste containers that prevent the development of noxious odors. Category IC (States; AHJ) E. If treatment options are not available at the site where the medical waste is generated, transport regulated medical wastes in closed, impervious containers to the on-site treatment location or to another facility for treatment as appropriate. Category IC (States; AHJ)\n# I.IV. Treatment and Disposal of Regulated Medical Wastes\nA. Treat regulated medical wastes by using a method (e.g., steam sterilization, incineration, interment, or an alternative treatment technology) approved by the appropriate authority having jurisdiction (AHJ) (e.g., states, Indian Health Service [IHS], Veterans Affairs [VA]) before disposal in a sanitary landfill. Category IC (States, AHJ) B. Follow precautions for treating microbiological wastes (e.g., amplified cultures and stocks of microorganisms). 1013 Category IC (DHHS: BMBL) 1. Biosafety level 4 laboratories must inactivate microbiological wastes in the laboratory by using an approved inactivation method (e.g., autoclaving) before transport to and disposal in a sanitary landfill. 1013 Category IC (DHHS: BMBL) 2. Biosafety level 3 laboratories must inactivate microbiological wastes in the laboratory by using an approved inactivation method (e.g., autoclaving) or incinerate them at the facility before transport to and disposal in a sanitary landfill. 1013 Category IC (DHHS: BMBL) C. Biosafety levels 1 and 2 laboratories should develop strategies to inactivate amplified microbial cultures and stocks onsite by using an approved inactivation method (e.g., autoclaving) instead of packaging and shipping untreated wastes to an offsite facility for treatment and disposal. 1013,[1419][1420][1421] Category II\n# Part IV. Appendices Appendix A. Glossary of Terms\nAcceptable indoor air quality: air in which there are no known contaminants at harmful concentrations as determined by knowledgeble authorities and with which a substantial majority (≥80%) of the people exposed do not express dissatisfaction. ACGIH: American Conference of Governmental Industrial Hygienists. Action level: the concentration of a contaminant at which steps should be taken to interrupt the trend toward higher, unacceptable levels. Aerosol: particles of respirable size generated by both humans and environmental sources and that have the capability of remaining viable and airborne for extended periods in the indoor environment. AIA: American Institute of Architects, a professional group responsible for publishing the Guidelines for Design and Construction of Hospitals and Healthcare Facilities, a consensus document for design and construction of health-care facilities endorsed by the U.S. Department of Health and Human Services, healthcare professionals, and professional organizations.\n# Air changes per hour (ACH):\nthe ratio of the volume of air flowing through a space in a certain period of time (the airflow rate) to the volume of that space (the room volume). This ratio is expressed as the number of air changes per hour (ACH).\nAir mixing: the degree to which air supplied to a room mixes with the air already in the room, usually expressed as a mixing factor. This factor varies from 1 (for perfect mixing) to 10 (for poor mixing). It is used as a multiplier to determine the actual airflow required (i.e., the recommended ACH multiplied by the mixing factor equals the actual ACH required). Airborne transmission: a means of spreading infection when airborne droplet nuclei (small particle residue of evaporated droplets ≤5 μm in size containing microorganisms that remain suspended in air for long periods of time) are inhaled by the susceptible host. Air-cleaning system: a device or combination of devices applied to reduce the concentration of airborne contaminants (e.g., microorganisms, dusts, fumes, aerosols, other particulate matter, and gases).\nAir conditioning: the process of treating air to meet the requirements of a conditioned space by controlling its temperature, humidity, cleanliness, and distribution. Allogeneic: non-twin, non-self. The term refers to transplanted tissue from a donor closely matched to a recipient but not related to that person. Ambient air: the air surrounding an object. Anemometer: a flow meter which measures the wind force and velocity of air. An anemometer is often used as a means of determining the volume of air being drawn into an air sampler. Anteroom: a small room leading from a corridor into an isolation room. This room can act as an airlock, preventing the escape of contaminants from the isolation room into the corridor. ASHE: American Society for Healthcare Engineering, an association affiliated with the American Hospital Association. ASHRAE: American Society of Heating, Refrigerating, and Air-Conditioning Engineers Inc.\n# Autologous self:\nThe term refers to transplanted tissue whose source is the same as the recipient, or an identical twin. Automated cycler: a machine used during peritoneal dialysis which pumps fluid into and out of the patient while he/she sleeps. Biochemical oxygen demand (BOD): a measure of the amount of oxygen removed from aquatic environments by aerobic microorganisms for their metabolic requirements. Measurement of BOD is used to determine the level of organic pollution of a stream or lake. The greater the BOD, the greater the degree of water pollution. The term is also referred to as Biological Oxygen Demand (BOD). Biological oxygen demand (BOD): an indirect measure of the concentration of biologically degradable material present in organic wastes (pertaining to water quality). It usually reflects the amount of oxygen consumed in five days by biological processes breaking down organic waste (BOD5). Biosafety level: a combination of microbiological practices, laboratory facilities, and safety equipment determined to be sufficient to reduce or prevent occupational exposures of laboratory personnel to the Intermediate-level disinfection: a disinfection process that inactivates vegetative bacteria, most fungi, mycobacteria, and most viruses (particularly the enveloped viruses), but does not inactivate bacterial spores. Isoform: a possible configuration (tertiary structure) of a protein molecule. With respect to prion proteins, the molecules with large amounts of α-conformation are the normal isoform of that particular protein, whereas those prions with large amounts of β-sheet conformation are the proteins associated with the development of spongiform encephalopathy (e.g., Creutzfeldt-Jakob disease [CJD]). Laminar flow: HEPA-filtered air that is blown into a room at a rate of 90 ± 10 feet/min in a unidirectional pattern with 100 ACH-400 ACH. Large enveloped virus: viruses whose particle diameter is >50 nm and whose outer surface is covered by a lipid-containing structure derived from the membranes of the host cells. Examples of large enveloped viruses include influenza viruses, herpes simplex viruses, and poxviruses. Laser plume: the transfer of electromagnetic energy into tissues which results in a release of particles, gases, and tissue debris. Lipid-containing viruses: viruses whose particle contains lipid components. The term is generally synonymous with enveloped viruses whose outer surface is derived from host cell membranes. Lipidcontaining viruses are sensitive to the inactivating effects of liquid chemical germicides. Lithotriptors: instruments used for crushing caliculi (i.e., calcified stones, and sand) in the bladder or kidneys.\nLow efficiency filter: the prefilter with a particle-removal efficiency of approximately 30% through which incoming air first passes. See also Prefilter. Low-level disinfection: a disinfection process that will inactivate most vegetative bacteria, some fungi, and some viruses, but cannot be relied upon to inactivate resistant microorganisms (e.g., mycobacteria or bacterial spores). Makeup air: outdoor air supplied to the ventilation system to replace exhaust air. Makeup water: a cold water supply source for a cooling tower.\nManometer: a device that measures the pressure of liquids and gases. A manometer is used to verify air filter performance by measuring pressure differentials on either side of the filter. Membrane filtration: an assay method suitable for recovery and enumeration of microorganisms from liquid samples. This method is used when sample volume is large and anticipated microbial contamination levels are low. Mesophilic: that which favors a moderate temperature. For mesophilic bacteria, a temperature range of 68°F-131°F (20°C-55°C) is favorable for their growth and proliferation.\nMixing box: the site where the cold and hot air streams mix in the HVAC system, usually situated close to the air outlet for the room.\nMixing faucet: a faucet that mixes hot and cold water to produce water at a desired temperature. MMAD: Mass Median Aerodynamic Diameter. This is the unit used by ACGIH to describe the size of particles when particulate air sampling is conducted. Moniliaceous: hyaline or brightly colored. This is a laboratory term for the distinctive characteristics of certain opportunistic fungi in culture (e.g., Aspergillus spp. and Fusarium spp.). Monochloramine: the result of the reaction between chlorine and ammonia that contains only one chlorine atom. Monochloramine is used by municipal water systems as a water treatment. Natural ventilation: the movement of outdoor air into a space through intentionally provided openings (i.e., windows, doors, or nonpowered ventilators). Negative pressure: air pressure differential between two adjacent airspaces such that air flow is directed into the room relative to the corridor ventilation (i.e., room air is prevented from flowing out of the room and into adjacent areas). Neutropenia: a medical condition in which the patient's concentration of neutrophils is substantially less than that in the normal range. Severe neutropenia occurs when the concentration is <1,000 polymorphonuclear cells/μL for 2 weeks or <100 polymorphonuclear cells /mL for 1 week, particularly for hematopoietic stem cell transplant (HSCT) recipients. Noncritical devices: medical devices or surfaces that come into contact with only intact skin. The risk of infection from use of these devices is low.\nNon-enveloped virus: a virus whose particle is not covered by a structure derived from a membrane of the host cell. Non-enveloped viruses have little or no lipid compounds in their biochemical composition, a characteristic that is significant to their inherent resistance to the action of chemical germicides. Nosocomial: an occurrence, usually an infection, that is acquired in a hospital as a result of medical care. NTM: nontuberculous mycobacteria. These organisms are also known as atypical mycobacteria, or as \"Mycobacteria other than tuberculosis\" (MOTT). This descriptive term refers to any of the fast-or slowgrowing Mycobacterium spp. found in primarily in natural or man-made waters, but it excludes Mycobacterium tuberculosis and its variants. Nuisance dust: generally innocuous dust, not recognized as the direct cause of serious pathological conditions. Oocysts: a cyst in which sporozoites are formed; a reproductive aspect of the life cycle of a number of parasitic agents (e.g., Cryptosporidium spp., and Cyclospora spp.).\nOutdoor air: air taken from the external atmosphere and, therefore, not previously circulated through the ventilation system. Parallel streamlines: a unidirectional airflow pattern achieved in a laminar flow setting, characterized by little or no mixing of air.\nParticulate matter (particles): a state of matter in which solid or liquid substances exist in the form of aggregated molecules or particles. Airborne particulate matter is typically in the size range of 0.01-100 μm diameter.\nPasteurization: a disinfecting method for liquids during which the liquids are heated to 140°F (60°C) for a short time (≥30 mins.) to significantly reduce the numbers of pathogenic or spoilage microorganisms.\nPlinth: a treatment table or a piece of equipment used to reposition the patient for treatment.\nPortable room-air HEPA recirculation units: free-standing portable devices that remove airborne contaminants by recirculating air through a HEPA filter.\nPositive pressure: air pressure differential between two adjacent air spaces such that air flow is directed from the room relative to the corridor ventilation (i.e., air from corridors and adjacent areas is prevented from entering the room). Potable (drinking) water: water that is fit to drink. The microbiological quality of this water as defined by EPA microbiological standards from the Surface Water Treatment Rule: a. Giardia lamblia: 99.9% killed/inactivated b. viruses: 99.9% inactivated; c. Legionella spp.: no limit, but if Giardia and viruses are inactivated, Legionella will also be controlled; d. heterotrophic plate count [HPC]: ≤500 CFU/mL; and e. >5% of water samples total coliform-positive in a month. PPE: Personal Protective Equipment. ppm: parts per million. The term is a measure of concentration in solution. Chlorine bleaches (undiluted) that are available in the U.S. (5.25%-6.15% sodium hypochlorite) contain approximately 50,000-61,500 parts per million of free and available chlorine. Prefilter: the first filter for incoming fresh air in a HVAC system. This filter is approximately 30% efficient in removing particles from the air. See also Low-Efficiency Filter. Prion: a class of agent associated with the transmission of diseases knowns as transmissible spongiform encephalopathies (TSEs). Prions are considered to consist of protein only, and the abnormal isoform of this protein is thought to be the agent that causes diseases such as Creutzfeldt-Jakob disease (CJD), kuru, scrapie, bovine spongiform encephalopathy (BSE), and the human version of BSE which is variant CJD (vCJD). Product water: water produced by a water treatment system or individual component of that system. Protective environment: a special care area, usually in a hospital, designed to prevent transmission of opportunistic airborne pathogens to severely immunosuppressed patients. Pseudoepidemic (pseudo-outbreak): a cluster of positive microbiologic cultures in the absence of clinical disease. A pseudoepidemic usually results from contamination of the laboratory apparatus and process used to recover microorganisms. Pyrogenic: an endotoxin burden such that a patient would receive ≥5 endotoxin units (EU) per kilogram of body weight per hour, thereby causing a febrile response. In dialysis this usually refers to water or dialysate having endotoxin concentrations of ≥5 EU/mL.\nRank order: a strategy for assessing overall indoor air quality and filter performance by comparing airborne particle counts from lowest to highest (i.e., from the best filtered air spaces to those with the least filtration). RAPD: a method of genotyping microorganisms by randomly amplified polymorphic DNA. This is one version of the polymerase chain reaction method. Recirculated air: air removed from the conditioned space and intended for reuse as supply air.\nRelative humidity: the ratio of the amount of water vapor in the atmosphere to the amount necessary for saturation at the same temperature. Relative humidity is expressed in terms of percent and measures the percentage of saturation. At 100% relative humidity, the air is saturated. The relative humidity decreases when the temperature is increased without changing the amount of moisture in the air. Reprocessing (of medical instruments): the procedures or steps taken to make a medical instrument safe for use on the next patient. Reprocessing encompasses both cleaning and the final or terminal step (i.e., sterilization or disinfection) which is determined by the intended use of the instrument according to the Spaulding classification.\nResiduals: the presence and concentration of a chemical in media (e.g., water) or on a surface after the chemical has been added.\nReservoir: a nonclinical source of infection.\nRespirable particles: those particles that penetrate into and are deposited in the nonciliated portion of the lung. Particles >10 μm in diameter are not respirable.\nReturn air: air removed from a space to be then recirculated.\nReverse osmosis (RO): an advanced method of water or wastewater treatment that relies on a semipermeable membrane to separate waters from pollutants. An external force is used to reverse the normal osmotic process resulting in the solvent moving from a solution of higher concentration to one of lower concentration.\nRiser: water piping that connects the circulating water supply line, from the level of the base of the tower or supply header, to the tower's distribution system. RODAC: Replicate Organism Direct Agar Contact. This term refers to a nutrient agar plate whose convex agar surface is directly pressed onto an environmental surface for the purpose of microbiologic sampling of that surface. Room-air HEPA recirculation systems and units: devices (either fixed or portable) that remove airborne contaminants by recirculating air through a HEPA filter. Routine sampling: environmental sampling conducted without a specific, intended purpose and with no action plan dependent on the results obtained.\nSanitizer: an agent that reduces microbial contamination to safe levels as judged by public health standards or requirements. Saprophytic: a naturally-occurring microbial contaminant. Sedimentation: the act or process of depositing sediment from suspension in water. The term also refers to the process whereby solids settle out of wastewater by gravity during treatment. Semicritical devices: medical devices that come into contact with mucous membranes or non-intact skin. Service animal: any animal individually trained to do work or perform tasks for the benefit of a person with a disability. Shedding: the generation and dispersion of particles and spores by sources within the patient area, through activities such as patient movement and airflow over surfaces. Single-pass ventilation: ventilation in which 100% of the air supplied to an area is exhausted to the outside. Small, non-enveloped viruses: viruses whose particle diameter is <50 nm and whose outer surface is the protein of the particle itself and not that of host cell membrane components. Examples of small, nonenveloped viruses are polioviruses and hepatitis A virus. Spaulding Classification: the categorization of inanimate medical device surfaces in the medical environment as proposed in 1972 by Dr. Earle Spaulding. Surfaces are divided into three general categories, based on the theoretical risk of infection if the surfaces are contaminated at time of use. The categories are \"critical,\" \"semicritical,\" and \"noncritical.\" Specific humidity: the mass of water vapor per unit mass of moist air. It is expressed as grains of water per pound of dry air, or pounds of water per pound of dry air. The specific humidity changes as moisture is added or removed. However, temperature changes do not change the specific humidity unless the air is cooled below the dew point.\nSplatter: visible drops of liquid or body fluid that are expelled forcibly into the air and settle out quickly, as distinguished from particles of an aerosol which remain airborne indefinitely. Steady state: the usual state of an area. Sterilization: the use of a physical or chemical procedure to destroy all microbial life, including large numbers of highly-resistant bacterial endospores. Stop valve: a valve that regulates the flow of fluid through a pipe. The term may also refer to a faucet. Substitution fluid: fluid that is used for fluid management of patients receiving hemodiafiltration. This fluid can be prepared on-line at the machine through a series of ultrafilters or with the use of sterile peritoneal dialysis fluid. Supply air: air that is delivered to the conditioned space and used for ventilation, heating, cooling, humidification, or dehumidification.\nTensile strength: the resistance of a material to a force tending to tear it apart, measured as the maximum tension the material can withstand without tearing. Ultrafilter: a membrane filter with a pore size in the range of 0.001-0.05 μm, the performance of which is usually rated in terms of a nominal molecular weight cut-off (defined as the smallest molecular weight species for which the filter membrance has more than 90% rejection).\nUltrafiltered dialysate: the process by which dialysate is passed through a filter having a molecular weight cut-off of approximately 1 kilodalton for the purpose of removing bacteria and endotoxin from the bath. Ultraviolet germicidal irradiation (UVGI): the use of ultraviolet radiation to kill or inactivate microorganisms.\nUltraviolet germicidal irradiation lamps: lamps that kill or inactivate microorganisms by emitting ultraviolet germicidal radiation, predominantly at a wavelength of 254 nm. UVGI lamps can be used in ceiling or wall fixtures or within air ducts of ventilation systems.\nVapor pressure: the pressure exerted by free molecules at the surface of a solid or liquid. Vapor pressure is a function of temperature, increasing as the temperature rises.\nVegetative bacteria: bacteria that are actively growing and metabolizing, as opposed to a bacterial state of quiescence that is achieved when certain bacteria (gram-positive bacilli) convert to spores when the environment can no longer support active growth. Vehicle: any object, person, surface, fomite, or media that may carry and transfer infectious microorganisms from one site to another.\nVentilation: the process of supplying and removing air by natural or mechanical means to and from any space. Such air may or may not be conditioned. Ventilation air: that portion of the supply air consisting of outdoor air plus any recirculated air that has been treated for the purpose of maintaining acceptable indoor air quality. Ventilation, dilution: an engineering control technique to dilute and remove airborne contaminants by the flow of air into and out of an area. Air that contains droplet nuclei is removed and replaced by contaminantfree air. If the flow is sufficient, droplet nuclei become dispersed, and their concentration in the air is diminished. Ventilation, local exhaust: ventilation used to capture and removed airborne contaminants by enclosing the contaminant source (the patient) or by placing an exhaust hood close to the contaminant source. v/v: volume to volume. This term is an expression of concentration of a percentage solution when the principle component is added as a liquid to the diluent. w/v: weight to volume. This term is an expression of concentration of a percentage solution when the principle component is added as a solid to the diluent.\nWeight-arrestance: a measure of filter efficiency, used primarily when describing the performance of lowand medium-efficiency filters. The measurement of weight-arrestance is performed by feeding a standardized synthetic dust to the filter and weighing the fraction of the dust removed. Q / V = ACH ¶ Values apply to an empty room with no aerosol-generating source. With a person present and generating aerosol, this table would not apply. Other equations are available that include a constant generating source. However, certain diseases (e.g., infectious tuberculosis) are not likely to be aerosolized at a constant rate. The times given assume perfect mixing of the air within the space (i.e., mixing factor = 1). However, perfect mixing usually does not occur. Removal times will be longer in rooms or areas with imperfect mixing or air stagnation. 213 Caution should be exercised in using this table in such situations. For booths or other local ventilation enclosures, manufacturers' instructions should be consulted.\n# Appendix B. Air 1. Airborne Contaminant Removal\n\n# Ventilation Specifications for Health-Care Facilities\nThe following tables from the AIA Guidelines for Design and Construction of Hospitals and Health-Care Facilities, 2001 are reprinted with permission of the American Institute of Architects and the publisher (The Facilities Guidelines Institute). 120 Note: This table is Table 7 20. Food preparation centers shall have ventilation systems whose air supply mechanisms are interfaced appropriately with exhaust hood controls or relief vents so that exfiltration or infiltration to or from exit corridors does not compromise the exit corridor restrictions of NFPA 90A, the pressure requirements of NFPA 96, or the maximum defined in the table. The number of air changes may be reduced or varied to any extent required for odor control when the space is not in use. See Section 7.31.D1.p in the AIA guideline (reference 120).\n# Appendix I:\nA7. Recirculating devices with HEPA filters may have potential uses in existing facilities as interim, supplemental environmental controls to meet requirements for the control of airborne infectious agents. Limitations in design must be recognized. The design of either portable or fixed systems should prevent stagnation and short circuiting of airflow. The supply and exhaust locations should direct clean air to areas where health-care workers are likely to work, across the infectious source, and then to the exhaust, so that the healthcare worker is not in position between the infectious source and the exhaust location. The design of such systems should also allow for easy access for scheduled preventative maintenance and cleaning.\nA11. The verification of airflow direction can include a simple visual method such as smoke trail, ball-in-tube, or flutterstrip. These devices will require a minimum differential air pressure to indicate airflow direction. Notes:\n1. The ventilation rates in this table cover ventilation for comfort, as well as for asepsis and odor control in areas of nursing facilities that directly affect resident care and are determined based on nursing facilities being predominantly \"No Smoking\" facilities. Where smoking may be allowed, ventilation rates will need adjustment. Areas where specific ventilation rates are not given in the table shall be ventilated in accordance with ASHRAE Standard 62, Ventilation for Acceptable Indoor Air Quality, and ASHRAE Handbook -HVAC Applications. OSHA standards and/or NIOSH criteria require special ventilation requirements for employee health and safety within nursing facilities.\n2. Design of the ventilation system shall, insofar as possible, provide that air movement is from clean to less clean areas. However, continuous compliance may be impractical with full utilization of some forms of variable air volume and load shedding systems that may be used for energy conservation.\nAreas that do require positive and continuous control are noted with \"Out\" or \"In\" to indicate the required direction of air movement in relation to the space named. Rate of air movement may, of course, be varied as needed within the limits required for positive control. Where indication of air movement direction is enclosed in parentheses, continuous directional control is required only when the specialized equipment or device is in use or where room use may otherwise compromise the intent of movement from clean to less clean. Air movement for rooms with dashes and nonpatient areas may vary as necessary to satisfy the requirements of those spaces. Additional adjustments may be needed when space is unused or unoccupied and air systems are deenergized or reduced.\n# Appendix C. Water 1. Biofilms\nMicroorganisms have a tendency to associate with and stick to surfaces. These adherent organisms can initiate and develop biofilms, which are comprised of cells embedded in a matrix of extracellularly produced polymers and associated abiotic particles. 1438 It is inevitable that biofilms will form in most water systems. In the health-care facility environment, biofilms may be found in the potable water supply piping, hot water tanks, air conditioning cooling towers, or in sinks, sink traps, aerators, or shower heads. Biofilms, especially in water systems, are not present as a continuous slime or film, but are more often scanty and heterogeneous in nature. 1439 Biofilms may form under stagnant as well as flowing conditions, so storage tanks, in addition to water system piping, may be vulnerable to the development of biofilm, especially if water temperatures are low enough to allow the growth of thermophilic bacteria (e.g., Legionella spp.). Favorable conditions for biofilm formation are present if these structures and equipment are not cleaned for extended periods of time. 1440 Algae, protozoa, and fungi may be present in biofilms, but the predominant microorganisms of water system biofilms are gram-negative bacteria. Although most of these organisms will not normally pose a problem for healthy individuals, certain biofilm bacteria (e.g., Pseudomonas aeruginosa, Klebsiella spp., Pantoea agglomerans, and Enterobacter cloacae) all may be agents for opportunistic infections for immunocompromised individuals. 1441,1442 These biofilm organisms may easily contaminate indwelling medical devices or intravenous (IV) fluids, and they could be transferred on the hands of health-care workers. [1441][1442][1443][1444] Biofilms may potentially provide an environment for the survival of pathogenic organisms, such as Legionella pneumophila and E. coli O157:H7. Although the association of biofilms and medical devices provides a plausible explanation for a variety of health-care associated infections, it is not clear how the presence of biofilms in the water system may influence the rates of health-care-associated waterborne infection.\nOrganisms within biofilms behave quite differently than their planktonic (i.e., free floating) counterparts.\nResearch has shown that biofilm-associated organisms are more resistant to antibiotics and disinfectants than are planktonic organisms, either because the cells are protected by the polymer matrix, or because they are physiologically different. [1445][1446][1447][1448][1449][1450] Nevertheless, municipal water utilities attempt to maintain a chlorine residual in the distribution system to discourage microbiological growth. Though chlorine in its various forms is a proven disinfectant, it has been shown to be less effective against biofilm bacteria. 1448 Higher levels of chlorine for longer contact times are necessary to eliminate biofilms.\nRoutine sampling of health-care facility water systems for biofilms is not warranted. If an epidemiologic investigation points to the water supply system as a possible source of infection, then water sampling for biofilm organisms should be considered so that prevention and control strategies can be developed. An established biofilm is is difficult to remove totally in existing piping. Strategies to remediate biofilms in a water system would include flushing the system piping, hot water tank, dead legs, and those areas of the facility's water system subject to low or intermittent flow. The benefits of this treatment would include a. elimination of corrosion deposits and sludge from the bottom of hot water tanks, b. removal of biofilms from shower heads and sink aerators, and c. circulation of fresh water containing elevated chlorine residuals into the health-care facility water system.\nThe general strategy for evaluating water system biofilm depends on a comparision of the bacteriological quality of the incoming municipal water and that of water sampled from within facility's distribution system. Heterotrophic plate counts and coliform counts, both of which are routinely run by the municipal water utility, will at least provide in indication of the potential for biofilm formation. Heterotrophic plate count levels in potable water should be <500 CFU/mL. These levels may increase on occasion, but counts consistently >500 CFU/mL would indicate a general decrease in water quality. A direct correlation between heterotrophic plate count and biofilm levels has been demonstrated. 1450 Therefore, an increase in G. Refill the system with water and repeat the procedure outline in steps 2-7 in I-B above.\n# III. Perform mechanical cleaning.\nA. After water from the second chemical disinfection has been drained, shut down the CT/EC. B. Inspect all water-contact areas for sediment, sludge, and scale. Using brushes and/or a lowpressure water hose, thoroughly clean all CT/EC water-contact areas, including the basin, sump, fill, spray nozzles, and fittings. Replace components as needed. C. If possible, clean CT/EC water-contact areas within the chillers.\n# IV. Perform these procedures after mechanical cleaning.\nA. Fill the system with water and add chlorine to achieve an FRC level of 10 mg/L. B. Circulate the water for 1 hour, then open the blowdown valve and flush the entire system until the water is free of turbidity. C. Drain the system. D. Open any air-intake vents that were closed before cleaning. E. Fill the system with water. The CT/EC may be put back into service using an effective watertreatment program.\n# Maintenance Procedures Used to Decrease Survival and Multiplications of Legionella spp. in Potable-Water Distribution Systems\nWherever allowable by state code, provide water at ≥124°F (≥51°C) at all points in the heated water system, including the taps. This requires that water in calorifiers (e.g., water heaters) be maintained at ≥140°F (≥60°C). In the United Kingdom, where maintenance of water temperatures at ≥122°F (≥50°C) in hospitals has been mandated, installation of blending or mixing valves at or near taps to reduce the water temperature to ≤109.4°F (≤63°C) has been recommended in certain settings to reduce the risk for scald injury to patients, visitors, and health care workers. 726 However, Legionella spp. can multiply even in short segments of pipe containing water at this temperature. Increasing the flow rate from the hot-watercirculation system may help lessen the likelihood of water stagnation and cooling. 711,1465 Insulation of plumbing to ensure delivery of cold (<68°F [<20°C]) water to water heaters (and to cold-water outlets) may diminish the opportunity for bacterial multiplication. 456 Both dead legs and capped spurs within the plumbing system provide areas of stagnation and cooling to <122°F (<50°C) regardless of the circulating water temperature; these segments may need to be removed to prevent colonization. 704 Rubber fittings within plumbing systems have been associated with persistent colonization, and replacement of these fittings may be required for Legionella spp. eradication. 1467 Continuous chlorination to maintain concentrations of free residual chlorine at 1-2 mg/L (1-2 ppm) at the tap is an alternative option for treatment. This requires the placement of flow-adjusted, continuous injectors of chlorine throughout the water distribution system. Adverse effects of continuous chlorination can include accelerated corrosion of plumbing (resulting in system leaks) and production of potentially carcinogenic trihalomethanes. However, when levels of free residual chlorine are below 3 mg/L (3 ppm), trihalomethane levels are kept below the maximum safety level recommended by the EPA. 727, 1468, 1469 228 \n# Appendix D. Insects and Microorganisms\nFormat Change [February 2016]: The format of this section was changed to improve readability and accessibility. The content is unchanged. \n# Appendix E. Information Resources\nThe following sources of information may be helpful to the reader. Some of these are available at no charge, while others are available for purchase from the publisher. \n# Air and Water\n\n# Appendix F. Areas of Future Research Air\n• Standardize the methodology and interpretation of microbiologic air sampling (e.g., determine action levels or minimum infectious dose for aspergillosis, and evaluate the significance of airborne bacteria and fungi in the surgical field and the impact on postoperative SSI). • Develop new molecular typing methods to better define the epidemiology of health-care associated outbreaks of aspergillosis and to associate isolates recovered from both clinical and environmental sources. • Develop new methods for the diagnosis of aspergillosis that can lead reliably to early recognition of infection. • Assess the value of laminar flow technology for surgeries other than for joint replacement surgery.\n• Determine if particulate sampling can be routinely performed in lieu of microbiologic sampling for purposes such as determining air quality of clean environments (e.g., operating rooms, HSCT units).\n# Water\n• Evaluate new methods of water treatment, both in the facility and at the water utility (e.g., ozone, chlorine dioxide, copper/silver/monochloramine) and perform cost-benefit analyses of treatment in preventing health-care associated legionellosis. • Evaluate the role of biofilms in overall water quality and determine the impact of water treatments for the control of biofilm in distribution systems. • Determine if the use of ultrapure fluids in dialysis is feasible and warranted, and determine the action level for the final bath. • Develop quality assurance protocols and validated methods for sampling filtered rinse water used with AERs and determine acceptable microbiologic quality of AER rinse water.\n# Environmental Services\n• Evaluate the innate resistance of microorganisms to the action of chemical germicides, and determine what, if any, linkage there may be between antibiotic resistance and resistance to disinfectants.\n# Laundry and Bedding\n• Evaluate the microbial inactivation capabilities of new laundry detergents, bleach substitutes, other laundry additives, and new laundry technologies.\n# Animals in Health-Care Facilities\n• Conduct surveillance to monitor incidence of infections among patients in facilities that use animal programs, and conduct investigations to determine new infection control strategies to prevent these infections. • Evaluate the epidemiologic impact of performing procedures on animals (e.g., surgery or imaging) in human health-care facilities.\n# Regulated Medical Waste\n• Determine the efficiency of current medical waste treatment technologies to inactivate emerging pathogens that may be present in medical waste (e.g., SARS-coV). • Explore options to enable health-care facilities to reinstate the capacity to inactivate microbiological cultures and stocks 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DISTINCT title\n \nFROM train\nWHERE title ILIKE '%peptic ulcer%'\n OR title ILIKE '%addict%'\nOR title ILIKE '%alcoholism%'\nOR title ILIKE '%substance abuse%'\nOR title ILIKE '%drug abuse%'\nOR title ILIKE '%dependence%'\nOR title ILIKE '%use disorder%'\nOR title ILIKE '%pylori %'\nOR title ILIKE '%ibs%'\nOR title iLIKE '%irritable bowel%'\n OR title ILIKE'%psychogen%'\n OR title ILIKE '%compliance%'\n OR title ILIKE '%adherence%'\n OR title ILIKE 'functional%'\n OR title ILIKE '%psychophysiol%'\n OR title ILIKE '%psychosomatic%'\n OR title ILIKE '%ME/CFS%'\n OR title ILIKE '%chronic fatigue syndrome%'\n OR title ILIKE '%substance use%'\n OR title ILIKE '%anorexi%'\n OR title ILIKE '%resistant depression%'\nOR title ILIKE '%eating disorder%'\n OR title ILIKE '%disordered eating%'\n OR title ILIKE '%long covid%';","title":"Medical Guidelines Search Results","createdAt":"2026-04-07T02:40:18.798Z","slug":"CNJhGxt","private":false,"justification":"Identifies and retrieves distinct research paper titles related to various medical and psychological conditions, revealing the scope and focus areas within the dataset that might be relevant for understanding disease prevalence or research interest patterns.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"WITH extracted AS (\n SELECT\n source,\n title,\n clean_text,\n regexp_extract_all(clean_text, '(?:19|20)\\w{2,}') AS all_matches,\n regexp_split_to_array(clean_text, '(?:19|20)\\w{2,}') AS all_splits\n FROM train\n LIMIT 200\n),\npositioned AS (\n SELECT\n source,\n title,\n clean_text,\n all_matches,\n all_splits,\n unnest(all_matches) AS matched_str,\n generate_subscripts(all_matches, 1) AS match_idx\n FROM extracted\n),\nwith_positions AS (\n SELECT\n source,\n title,\n clean_text,\n match_idx,\n matched_str,\n -- position of match[i] = total chars in splits[1..i] + total chars in matches[1..i-1] + 1\n -- = length(concat of all_splits[1..i]) + length(concat of all_matches[1..i-1]) + 1\n length(array_to_string(all_splits[1:match_idx], ''))\n + length(array_to_string(all_matches[1:match_idx-1], ''))\n + 1 AS match_start\n FROM positioned\n),\nwith_windows AS (\n SELECT\n source,\n title,\n clean_text,\n match_idx,\n matched_str,\n match_start,\n GREATEST(1, match_start - 20)::BIGINT AS window_start,\n (match_start + length(matched_str) + 20)::BIGINT AS window_end\n FROM with_positions\n WHERE match_start IS NOT NULL AND match_start > 0\n),\nfiltered AS (\n SELECT\n w1.source,\n w1.title,\n w1.clean_text,\n w1.match_idx,\n w1.matched_str,\n w1.match_start,\n w1.window_start,\n w1.window_end,\n NOT EXISTS (\n SELECT 1\n FROM with_windows w2\n WHERE w2.source = w1.source\n AND w2.title = w1.title\n AND w2.clean_text = w1.clean_text\n AND w2.match_idx < w1.match_idx\n AND w1.match_start >= w2.window_start\n AND w1.match_start <= w2.window_end\n ) AS is_new_window\n FROM with_windows w1\n),\nnew_windows_only AS (\n SELECT\n source,\n title,\n clean_text,\n match_idx,\n window_start,\n window_end,\n ROW_NUMBER() OVER (\n PARTITION BY source, title, clean_text\n ORDER BY match_idx\n ) AS context_num\n FROM filtered\n WHERE is_new_window = TRUE\n),\nwith_context AS (\n SELECT\n source,\n title,\n clean_text,\n context_num,\n substr(\n clean_text,\n window_start::BIGINT,\n (window_end - window_start)::BIGINT\n ) AS context,\n context_num = MAX(context_num) OVER (\n PARTITION BY source, title, clean_text\n ) AS is_last\n FROM new_windows_only\n)\nSELECT\n source,\n title,\n clean_text,\n MAX(CASE WHEN context_num = 1 THEN context END) AS date_context_1,\n MAX(CASE WHEN context_num = 2 THEN context END) AS date_context_2,\n MAX(CASE WHEN context_num = 3 THEN context END) AS date_context_3,\n MAX(CASE WHEN context_num = 4 THEN context END) AS date_context_4,\n MAX(CASE WHEN context_num = 5 THEN context END) AS date_context_5,\n MAX(CASE WHEN is_last THEN context END) AS date_context_final\nFROM with_context\nGROUP BY source, title, clean_text;","title":"SQL Console for epfl-llm/guidelines","createdAt":"2026-04-05T17:24:33.471Z","slug":"rfYAc4t","private":false,"justification":"This query extracts and contextualizes date patterns from text data, revealing temporal information embedded within documents which can help identify time-related trends and patterns in the content.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n -- Counts of 'none' occurrences\n COUNT(CASE WHEN lower(raw_text) = 'none' THEN 1 END) AS raw_text_none_count,\n COUNT(CASE WHEN lower(clean_text) = 'none' THEN 1 END) AS clean_text_none_count,\n \n -- Total row count\n COUNT(*) AS total_rows,\n \n -- Percentage of 'none' occurrences\n ROUND(100.0 * COUNT(CASE WHEN lower(raw_text) = 'none' THEN 1 END) / COUNT(*), 2) AS raw_text_none_pct,\n ROUND(100.0 * COUNT(CASE WHEN lower(clean_text) = 'none' THEN 1 END) / COUNT(*), 2) AS clean_text_none_pct,\n \n -- Average lengths\n ROUND(AVG(CASE WHEN lower(raw_text) = 'none' THEN length(clean_text) END), 2) AS avg_clean_text_length_in_none_raw_text_rows,\n ROUND(AVG(length(clean_text)), 2) AS avg_clean_text_length_entire_dataset\nFROM train;","title":"Count and Percentage of 'None'","createdAt":"2025-06-04T09:25:55.445Z","slug":"Gg9tI4f","private":false,"justification":"The query reveals the frequency of 'none' values in raw and clean text fields, their percentage in the dataset, and average text length differences, providing valuable insights for data cleaning and quality assessment.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n DISTINCT title\n \nFROM train\nWHERE title ILIKE '%psychogen%'\n OR title ILIKE '%compliance%'\n OR title ILIKE '%adherence%'\n OR title ILIKE 'functional%'\n OR title ILIKE '%psychophysiol%'\n OR title ILIKE '%psychosomatic%'\n OR title ILIKE '%ME/CFS%'\n OR title ILIKE '%overweight%'\n OR title ILIKE '%chronic fatigue syndrome%'\n -- OR title ILIKE '%obes%'\n OR title ILIKE '%substance use%'\n OR title ILIKE '%anorexi%'\n -- OR title ILIKE '%resistant depression%'\nOR title ILIKE '%eating disorder%'\n OR title ILIKE '%disordered eating%'\n OR title ILIKE '%long covid%';","title":"Unique titles stigmatized conditions","createdAt":"2026-04-06T12:56:57.347Z","slug":"lelqsSl","private":false,"justification":"Filters and retrieves distinct article titles containing various mental health, behavioral, and chronic condition related terms to identify research topics in psychology and medicine.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n DISTINCT title\n \nFROM train\nWHERE title ILIKE '%ME/CFS%'\n OR title ILIKE '%chronic fatigue syndrome%'\n OR title ILIKE '%obes%'\n OR title ILIKE '%substance use%'\n OR title ILIKE '%anorexi%'\n -- OR title ILIKE '%resistant depression%'\nOR title ILIKE '%eating disorder%'\n OR title ILIKE '%disordered eating%'\nLIMIT 100;","title":"ME/CFS, Obesity, SUD, ED Studies","createdAt":"2026-04-06T03:30:58.567Z","slug":"72n7WXX","private":false,"justification":"Retrieves distinct article titles containing keywords related to specific medical conditions, providing a useful starting point for exploring research topics in chronic fatigue, obesity, substance use, and eating disorders.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n source,\n title,\n clean_text,\n regexp_extract(clean_text, '.{0,50}(?:January|February|March|April|May|June|July|August|September|October|November|December).{0,50}') AS date_context\nFROM train\nWHERE regexp_matches(clean_text, '\\b(?:January|February|March|April|May|June|July|August|September|October|November|December)\\b')\nLIMIT 100;","title":"Guidelines with Date Context Extraction","createdAt":"2026-04-06T02:57:02.300Z","slug":"Orxo4Pk","private":false,"justification":"Extracts text snippets containing month names to identify temporal references, which could help in understanding time-related patterns in the training data.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT *\nFROM train\nWHERE \n (\n (length(clean_text) - length(replace(lower(clean_text), 'bipolar', ''))) / length('bipolar') >= 5\n OR \n (length(clean_text) - length(replace(lower(clean_text), 'depression', ''))) / length('depression') >= 5\n );\n","title":"SQL Console for epfl-llm/guidelines","createdAt":"2026-01-05T16:58:45.607Z","slug":"WS5hOeI","private":false,"justification":"Identifies records containing frequent occurrences of mental health keywords, providing basic filtering for text analysis but offering limited insight beyond keyword frequency counting.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT \n clean_text,\n (length(clean_text) - length(replace(lower(clean_text), 'bipolar disorder', ''))) / length('bipolar disorder') \n AS bipolar_count\nFROM train\nWHERE (length(clean_text) - length(replace(lower(clean_text), 'bipolar disorder', ''))) / length('bipolar disorder') >= 3\nORDER BY bipolar_count DESC\nLIMIT 100000;","title":"Top Texts with Bisplar Disorder","createdAt":"2026-01-05T16:30:50.538Z","slug":"i66tXEM","private":false,"justification":"Identifies texts with high frequency of \"bipolar disorder\" mentions, useful for understanding how often this term appears in the dataset but doesn't reveal deeper patterns or relationships.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n DISTINCT title\n \nFROM train\nWHERE title ILIKE '%peptic ulcer%'\nOR title ILIKE '%pylori%'\n-- OR title ILIKE '%ibs%'\n-- OR title iLIKE '%irritable bowel%'\n-- OR title ILIKE'%psychogen%'\n-- OR title ILIKE '%compliance%'\n-- OR title ILIKE '%adherence%'\n-- OR title ILIKE 'functional%'\n-- OR title ILIKE '%psychophysiol%'\n-- OR title ILIKE '%psychosomatic%'\n-- OR title ILIKE '%ME/CFS%'\n-- OR title ILIKE '%overweight%'\n-- OR title ILIKE '%chronic fatigue syndrome%'\n-- -- OR title ILIKE '%obes%'\n-- OR title ILIKE '%substance use%'\n-- OR title ILIKE '%anorexi%'\n-- -- OR title ILIKE '%resistant depression%'\n-- OR title ILIKE '%eating disorder%'\n-- OR title ILIKE '%disordered eating%'\n-- OR title ILIKE '%long covid%';","title":"Peptic Ulcer and H. Pylori","createdAt":"2026-04-07T02:28:46.947Z","slug":"g-D5vjy","private":false,"justification":"Retrieves distinct article titles containing specific medical terms related to digestive disorders and mental health conditions, providing basic filtering of relevant literature but offering limited analytical value beyond simple keyword matching.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT *\nFROM train\nWHERE \n (\n (length(clean_text) - length(replace(lower(clean_text), 'bipolar_disorder', ''))) / length('bipolar_disorder') >= 5\n OR \n (length(clean_text) - length(replace(lower(clean_text), 'depression', ''))) / length('depression') >= 5\n )\nLIMIT 100000;","title":"Filter Bipolar, Depression Mentions","createdAt":"2026-01-05T16:51:38.821Z","slug":"9DBkcja","private":false,"justification":"Filters for records containing the terms \"bipolar_disorder\" or \"depression\" at least 5 times each, but doesn't provide meaningful analysis beyond basic keyword frequency counting.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT *\nFROM train\nWHERE contains(clean_text, 'bipolar disorder')\nLIMIT 100000;","title":"Bipolar Disorder Training Data","createdAt":"2026-01-05T16:03:09.077Z","slug":"Q8So_Zk","private":false,"justification":"Performs basic filtering to find records containing \"bipolar disorder\" in the clean_text field, which is useful for initial topic exploration but doesn't provide deeper analytical insights.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT *\nFROM train\nWHERE source = 'pubmed'\nLIMIT 100;","title":"PubMed Guidelines Sample","createdAt":"2025-09-11T18:51:13.752Z","slug":"OXKa-fR","private":false,"justification":"Retrieves 100 samples from the 'train' dataset where the source is 'pubmed', providing a basic view of the data but limited analytical value.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n MIN(LENGTH(clean_text)) AS min_clean_length,\n MAX(LENGTH(clean_text)) AS max_clean_length,\n MIN(LENGTH(raw_text)) AS min_raw_length,\n MAX(LENGTH(raw_text)) AS max_raw_length\nFROM train;","title":"Text Length Statistics","createdAt":"2025-06-04T09:31:10.914Z","slug":"xlW4ilr","private":false,"justification":"Provides the minimum and maximum lengths of both cleaned and raw text, offering basic insights into text length variation.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n COUNT(CASE WHEN lower(raw_text) = 'none' THEN 1 END) AS raw_text_none_count,\n COUNT(CASE WHEN lower(clean_text) = 'none' THEN 1 END) AS clean_text_none_count,\n COUNT(*) AS total_rows,\n ROUND(100.0 * COUNT(CASE WHEN lower(raw_text) = 'none' THEN 1 END) / COUNT(*), 2) AS raw_text_none_pct,\n ROUND(100.0 * COUNT(CASE WHEN lower(clean_text) = 'none' THEN 1 END) / COUNT(*), 2) AS clean_text_none_pct\nFROM train;","title":"Count None Values in Text Columns","createdAt":"2025-06-04T09:18:45.124Z","slug":"aqrbJ7J","private":false,"justification":"Counts the occurrences and percentages of rows where 'raw_text' or 'clean_text' is 'none', providing a basic overview of missing or placeholder data.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT\n *,\n LENGTH(clean_text) AS clean_text_length,\n LENGTH(raw_text) AS raw_text_length\nFROM train\nORDER BY clean_text_length DESC\nLIMIT 100;","title":"Top 100 Longest Clean Texts","createdAt":"2025-06-04T08:40:37.295Z","slug":"UK2264G","private":false,"justification":"Retrieves the 100 longest cleaned text entries along with their raw text versions, offering basic insight into text length differences.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT \n *,\n LENGTH(clean_text) AS clean_text_length\nFROM train\nORDER BY clean_text_length DESC\nLIMIT 100;","title":"Longest Clean Text Entries","createdAt":"2025-06-04T08:37:44.088Z","slug":"5NT4qgP","private":false,"justification":"Returns the 100 longest clean texts in the dataset, which could help identify unusually long entries for quality review.","viewNames":["train"]},{"views":[{"key":"default/train","displayName":"train","viewName":"train"}],"sql":"SELECT \n id,\n title,\n LENGTH(clean_text) AS clean_text_length\nFROM train\nORDER BY clean_text_length DESC\nLIMIT 100;","title":"Longest Clean Text Entries","createdAt":"2025-06-04T08:34:40.035Z","slug":"agI8iOd","private":false,"justification":"Returns the 100 longest cleaned text entries by id and title, providing basic information about the longest entries without significant analytical insight.","viewNames":["train"]}],"user":[]}}">
id stringlengths 40 40 | source stringclasses 9
values | title stringlengths 2 345 | clean_text stringlengths 35 1.63M | raw_text stringlengths 4 1.63M | url stringlengths 4 498 | overview stringlengths 0 10k |
|---|---|---|---|---|---|---|
4b24b9885596178647e3576ebc74fe2c1fafc929 | cdc | None | These recommendations update information on the vaccine and antiviral agents available for controlling influenza during the 1996-97 influenza season (superseding MMWR 1995;44(No. RR-3):1-22). The principal changes include information about a) the influenza virus strains included in the trivalent vaccine for 1996-97 and... | These recommendations update information on the vaccine and antiviral agents available for controlling influenza during the 1996-97 influenza season (superseding MMWR 1995;44(No. RR-3):1-22). The principal changes include information about a) the influenza virus strains included in the trivalent vaccine for 1996-97 and... | None | None |
3e2c15f87569d17809327ee84752d8ece448fbbb | cdc | None | Rapid, readily available, and accurate diagnosis of rabies is the keystone of prevention. All surveillance activity and description of the complex epizootiologic characteristics of rabies in the United States is based on laboratory diagnosis. Veterinarians are the first line of defense against rabies when responding to... | #
Rapid, readily available, and accurate diagnosis of rabies is the keystone of prevention. All surveillance activity and description of the complex epizootiologic characteristics of rabies in the United States is based on laboratory diagnosis. Veterinarians are the first line of defense against rabies when responding... | None | None |
f94b7aca6f54717b42e20a52792fa4e78e8360ae | cdc | None | These recommendations update information on the vaccine and antiviral agents available for controlling influenza during the 1992-1993 influenza season (superseding the MMWR 1991;40(no. RR-6):1-15.) The primary changes include statements about vaccination of persons with known hypersensitivity to eggs or other component... | These recommendations update information on the vaccine and antiviral agents available for controlling influenza during the 1992-1993 influenza season (superseding the MMWR 1991;40(no. RR-6):1-15.) The primary changes include statements about vaccination of persons with known hypersensitivity to eggs or other component... | None | None |
ec5b6c37f288246e848c210f10218a0710cfda4b | cdc | None | The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to chloroform in the workplace be controlled by adherence to the follow ing sections. The standard is designed to protect the health and provide fo r the safety of work ers fo r up to a 10-hour workday, 40-hour work week o... | #
The National Institute for Occupational Safety and Health (NIOSH) recommends that worker exposure to chloroform in the workplace be controlled by adherence to the follow ing sections. The standard is designed to protect the health and provide fo r the safety of work ers fo r up to a 10-hour workday, 40-hour work wee... | None | None |
272091323f74c82c1dd5bd06582893c761be9910 | cdc | None | # Injury claims
All vaccines included in the adult immunization schedule except pneumococcal 23-valent polysaccharide (PPSV23) and zoster (RZV, ZVL) vaccines are covered by the Vaccine Injury Compensation Program. Information on how to file a vaccine injury claim is available at www.hrsa.gov/vaccinecompensation.
# Que... | # Injury claims
All vaccines included in the adult immunization schedule except pneumococcal 23-valent polysaccharide (PPSV23) and zoster (RZV, ZVL) vaccines are covered by the Vaccine Injury Compensation Program. Information on how to file a vaccine injury claim is available at www.hrsa.gov/vaccinecompensation.
# Ques... | None | None |
2cd1a80ccc5ec240d647f984bbec24679abd088d | cdc | None | new information was presented to the Advisory Committee on Immunization Practices (ACIP) regarding the risk for febrile seizures among children aged 12--23 months after administration of the combination measles, mumps, rubella, and varicella (MMRV) vaccine (ProQuad ® , Merck & Co., Inc., Whitehouse Station, New Jersey)... | new information was presented to the Advisory Committee on Immunization Practices (ACIP) regarding the risk for febrile seizures among children aged 12--23 months after administration of the combination measles, mumps, rubella, and varicella (MMRV) vaccine (ProQuad ® , Merck & Co., Inc., Whitehouse Station, New Jersey)... | None | None |
e7505befd09ff3ee702a6fafc02c272ff596b68f | cdc | None | CDC Malaria Hotline: (770) 488-7788 or (855) 856-4713 toll-free Monday-Friday 9 am to 5 pm EST -(770) 488-7100 after hours, weekends and holidays Clinical Diagnosis/ Plasmodium species Region Infection Acquired Recommended Drug and Adult Dose 1 Recommended Drug and Pediatric Dose 1 Pediatric dose should NEVER exceed ad... | CDC Malaria Hotline: (770) 488-7788 or (855) 856-4713 toll-free Monday-Friday 9 am to 5 pm EST -(770) 488-7100 after hours, weekends and holidays Clinical Diagnosis/ Plasmodium species Region Infection Acquired Recommended Drug and Adult Dose 1 Recommended Drug and Pediatric Dose 1 Pediatric dose should NEVER exceed ad... | None | None |
750e26d9da7066b8352c4f67070690a4603448c7 | cdc | None | All animal rabies vaccines should be restricted to use by, or under the direct supervision of, a veterinarian.In comprehensive rabies-control programs, only vaccines with a 3-year duration of immunity should be used. This constitutes the most effective method of increasing the proportion of immunized dogs and cats in a... | All animal rabies vaccines should be restricted to use by, or under the direct supervision of, a veterinarian.In comprehensive rabies-control programs, only vaccines with a 3-year duration of immunity should be used. This constitutes the most effective method of increasing the proportion of immunized dogs and cats in a... | None | None |
60d48ae6cad0ed90a4a05c4f091e5ab648dc93a9 | cdc | None | The standard is designed to protect the health and safety of workers for an 8-hour day, 40-hour week over a working lifetime; compliance with the standard should therefore prevent adverse effects of toluene on the health and safety of workers. The standard is measurable by techniques that are valid, reproducible, and a... | The standard is designed to protect the health and safety of workers for an 8-hour day, 40-hour week over a working lifetime; compliance with the standard should therefore prevent adverse effects of toluene on the health and safety of workers. The standard is measurable by techniques that are valid, reproducible, and a... | None | None |
2113944154b2d4c3d94ea78b990ef6347af9d591 | cdc | None | # Contents
# Executive Summary
The Division of HIV/AIDS Prevention at the Centers for Disease Control and Prevention (CDC) was charged by the National HIV/AIDS Strategy to provide "technical assistance to localities to collect data to calculate community viral load" . Guidance on Community Viral Load: A Family of Mea... | # Contents
# Executive Summary
The Division of HIV/AIDS Prevention at the Centers for Disease Control and Prevention (CDC) was charged by the National HIV/AIDS Strategy to provide "technical assistance to [HIV reporting] localities to collect data to calculate community viral load" [1]. Guidance on Community Viral Loa... | None | None |
ddd02126f3f1b16a6ef5664a018e1c2b3d394f2e | cdc | None | Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use.# Introduction
Genetic testing encompasses a broad range of laboratory tests performed to analyze DNA, RNA, chromosomes, proteins, and certain metabolites using biochemical, cytogenetic, or molecular m... | Presentations will not include any discussion of the unlabeled use of a product or a product under investigational use.# Introduction
Genetic testing encompasses a broad range of laboratory tests performed to analyze DNA, RNA, chromosomes, proteins, and certain metabolites using biochemical, cytogenetic, or molecular m... | None | None |
df4271ffee278081e5bd60585cd3d48376a128ec | cdc | None | In January 1991, epidem ic cholera appeared in Peru and quickly spread to m any o the r Latin Am erican countries. Because reporting o f cholera cases was often delayed in som e areas, the scope o f the epidem ic was unclear. An assessment o f the conduct o f surveillance fo r cholera in several countries identifie d s... | In January 1991, epidem ic cholera appeared in Peru and quickly spread to m any o the r Latin Am erican countries. Because reporting o f cholera cases was often delayed in som e areas, the scope o f the epidem ic was unclear. An assessment o f the conduct o f surveillance fo r cholera in several countries identifie d s... | None | None |
f2c809722977ce0efe5010d17dd85a2163dac561 | cdc | None | The need for a single childhood immunization schedule prompted the unification of previous vaccine recommendations made by the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP). In addition to presenting the newly recommended schedule for the administration of vaccines dur... | The need for a single childhood immunization schedule prompted the unification of previous vaccine recommendations made by the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP). In addition to presenting the newly recommended schedule for the administration of vaccines dur... | None | None |
b60c81d032f5b61a9833e1ff7d6f5cb1d9d34f86 | cdc | None | The Collaborative Strategy on Bed Bugs reflects a broad-based consensus of federal agencies. It is an outcome of the interagency Federal Bed Bug Workgroup. The Strategy was authored by key agencies (EPA, HHS , HUD, and USDA) and includes technical information and input from the Department of Defense and the National In... | The Collaborative Strategy on Bed Bugs reflects a broad-based consensus of federal agencies. It is an outcome of the interagency Federal Bed Bug Workgroup. The Strategy was authored by key agencies (EPA, HHS [CDC], HUD, and USDA) and includes technical information and input from the Department of Defense and the Nation... | None | None |
1550536f2feb3b6ca308c9d0cf4401deac6ca980 | cdc | None | Universal HIV testing of pregnant women in the United States is the key to prevention of mother-to-child transmission of HIV. Repeat testing in the third trimester and rapid HIV testing at labor and delivery are additional strategies to further reduce the rate of perinatal HIV transmission. Prevention of mother-to-chil... | Universal HIV testing of pregnant women in the United States is the key to prevention of mother-to-child transmission of HIV. Repeat testing in the third trimester and rapid HIV testing at labor and delivery are additional strategies to further reduce the rate of perinatal HIV transmission. Prevention of mother-to-chil... | None | None |
481af9e6404daf88c1b771283e9f19d57bf30251 | cdc | None | The Occupational Safety and Health Act of 1970 emphasized the need for standards to protect the health and safety of workers exposed to an ever increasing number of potential hazards in the workplace. Section 22(d)(2) of the Act authorizes the Director of the National In stitu te for Occupational Safety and Health (NIO... | The Occupational Safety and Health Act of 1970 emphasized the need for standards to protect the health and safety of workers exposed to an ever increasing number of potential hazards in the workplace. Section 22(d)(2) of the Act authorizes the Director of the National In stitu te for Occupational Safety and Health (NIO... | None | None |
39baa8b6e9feea2021ca376619c2de33e0e7129b | cdc | None | Seal all openings where piping and other items penetrate through the deck.#
VSP would like to acknowledge the following organizations and companies for their cooperative efforts in the revisions of the VSP 2011 Construction Guidelines. The cover art was designed by Carrie Green.
# Background and Purpose
The Centers fo... | Seal all openings where piping and other items penetrate through the deck.#
VSP would like to acknowledge the following organizations and companies for their cooperative efforts in the revisions of the VSP 2011 Construction Guidelines. The cover art was designed by Carrie Green.
# Background and Purpose
The Centers ... | None | None |
3e133b195dc705156e36720a0045594a70ca995f | cdc | None | Objective The Working Group on Civilian Biodefense has developed consensusbased recommendations for measures to be taken by medical and public health professionals following the use of plague as a biological weapon against a civilian population.The working group included 25 representatives from major academic medical c... | Objective The Working Group on Civilian Biodefense has developed consensusbased recommendations for measures to be taken by medical and public health professionals following the use of plague as a biological weapon against a civilian population.The working group included 25 representatives from major academic medical c... | None | None |
38cb999ff54491fb321d04c5e42fc0754a22d916 | cdc | None | In February 1999, the Advisory Committee on Immunization Practices (ACIP) expanded recommendations for varicella (chickenpox) vaccine to promote wider use of the vaccine for susceptible children and adults. The updated recommendations include establishing child care and school entry requirements, use of the vaccine fol... | In February 1999, the Advisory Committee on Immunization Practices (ACIP) expanded recommendations for varicella (chickenpox) vaccine to promote wider use of the vaccine for susceptible children and adults. The updated recommendations include establishing child care and school entry requirements, use of the vaccine fol... | None | None |
5f1f83571e88de8c20043846c9f0accfac833ea1 | cdc | None | for work for the performance of these task order contracts. The Board may revise or accept the IGCE, the task order, and/or some or all of the ABRWH independent dose reconstruction review of contractor's bids. These contracts will serve to provide technical support consultation to assist the ABRWH in fulfilling its sta... | for work for the performance of these task order contracts. The Board may revise or accept the IGCE, the task order, and/or some or all of the ABRWH independent dose reconstruction review of contractor's bids. These contracts will serve to provide technical support consultation to assist the ABRWH in fulfilling its sta... | None | None |
dc9dcf4049457d24e4193bb6e544a719b87a6587 | cdc | None | Gonorrhea is a major cause of serious reproductive complications in women and can facilitate human immunodeficiency virus (HIV) transmission (1). Effective treatment is a cornerstone of U.S. gonorrhea control efforts, but treatment of gonorrhea has been complicated by the ability of Neisseria gonorrhoeae to develop ant... | #
Gonorrhea is a major cause of serious reproductive complications in women and can facilitate human immunodeficiency virus (HIV) transmission (1). Effective treatment is a cornerstone of U.S. gonorrhea control efforts, but treatment of gonorrhea has been complicated by the ability of Neisseria gonorrhoeae to develop ... | None | None |
8717b3f5b275c1c68bb4e98b5f0eb9076b2c8f06 | cdc | None | Two live, attenuated varicella zoster virus-containing vaccines are available in the United States for prevention o f varicella: 1) a single-antigen varicella vaccine (VARIVAX,# CONTENTS______________________________________
# Introduction
Varicella is a highly infectious disease caused by the vari cella-zoster virus ... | Two live, attenuated varicella zoster virus-containing vaccines are available in the United States for prevention o f varicella: 1) a single-antigen varicella vaccine (VARIVAX,# CONTENTS______________________________________
# Introduction
Varicella is a highly infectious disease caused by the vari cella-zoster virus ... | None | None |
de170adb729bbbf9e6682e4269de540708c9c778 | cdc | None | This report provides updated recommendations for prevention and control of hantavirus infections associated with rodents in the United States. It supersedes the previous report (CDC. Hantavirus infection-southwestern United States: interim recommendations for risk reduction. MMWR 1993;42:1-13). These recommendations ar... | This report provides updated recommendations for prevention and control of hantavirus infections associated with rodents in the United States. It supersedes the previous report (CDC. Hantavirus infection-southwestern United States: interim recommendations for risk reduction. MMWR 1993;42[No. RR-11]:1-13). These recomme... | None | None |
9e462dc33f3c61e455ca5e3287f14345f0ce749a | cdc | None | # Introduction
This document describes CDC's Office of the Associate Director for Science (OADS) requirements for disclosing the competing interests of authors and members of steering committees and workgroups who develop and report on CDC guidelines and recommendations. A competing interest exists when professional ju... | # Introduction
This document describes CDC's Office of the Associate Director for Science (OADS) requirements for disclosing the competing interests of authors and members of steering committees and workgroups who develop and report on CDC guidelines and recommendations. A competing interest exists when professional ju... | None | None |
216f88b4f77f2104bf1bd01d3c1c593a3587eb11 | cdc | None | Objective To review and update consensus-based recommendations for medical and public health professionals following a Bacillus anthracis attack against a civilian population. Participants The working group included 23 experts from academic medical centers, research organizations, and governmental, military, public hea... | Objective To review and update consensus-based recommendations for medical and public health professionals following a Bacillus anthracis attack against a civilian population. Participants The working group included 23 experts from academic medical centers, research organizations, and governmental, military, public hea... | None | None |
30e3183532fd99a89e5845e678bb5b6ee2393c23 | cdc | None | For information about other occupational safety and health problems, call 1-800-35-NIQSH ii DHHS (NIOSH) Publication No. 93-103 PREFACE A memorandum has been signed between the Centers for Disease Control, National Institute for Occupational Safety and Health (NIOSH), USA, and the Nordic Expert Group for Documentation ... | For information about other occupational safety and health problems, call 1-800-35-NIQSH ii DHHS (NIOSH) Publication No. 93-103 PREFACE A memorandum has been signed between the Centers for Disease Control, National Institute for Occupational Safety and Health (NIOSH), USA, and the Nordic Expert Group for Documentation ... | None | None |
25c2b022642f2e4ccdfee9afb88aefece0604c89 | cdc | None | Ceftriaxone 1 g, IM or IV, every 24 hours or Ceftizoxime 1 g, IV, every 8 hours or Cefotaxime 1 g, IV, every 8 hours. Patients who are allergic to (3-lactam drugs should be treated with spectinomycin 2 g IM every 12 hours. "Erythromycin stearate 500 mg or erythromycin ethylsuccinate 800 mg or equivalent may be substitu... | Ceftriaxone 1 g, IM or IV, every 24 hours or Ceftizoxime 1 g, IV, every 8 hours or Cefotaxime 1 g, IV, every 8 hours. Patients who are allergic to (3-lactam drugs should be treated with spectinomycin 2 g IM every 12 hours. "Erythromycin stearate 500 mg or erythromycin ethylsuccinate 800 mg or equivalent may be substitu... | None | None |
436df2c0ee5fb7d33901b1a13f5bfbd8602037c5 | cdc | None | # DISCLAIMER
Mention of company name or product does not constitute endorsement by the National Institute for Occupational Safety and Health.
# DHEW (NIOSH) Publication No. 77-200
# PREFACE
The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers exp... | # DISCLAIMER
Mention of company name or product does not constitute endorsement by the National Institute for Occupational Safety and Health.
# DHEW (NIOSH) Publication No. 77-200
# PREFACE
The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers expo... | None | None |
0865596bae6bff9e11e5f72a79b844a3bc4c6d42 | cdc | None | CDC, our planners, and our presenters wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters, with the exception of Barbara Body, who works for LabCorp and serves on the Advisory Board of Becton D... | CDC, our planners, and our presenters wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters, with the exception of Barbara Body, who works for LabCorp and serves on the Advisory Board of Becton D... | None | None |
2076612ec6159079744e22d576e5a6a044a41a9d | cdc | None | British thermal unit CDC Centers for Disease Control and Prevention CFR Code of Federal Regulations CGA Canadian Gas Association CO carbon monoxide CPR cardiopulmonary resuscitation CPSC Consumer Product Safety Commission CSIA Chimney Safety Institute of America ABPA The American Backflow Prevention Association, Devel... | British thermal unit CDC Centers for Disease Control and Prevention CFR Code of Federal Regulations CGA Canadian Gas Association CO carbon monoxide CPR cardiopulmonary resuscitation CPSC Consumer Product Safety Commission CSIA Chimney Safety Institute of America ABPA The American Backflow Prevention Association, http:/... | None | None |
61bdee57235e55e486784be6fa54e2aa433a72f8 | cdc | None | # DISCLAIMER
Mention of company names or products does not co n stitu te endorsement by the National In s titu te for Occupational Safety and Health.
# D H H S (N IO S H ) Publication No. 81-131
# PREFACE
The Occupational Safety and Health Act of 1970 emphasizes the need to p ro tect the h ealth and safety of workers... | # DISCLAIMER
Mention of company names or products does not co n stitu te endorsement by the National In s titu te for Occupational Safety and Health.
# D H H S (N IO S H ) Publication No. 81-131
# PREFACE
The Occupational Safety and Health Act of 1970 emphasizes the need to p ro tect the h ealth and safety of workers ... | None | None |
24dc9ff81d2ab9497d59f1d4ddd62ddc887975be | cdc | None | Through the Act, Congress charged NIOSH with recommending occupational safety and health standards and describing exposure limits that are safe for various periods of employment. These limits include but are not limited to the exposures at which no worker will suffer diminished health, functional capacity, or life expe... | Through the Act, Congress charged NIOSH with recommending occupational safety and health standards and describing exposure limits that are safe for various periods of employment. These limits include but are not limited to the exposures at which no worker will suffer diminished health, functional capacity, or life expe... | None | None |
6c94615955f4d886d26d5cbb9fee84b75389ad3e | cdc | None | Multiple venues encourage or permit the public to come in contact with animals, resulting in millions of human-animal contacts each year. These settings include county or state fairs, petting zoos, animal swap meets, pet stores, zoologic institutions, circuses, carnivals, farm tours, livestock-birthing exhibits, educat... | Multiple venues encourage or permit the public to come in contact with animals, resulting in millions of human-animal contacts each year. These settings include county or state fairs, petting zoos, animal swap meets, pet stores, zoologic institutions, circuses, carnivals, farm tours, livestock-birthing exhibits, educat... | None | None |
d617d9757c1c97f7a066c1fdf54865052af11c4e | cdc | None | In July 197 5, a private physician submitted a blood sample to the Center for Disease Control (CDC) to be analyzed for kepone, a chlorinated hydro carbon pesticide. The sample had been obtained from a kepone production worker who suffered from weight loss, nystagmus, and tremors. CDC notified the State epidemiologist t... | In July 197 5, a private physician submitted a blood sample to the Center for Disease Control (CDC) to be analyzed for kepone, a chlorinated hydro carbon pesticide. The sample had been obtained from a kepone production worker who suffered from weight loss, nystagmus, and tremors. CDC notified the State epidemiologist t... | None | None |
9aae22dea747bf232bb655af93d600ab551a7731 | cdc | None | CDC recommends that all states and territories conduct case surveillance for human immunodeficiency virus (HIV) infection as an extension of current acquired immunodeficiency syndrome (AIDS) surveillance activities. The expansion of national surveillance to include both HIV infection and AIDS cases is a necessary respo... | CDC recommends that all states and territories conduct case surveillance for human immunodeficiency virus (HIV) infection as an extension of current acquired immunodeficiency syndrome (AIDS) surveillance activities. The expansion of national surveillance to include both HIV infection and AIDS cases is a necessary respo... | None | None |
38ebe37244075c4b366bb49898da1995bb3bee5b | cdc | None | Incidence rates of suicide and attempted suicide among adolescents and young adults aged 15-24 years continue to remain at high levels. In 1992, to aid communities in developing new or augmenting existing suicide prevention programs directed toward this age group, CDC's National Center for Injury Prevention and Control... | Incidence rates of suicide and attempted suicide among adolescents and young adults aged 15-24 years continue to remain at high levels. In 1992, to aid communities in developing new or augmenting existing suicide prevention programs directed toward this age group, CDC's National Center for Injury Prevention and Control... | None | None |
15463d133cd19aa564553bff697708aaaaad6ac3 | cdc | None | timely efforts to reduce the number of infected adult mosquitoes will optimally impact human WNV case incidence when environmental surveillance indicates substantial WNV epizootic activity or when many human cases occur early in the season (e.g., June or July.) This document provides guidance for communities and public... | timely efforts to reduce the number of infected adult mosquitoes will optimally impact human WNV case incidence when environmental surveillance indicates substantial WNV epizootic activity or when many human cases occur early in the season (e.g., June or July.) This document provides guidance for communities and public... | None | None |
5f1b33220832d20ea6b33dd942b1b5b602e3a571 | cdc | None | These guidelines for the treatment of patients with sexually transmitted diseases (STDs) were developed by staff members of CDC after consultation with a group of invited experts who met in Atlanta on January 19-21, 1993. Included are new recommendations for single-dose oral therapy for gonococcal infections, chlamydia... | These guidelines for the treatment of patients with sexually transmitted diseases (STDs) were developed by staff members of CDC after consultation with a group of invited experts who met in Atlanta on January 19-21, 1993. Included are new recommendations for single-dose oral therapy for gonococcal infections, chlamydia... | None | None |
751fddd552ad83bdca529e1beeb9107556530d13 | cdc | None | # BACkGROUND
The optimal way to reduce the morbidity, mortality, and socioeconomic consequences of injuries is to prevent their occurrence. 1,2 When an injury does occur, however, emergency medical service (EMS) providers must ensure that patients receive prompt emergency care at the scene and are transported to an app... | # BACkGROUND
The optimal way to reduce the morbidity, mortality, and socioeconomic consequences of injuries is to prevent their occurrence. 1,2 When an injury does occur, however, emergency medical service (EMS) providers must ensure that patients receive prompt emergency care at the scene and are transported to an app... | None | None |
371187c5b817f7160bb8a0536f57286e336069b1 | cdc | None | This schedule includes recommendations in effect as of January 1, 2015. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Vacci... | This schedule includes recommendations in effect as of January 1, 2015. Any dose not administered at the recommended age should be administered at a subsequent visit, when indicated and feasible. The use of a combination vaccine generally is preferred over separate injections of its equivalent component vaccines. Vacci... | None | None |
f4dc82e2112c6b8362c0ef18f9d7cb5157bba8c4 | cdc | None | On October 27, 2010, the Advisory Committee on Immunization Practices (ACIP) approved updated recommendations for the use of quadrivalent (serogroups A, C, Y, and W-135) meningococcal conjugate vaccines (Menveo, Novartis; and Menactra, Sanofi Pasteur) in adolescents and persons at high risk for meningococcal disease. ... | On October 27, 2010, the Advisory Committee on Immunization Practices (ACIP) approved updated recommendations for the use of quadrivalent (serogroups A, C, Y, and W-135) meningococcal conjugate vaccines (Menveo, Novartis; and Menactra, Sanofi Pasteur) in adolescents and persons at high risk for meningococcal disease. ... | None | None |
2b2f33b58b76a53f89eff268e024210fd91ce8df | cdc | None | Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of LTBI... | #
Treatment of latent tuberculosis infection (LTBI) is critical to the control and elimination of tuberculosis disease (TB) in the United States. In 2011, CDC recommended a short-course combination regimen of once-weekly isoniazid and rifapentine for 12 weeks (3HP) by directly observed therapy (DOT) for treatment of L... | None | None |
b57f8cabcf562a2fda8969eb02152b89c3aaafbb | cdc | None | Chorionic villus sampling (CVS) and amniocentesis are prenatal diagnostic procedures that are performed to detect fetal abnormalities. In 1991, concerns about the relative safety of these procedures arose after reports were published that described a possible association between CVS and birth defects in infants. Subseq... | Chorionic villus sampling (CVS) and amniocentesis are prenatal diagnostic procedures that are performed to detect fetal abnormalities. In 1991, concerns about the relative safety of these procedures arose after reports were published that described a possible association between CVS and birth defects in infants. Subseq... | None | None |
ceb53016631748ec4177fea37488fd5455b9a68f | cdc | None | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
In the United States, epidemics of influenza typically occur during the winter months and have bee... | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
In the United States, epidemics of influenza typically occur during the winter months and have bee... | None | None |
080e0d6188acec2392d2232b36f533e6b1fc454d | cdc | None | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Summary
To improve the implementation of these guidelines, a working group of the Professional Education Subcom... | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Summary
To improve the implementation of these guidelines, a working group of the Professional Education Subcom... | None | None |
64809312c9a766784a1bb2d6f377e02495830ba0 | cdc | None | Interviewing case-patients about where and what they ate in the days or weeks before they got sick is a critical component to hypothesis generation during an outbreak investigation. Interviews can also identify high-risk casepatients who could spread their infections to others (e.g., food handlers, day care workers or ... | Interviewing case-patients about where and what they ate in the days or weeks before they got sick is a critical component to hypothesis generation during an outbreak investigation. Interviews can also identify high-risk casepatients who could spread their infections to others (e.g., food handlers, day care workers or ... | None | None |
2ce0c0644e33874f6c44ada3d471e3aa71941bad | cdc | None | # Executive Summary
The Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007 updates and expands the Guideline for Isolation Precautions in Hospitals. The following developments led to revision of the 1996 guideline:
1. The transition of healthcare delivery from ... | # Executive Summary
The Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007 updates and expands the Guideline for Isolation Precautions in Hospitals. The following developments led to revision of the 1996 guideline:
1. The transition of healthcare delivery from ... | None | None |
be5fa83f79f487d22ab6683f23fb04f3e7755c40 | cdc | None | The purpose of the memorandum is to exchange information and expertise in the area of occupational safety and health. One product of this agreement is the development of documents to provide the scientific basis for establishing recommended occupational exposure limits. These limits will be developed separately by the ... | The purpose of the memorandum is to exchange information and expertise in the area of occupational safety and health. One product of this agreement is the development of documents to provide the scientific basis for establishing recommended occupational exposure limits. These limits will be developed separately by the ... | None | None |
cdf6df06d30bffb3b69500df28af41f363e3d433 | cdc | None | Several developments have fueled the renewed interest in xenotransplantationthe use of live animal cells, tissues and organs in the treatment or mitigation of human disease. The world-wide, critical shortage of human organs available for transplantation and advances in genetic engineering and in the immunology and biol... | #
Several developments have fueled the renewed interest in xenotransplantationthe use of live animal cells, tissues and organs in the treatment or mitigation of human disease. The world-wide, critical shortage of human organs available for transplantation and advances in genetic engineering and in the immunology and b... | None | None |
56ae786521af9e4884bc31de2139f922faebbb7c | cdc | None | Routine infant immunization with PCV7 since 2000 has decreased rates of IPD in young children markedly, but IPD from non-PCV7 serotypes, - Cases per 100,000 population. A case of IPD was defined as isolation of Streptococcus pneumoniae from a normally sterile body site (primarily blood or cerebrospinal fluid) in a resi... | Routine infant immunization with PCV7 since 2000 has decreased rates of IPD in young children markedly, but IPD from non-PCV7 serotypes, * Cases per 100,000 population. A case of IPD was defined as isolation of Streptococcus pneumoniae from a normally sterile body site (primarily blood or cerebrospinal fluid) in a resi... | None | None |
841a02c51ef591fe48a6b772c59e62daa4466fd1 | cdc | None | On January 22, 1974, representatives from the B. F. Goodrich Chemical Company informed NIOSH that the deaths of several employees of their Louisville, Kentucky, plant might have been related to occupa tional exposures. An immediate industrial hygiene walk-through survey of the facility was conducted by NIOSH and result... | #
On January 22, 1974, representatives from the B. F. Goodrich Chemical Company informed NIOSH that the deaths of several employees of their Louisville, Kentucky, plant might have been related to occupa tional exposures. An immediate industrial hygiene walk-through survey of the facility was conducted by NIOSH and res... | None | None |
54529de143cdd9a528e6f0c7360ccc7dbbd2b871 | cdc | None | Morbidity and Mortality Weekly Report depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Epidemics of influenza typically occur during the winter mon... | Morbidity and Mortality Weekly Report depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Epidemics of influenza typically occur during the winter mon... | None | None |
c193601c7cbb60b584371ad7f6064ade278536e7 | cdc | None | Technology and youth seem destined for each other. They are both young, fast paced, and ever changing. In the last 20 years there has been an explosion in new technology. This new technology has been eagerly embraced by young people and has led to expanding knowledge, social networks, and vocabulary that includes insta... | Technology and youth seem destined for each other. They are both young, fast paced, and ever changing. In the last 20 years there has been an explosion in new technology. This new technology has been eagerly embraced by young people and has led to expanding knowledge, social networks, and vocabulary that includes insta... | None | None |
e4029ba2cb8bd40b19fd330caee93fd854d7ae2e | cdc | None | Understanding and Complying with Security Procedures/Training (Sections 15, 11(f) and 11(d)(7))23 Inspection of Suspicious Packages (Section 11(d)(4)# Introduction
Section 201 of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (P.L. 107-188)(the Act) requires the Secretary of the Depar... | Understanding and Complying with Security Procedures/Training (Sections 15, 11(f) and 11(d)(7))23 Inspection of Suspicious Packages (Section 11(d)(4)# Introduction
Section 201 of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (P.L. 107-188)(the Act) requires the Secretary of the Depar... | None | None |
f4a9ffe2377adc4b32c4c82ddaca0a22af30e3e1 | cdc | None | Participants who responded "yes" to either question were classified as having a disability. To assess self-rated health status, participants were asked, "Would you say that in general your health is excellent, very good, good, fair, or poor?" The following racial/ethnic categories were included in this analysis: white,... | Participants who responded "yes" to either question were classified as having a disability. To assess self-rated health status, participants were asked, "Would you say that in general your health is excellent, very good, good, fair, or poor?" The following racial/ethnic categories were included in this analysis: white,... | None | None |
b73ce531e4a2381d4f9c3063cdd9179ad2fe5815 | cdc | None | This publication offers a comprehensive collection of 70 "building blocks," which are primary prevention strategies that merit consideration by state and local governments and others in position to reduce exposure to hazards in housing and thereby help meet the Healthy People 2010 goal of eliminating childhood lead poi... | This publication offers a comprehensive collection of 70 "building blocks," which are primary prevention strategies that merit consideration by state and local governments and others in position to reduce exposure to hazards in housing and thereby help meet the Healthy People 2010 goal of eliminating childhood lead poi... | None | None |
d8f1644d7aaefcaa1d5b59a2bb635727fd65fb25 | cdc | None | The O ccu p atio n al S afety and H ealth A ct of 1970 em p hasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards. The National Institute for O ccu p atio n al S afety and H ealth (NIOSH) evaluates all availabl... | The O ccu p atio n al S afety and H ealth A ct of 1970 em p hasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards. The National Institute for O ccu p atio n al S afety and H ealth (NIOSH) evaluates all availabl... | None | None |
048dfe20ef67a94994b79b33bc29fce892ab9494 | cdc | None | For adults and adolescents (i.e., persons aged >13 years), the human immunodeficiency virus (HIV) infection classification system and the surveillance case definitions for HIV infection and acquired immunodeficiency syndrome (AIDS) have been revised and combined into a single case definition for HIV infection (1-3). In... | For adults and adolescents (i.e., persons aged >13 years), the human immunodeficiency virus (HIV) infection classification system and the surveillance case definitions for HIV infection and acquired immunodeficiency syndrome (AIDS) have been revised and combined into a single case definition for HIV infection (1-3). In... | None | None |
206253872ec53313c6e65cc859fb525d115fe2c1 | cdc | None | M ention o f the name o f any company or product does not constitute endorsement by the N ational Institute for Occupational Safety and Health. This document is in the public domain and may b e freely copied or reprinted. C opies o f this and other NIOSH docum ents are available from Publications D issem ination, DSDTT... | M ention o f the name o f any company or product does not constitute endorsement by the N ational Institute for Occupational Safety and Health. This document is in the public domain and may b e freely copied or reprinted. C opies o f this and other NIOSH docum ents are available from Publications D issem ination, DSDTT... | None | None |
7f7629e8eb67e4d7b71699b7fb5b75129c54f729 | cdc | None | Table of Contents (continued) IX. APPENDIX I -Sampling Procedure for Collection of Tetrachloroethylene X. APPENDIX II -Analytical Procedure for Determination of Tetrachloroethylene XI.# REVIEW CONSULTANTS vil I. RECOMMENDATIONS FOR A TETRACHLOROETHTLENE STANDARD
# RESPIRATOR SELECTION GUIDE FOR PROTECTION AGAINST TETR... | Table of Contents (continued) IX. APPENDIX I -Sampling Procedure for Collection of Tetrachloroethylene X. APPENDIX II -Analytical Procedure for Determination of Tetrachloroethylene XI.# REVIEW CONSULTANTS vil I. RECOMMENDATIONS FOR A TETRACHLOROETHTLENE STANDARD
# RESPIRATOR SELECTION GUIDE FOR PROTECTION AGAINST TETR... | None | None |
2da6bed82055f51e635d07042f49315431a31a24 | cdc | None | # Executive Summary
The Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008, presents evidencebased recommendations on the preferred methods for cleaning, disinfection and sterilization of patientcare medical devices and for cleaning and disinfecting the healthcare environment. This document sup... | # Executive Summary
The Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008, presents evidencebased recommendations on the preferred methods for cleaning, disinfection and sterilization of patientcare medical devices and for cleaning and disinfecting the healthcare environment. This document sup... | None | None |
48e842488c3e84e0540f7dfe55b00da932fef11e | cdc | None | data are insufficient to recommend use of the FDA-approved single-use rapid HIV-1/HIV-2 antigen/antibody combination immunoassay as the initial assay in the algorithm.# Recommended Laboratory HIV Testing Algorithm for Serum or Plasma Specimens
1. Laboratories should conduct initial testing for HIV with an FDA-approved ... | data are insufficient to recommend use of the FDA-approved single-use rapid HIV-1/HIV-2 antigen/antibody combination immunoassay as the initial assay in the algorithm.# Recommended Laboratory HIV Testing Algorithm for Serum or Plasma Specimens
1. Laboratories should conduct initial testing for HIV with an FDA-approved ... | None | None |
3d667d4b207667cffde2c5cbb930af668ffe138d | cdc | None | Low water volumes combined with high temperatures and heavy bather loads make public hot tub operation challenging. The result can be low disinfectant levels that allow the growth and spread of a variety of germs (e.g., Pseudomonas & Legionella) that can cause skin and respiratory Recreational Water Illnesses (RWIs). O... | Low water volumes combined with high temperatures and heavy bather loads make public hot tub operation challenging. The result can be low disinfectant levels that allow the growth and spread of a variety of germs (e.g., Pseudomonas & Legionella) that can cause skin and respiratory Recreational Water Illnesses (RWIs). O... | None | None |
e60f72e94f004f1c2e604408fcd83716db075137 | cdc | None | Drotrecogin-α (Xigris ® ) primarily is used to treat severe sepsis. The drug is a recombinant form of human activated protein C that has antithrombocytic, antiinflammatory, and profibrinolytic properties.#
Tickborne relapsing fever (TBRF) is a bacterial illness caused by certain species of Borrelia and transmitted thro... | Drotrecogin-α (Xigris ® ) primarily is used to treat severe sepsis. The drug is a recombinant form of human activated protein C that has antithrombocytic, antiinflammatory, and profibrinolytic properties.#
Tickborne relapsing fever (TBRF) is a bacterial illness caused by certain species of Borrelia and transmitted thr... | None | None |
8cc92c6d3daada3c45d2ba6e0632c262cbc74857 | cdc | None | # Immunization of Adolescents
Recommendations of the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American Medical Association Summary This report concerning the immunization of adolescents (i.e., persons 11-21 years of age, as defi... | # Immunization of Adolescents
Recommendations of the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American Medical Association Summary This report concerning the immunization of adolescents (i.e., persons 11-21 years of age, as defi... | None | None |
388c190233fb50a84f78521c909ab80422b2baa9 | cdc | None | # v SUMMARY AND CONCLUSIONS
Exposure to chrysene as an isolated chemical presently occurs only in specific occupations, i.e., chrysene synthesis, laboratory experimentation, and possibly in the synthesis of anthraquinone vat dyes. However, chrysene and its derivatives, e.g., certain methylchrysene isomers, along with h... | # v SUMMARY AND CONCLUSIONS
Exposure to chrysene as an isolated chemical presently occurs only in specific occupations, i.e., chrysene synthesis, laboratory experimentation, and possibly in the synthesis of anthraquinone vat dyes. However, chrysene and its derivatives, e.g., certain methylchrysene isomers, along with h... | None | None |
e7104f53fd20ee318f54e6b2d19962ac48b4c778 | cdc | None | The Advisory Committee on Immunization Practices (ACIP) annually publishes an immunization schedule for persons aged 0 through 18 years that summarizes recommendations for currently licensed vaccines for children aged 18 years and younger and includes recommendations in effect as of December 15, 2009. Changes to the pr... | The Advisory Committee on Immunization Practices (ACIP) annually publishes an immunization schedule for persons aged 0 through 18 years that summarizes recommendations for currently licensed vaccines for children aged 18 years and younger and includes recommendations in effect as of December 15, 2009. Changes to the pr... | None | None |
d8286bc30fb16f1b7bd438bc50b7771685f2ada5 | cdc | None | Respondents who reported currently smoking manufactured (i.e., commercial) cigarettes on a "daily" or "less than daily" basis. The term "smokers" in this report refers to current smokers of manufactured cigarettes. Smokers of other tobacco products, such as bidis, kreteks, hand-rolled cigarettes, cigars, pipes, and wat... | Respondents who reported currently smoking manufactured (i.e., commercial) cigarettes on a "daily" or "less than daily" basis. The term "smokers" in this report refers to current smokers of manufactured cigarettes. Smokers of other tobacco products, such as bidis, kreteks, hand-rolled cigarettes, cigars, pipes, and wat... | None | None |
d75fe9d0f4b21ac7a2f12bcaa5636737a7ce49a3 | cdc | None | # CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR TOLUENE DIISOCYANATE
# RECOMMENDATIONS FOR A TOLUENE DIISOCYANATE STANDARD
The
Administrative controls can also be used to reduce exposure to TDI. does not exceed 100 times the time-weighted average for continuous work, or 100 times the ce... | # CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR TOLUENE DIISOCYANATE
# RECOMMENDATIONS FOR A TOLUENE DIISOCYANATE STANDARD
The
Administrative controls can also be used to reduce exposure to TDI. does not exceed 100 times the time-weighted average for continuous work, or 100 times the ce... | None | None |
a2e0ddb96714cb5ae3252756abebaccc4e90112b | cdc | None | # Table of Contents
# I. Executive Summary
This guideline updates and expands the original Centers for Disease Control and Prevention (CDC) Guideline for Prevention of Catheter-associated Urinary Tract Infections (CAUTI) published in 1981. Several developments necessitated revision of the 1981 guideline, including new... | # Table of Contents
# I. Executive Summary
This guideline updates and expands the original Centers for Disease Control and Prevention (CDC) Guideline for Prevention of Catheter-associated Urinary Tract Infections (CAUTI) published in 1981. Several developments necessitated revision of the 1981 guideline, including new... | None | None |
41bdd01b73d09b39429d99c6b8132c36aefc7879 | cdc | None | Fetal alcohol syndrome (FAS) results from maternal alcohol use during pregnancy and carries lifelong consequences. Early recognition of FAS can result in better outcomes for persons who receive a diagnosis. Although FAS was first identified in 1973, persons with this condition often do not receive a diagnosis. In 2002,... | Fetal alcohol syndrome (FAS) results from maternal alcohol use during pregnancy and carries lifelong consequences. Early recognition of FAS can result in better outcomes for persons who receive a diagnosis. Although FAS was first identified in 1973, persons with this condition often do not receive a diagnosis. In 2002,... | None | None |
8735edab7c82a8d3649d03ae67a6167cdebb0ed7 | cdc | None | # CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR CARBON MONOXIDE
recommends that employee exposure to carbon monoxide (CO) at the workplace be controlled by requiring compliance with the standard set forth in the following eight sections.
Control of employee exposure to CO at his place of ... | # CRITERIA DOCUMENT: RECOMMENDATIONS FOR AN OCCUPATIONAL EXPOSURE STANDARD FOR CARBON MONOXIDE
recommends that employee exposure to carbon monoxide (CO) at the workplace be controlled by requiring compliance with the standard set forth in the following eight sections.
Control of employee exposure to CO at his place of ... | None | None |
13b728afc53ed7b202256ceba7c1ae3416008d2a | cdc | None | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices#
When first evaluated at WRAMC, the 22 patients had a median of three (range: one to nine) skin lesions, which r... | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices#
When first evaluated at WRAMC, the 22 patients had a median of three (range: one to nine) skin lesions, which ... | None | None |
25629bb57077b675ba61b02f3677d2ee20e15fcf | cdc | None | This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices . MMWR 2008... | This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMW... | None | None |
513f1be5e7056f2af22339a8a068ae820c67bd5b | cdc | None | CDC convened a workshop in Atlanta on March 26-28, 1991, to discuss chlamydia prevention. The following persons participated in the workshop and provided expert technical and scientific review:# INTRODUCTION
Chlamydia trachomatis infections are common in sexually active adolescents and young adults in the United States... | CDC convened a workshop in Atlanta on March 26-28, 1991, to discuss chlamydia prevention. The following persons participated in the workshop and provided expert technical and scientific review:# INTRODUCTION
Chlamydia trachomatis infections are common in sexually active adolescents and young adults in the United States... | None | None |
5039a8f36fe9a99ac0e87559a7caba25962db046 | cdc | None | Laboratory data, including CD4 and viral load test results, are an essential component of the national HIV surveillance system. CD4 and viral load data can be used to identify cases, classify stage of disease at diagnosis, and monitor disease progression. These data can also be used to evaluate HIV testing and preventi... | Laboratory data, including CD4 and viral load test results, are an essential component of the national HIV surveillance system. CD4 and viral load data can be used to identify cases, classify stage of disease at diagnosis, and monitor disease progression. These data can also be used to evaluate HIV testing and preventi... | None | None |
b807443b0086ba32386aac51b2328554d0479e1c | cdc | None | Services (HHS), including the Administration for Children and Families (ACF), Food and Drug Administration (FDA), and National Institutes of Health (NIH). CDC acknowledges Mr. Pete Hunt (HHS/CDC) for his role as lead author of these guidelines. CDC also acknowledges Dr.# Introduction
# Overview
Food allergies are a gr... | Services (HHS), including the Administration for Children and Families (ACF), Food and Drug Administration (FDA), and National Institutes of Health (NIH). CDC acknowledges Mr. Pete Hunt (HHS/CDC) for his role as lead author of these guidelines. CDC also acknowledges Dr.# Introduction
# Overview
Food allergies are a gr... | None | None |
2231652beaa28e66ae989dbe5b5cea95095b5125 | cdc | None | This report provides recommendations for use of a newly developed recombinant outer-surface protein A (rOspA) Lyme disease vaccine (LYMErix,™ SmithKline Beecham Pharmaceuticals) for persons aged 15-70 years in the United States. The purpose of these recommendations is to provide health-care providers, public health aut... | This report provides recommendations for use of a newly developed recombinant outer-surface protein A (rOspA) Lyme disease vaccine (LYMErix,™ SmithKline Beecham Pharmaceuticals) for persons aged 15-70 years in the United States. The purpose of these recommendations is to provide health-care providers, public health aut... | None | None |
06de1b920cca6d89d0a2e1383657a3f65ba74c9c | cdc | None | These recommendations include information on two vaccines recently licensed for use among infants: Haemophilus b Conjugate Vaccine (PRP-T ), manufactured by Pasteur Mérieux Vaccins, and TETRAMUNE TM , manufactured by Lederle Laboratories/Praxis Biologics. This statement also updates recommendations for use of other ava... | These recommendations include information on two vaccines recently licensed for use among infants: Haemophilus b Conjugate Vaccine (PRP-T [ActHIB TM , OmniHIB TM ]), manufactured by Pasteur Mérieux Vaccins, and TETRAMUNE TM , manufactured by Lederle Laboratories/Praxis Biologics. This statement also updates recommendat... | None | None |
db29efcc9b1369cc37601a2af1d1842df9202278 | cdc | None | the nation's, the proportion of total homicide-attributable YPLL in Michigan involving blacks is 68% compared with 44% in the nation. These differences largely reflect the higher homicide rate for blacks in Michigan than for the U.S. black population. Black homicide victims are also slightly younger than white victims ... | #
the nation's, the proportion of total homicide-attributable YPLL in Michigan involving blacks is 68% compared with 44% in the nation. These differences largely reflect the higher homicide rate for blacks in Michigan than for the U.S. black population. Black homicide victims are also slightly younger than white victi... | None | None |
616b92a2fa71d500b78c7cf8a3c4001ab569216a | cdc | None | # Prevention and Control of Influenza:
Part II, Antiviral Agents Recommendations of the Advisory Committee on Immunization Practices (ACIP) Summary These recommendations provide information about two antiviral agents: amantadine hydrochloride and rimantadine hydrochloride. These recommendations supersede MMWR 1992;41(N... | # Prevention and Control of Influenza:
Part II, Antiviral Agents Recommendations of the Advisory Committee on Immunization Practices (ACIP) Summary These recommendations provide information about two antiviral agents: amantadine hydrochloride and rimantadine hydrochloride. These recommendations supersede MMWR 1992;41(N... | None | None |
a7fa1391a44c61d819d26fb23ab93572c601a2ea | cdc | None | # Preventing and Controlling Oral and Pharyngeal Cancer
Recommendations from a National Strategic Planning Conference Summary In August 1996, CDC convened a national conference to develop strategies for preventing and controlling oral and pharyngeal cancer in the United States. The conference, which was cosponsored by ... | # Preventing and Controlling Oral and Pharyngeal Cancer
Recommendations from a National Strategic Planning Conference Summary In August 1996, CDC convened a national conference to develop strategies for preventing and controlling oral and pharyngeal cancer in the United States. The conference, which was cosponsored by ... | None | None |
8b96b7ae1309f9f046783485fed2205f7c8c8f52 | cdc | None | The term nosocomial infection is retained to refer only to infections acquired in hospitals. The term healthcare-associated infection (HAI) is used to refer to infections associated with healthcare delivery in any setting (e.g., hospitals, long-term care facilities, ambulatory settings, home care). This term reflects t... | The term nosocomial infection is retained to refer only to infections acquired in hospitals. The term healthcare-associated infection (HAI) is used to refer to infections associated with healthcare delivery in any setting (e.g., hospitals, long-term care facilities, ambulatory settings, home care). This term reflects t... | None | None |
f0cea40b8c66e7440fafad90fe85defd3516d7e8 | cdc | None | Centers for Disease Control and Prevention. Prevention and control of meningococcal disease and Meningococcal disease and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(No. RR-7):.# INTRODUCTION
Each year, 2,400-3,000 cases of meningococcal disease occur in th... | Centers for Disease Control and Prevention. Prevention and control of meningococcal disease and Meningococcal disease and college students: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2000;49(No. RR-7):[inclusive page numbers].# INTRODUCTION
Each year, 2,400-3,000 cases of meningoco... | None | None |
27ff075c6327e0c1913e2e54e034b81d55f23f55 | cdc | None | Compared with older children and adults, infants aged <12 months have substantially higher rates of pertussis and the largest burden of pertussis-related deaths. Since 2004, a mean of 3,055 infant pertussis cases with more than 19 deaths has been reported each year through the National Notifiable Diseases Surveillance ... | Compared with older children and adults, infants aged <12 months have substantially higher rates of pertussis and the largest burden of pertussis-related deaths. Since 2004, a mean of 3,055 infant pertussis cases with more than 19 deaths has been reported each year through the National Notifiable Diseases Surveillance ... | None | None |
0f8932a83e23cfcfd3cff542319409ed7ca645d4 | cdc | None | The purpose of this Compendium is to provide information on rabies to veterinarians, public health officials, and others concerned with rabies control. These recommendations serve as the basis for animal rabies-control programs throughout the United States and facilitate standardization of procedures among jurisdiction... | The purpose of this Compendium is to provide information on rabies to veterinarians, public health officials, and others concerned with rabies control. These recommendations serve as the basis for animal rabies-control programs throughout the United States and facilitate standardization of procedures among jurisdiction... | None | None |
24f7b3ef063e71fcf24f61d85b0392fa597aafb5 | cdc | None | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Epidemics of influenza typically occur during the winter months in temperate regions and have been... | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Epidemics of influenza typically occur during the winter months in temperate regions and have been... | None | None |
7419f776406ce1fca8ddeb54f33dad174d54cc7a | cdc | None | These guidelines update previous CDC recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) in the United States. The most notable changes in these guidelines reflect both the findings of clinical trials that evaluat... | These guidelines update previous CDC recommendations for the diagnosis, treatment, and prevention of tuberculosis (TB) among adults and children coinfected with human immunodeficiency virus (HIV) in the United States. The most notable changes in these guidelines reflect both the findings of clinical trials that evaluat... | None | None |
4b5462aaadea53125e82acbd0baadd033b202f99 | cdc | None | These recommendations update information concerning the vaccine and antiviral agents available for controlling influenza during the 1997-98 influenza season (superseding MMWR 1996;45:1-24). The principal changes include information about a) the influenza virus strains included in the trivalent vaccine for 1997-98, b) t... | These recommendations update information concerning the vaccine and antiviral agents available for controlling influenza during the 1997-98 influenza season (superseding MMWR 1996;45[No. RR-5]:1-24). The principal changes include information about a) the influenza virus strains included in the trivalent vaccine for 199... | None | None |
028c6680c036c4e0df096ea0e214fb6b6176929d | cdc | None | This report updates the previously published summary o f recommendations for vaccinating health-care personnel (HCP) in the United States (CDC. Immunization o f health-care workers: recommendations o f the Advisory Committee on Immunization Practices and the Hospital Infection Control Practices Advisory Committee . M... | This report updates the previously published summary o f recommendations for vaccinating health-care personnel (HCP) in the United States (CDC. Immunization o f health-care workers: recommendations o f the Advisory Committee on Immunization Practices [ACIP] and the Hospital Infection Control Practices Advisory Committ... | None | None |
11201a428de3597e55a15b5132d853a4e8b5050d | cdc | None | for their support in typing and preparing the document for pub I¡cation. Table 1-1.-Respirator recommendations Average work shift concentration gf radon progeny (WL) Respirator recommendations 0 to 0.083 (1/12) No respirator required >0.083 to 0.42 to i 0.83 Any air-purifying half-mask respirator equipped with a HEPA f... | for their support in typing and preparing the document for pub I¡cation. Table 1-1.-Respirator recommendations Average work shift concentration gf radon progeny (WL) Respirator recommendations 0 to 0.083 (1/12) No respirator required >0.083 to < 0.42 Any disposable respirator equipped with a HEPA § filter Any more prot... | None | None |
df3f848209ed7779016aeedd817b3c01bec92a8f | cdc | None | # CONTENTS
C D C encourages organizations that have previously relied on copying and posting PDFs o f the schedules to their websites to instead use a safer m ethod to consistently display current schedules. This form o f "content syndication" ensures that the most current and accurate immunization schedule information... | # CONTENTS
C D C encourages organizations that have previously relied on copying and posting PDFs o f the schedules to their websites to instead use a safer m ethod to consistently display current schedules. This form o f "content syndication" ensures that the most current and accurate immunization schedule information... | None | None |
f124c3c87ab6fa1003527cff1c175d12f286f9c9 | cdc | None | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Public health surveillance is the ongoing, systematic collection, analysis, interpretation, and di... | depar depar depar depar department of health and human ser tment of health and human ser tment of health and human ser tment of health and human ser tment of health and human services vices vices vices vices# Introduction
Public health surveillance is the ongoing, systematic collection, analysis, interpretation, and di... | None | None |
c3a0023064dec976d499d10a4f817f805180e6de | cdc | None | jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new ind... | jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB. Methods: Published systematic reviews, meta-analyses, and a new ind... | None | None |
342bf9187b6ba9baa1bc61dee0dc78a0f3f235e0 | cdc | None | F o r - « le by th e S u p e rin te n d e n t of D o c u m e n ts, U .S . G o vem m en t P rin tin g O ffic e , W ash in g to n , D .C . 20402 HEW Publication No. (NIOSH) 76-138 PREFACE The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers exposed t... | F o r * « le by th e S u p e rin te n d e n t of D o c u m e n ts, U .S . G o vem m en t P rin tin g O ffic e , W ash in g to n , D .C . 20402 HEW Publication No. (NIOSH) 76-138 PREFACE The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and safety of workers exposed t... | None | None |
0b698e0e189e28d0bd9597fafb6eb34f799adea1 | cdc | None | Disclosure of Relationship CDC, our planners, and our content experts wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. This documen... | Disclosure of Relationship CDC, our planners, and our content experts wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. Planners have reviewed content to ensure there is no bias. This documen... | None | None |
120c453465d9356f67b499584cff8f4189422c8f | cdc | None | # Footnotes (Figures 1 and 2)
The influenza vaccination footnote (#1) is revised and shortened to reflect a recommendation for vaccination of all persons aged 6 months and older, including all adults. The high-dose influenza vaccine (Fluzone), licensed in 2010 for adults aged 65 years and older, is mentioned as an opti... | # Footnotes (Figures 1 and 2)
The influenza vaccination footnote (#1) is revised and shortened to reflect a recommendation for vaccination of all persons aged 6 months and older, including all adults. The high-dose influenza vaccine (Fluzone), licensed in 2010 for adults aged 65 years and older, is mentioned as an opti... | None | None |
1d09e7ac7b1d01505aa5b76dc8e4910ca8d8c4e5 | cdc | None | The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards. The Division of Criteria Documentation and Standards Development, National Institute for Occupational Saf... | The Occupational Safety and Health Act of 1970 emphasizes the need for standards to protect the health and provide for the safety of workers occupationally exposed to an ever-increasing number of potential hazards. The Division of Criteria Documentation and Standards Development, National Institute for Occupational Saf... | None | None |
883a90399fa8c4919f46496c3187b11292afeac4 | cdc | None | Synopsis.................................... prevalence among patients seeking medical care at acute-care hospitals. The guidelines enable hospital staff members to perform a simple, rapid, and inexpensive survey to determine seroprevalence among the patient population, protecting the anonymity of those who are tested.... | #
Synopsis.................................... prevalence among patients seeking medical care at acute-care hospitals. The guidelines enable hospital staff members to perform a simple, rapid, and inexpensive survey to determine seroprevalence among the patient population, protecting the anonymity of those who are test... | None | None |
25af3fc78ea6c5e2ee5d21aa0aa6311fe12485e2 | cdc | None | Although the environment serves as a reservoir for a variety of microorganisms, it is rarely implicated in disease transmission except in the immunocompromised population. Inadvertent exposures to environmental opportunistic pathogens (e.g., Aspergillus spp. and Legionella spp.) or airborne pathogens (e.g., Mycobacteri... | Although the environment serves as a reservoir for a variety of microorganisms, it is rarely implicated in disease transmission except in the immunocompromised population. Inadvertent exposures to environmental opportunistic pathogens (e.g., Aspergillus spp. and Legionella spp.) or airborne pathogens (e.g., Mycobacteri... | None | None |
Subsets and Splits
Medical Guidelines Search Results
Identifies and retrieves distinct research paper titles related to various medical and psychological conditions, revealing the scope and focus areas within the dataset that might be relevant for understanding disease prevalence or research interest patterns.
SQL Console for epfl-llm/guidelines
This query extracts and contextualizes date patterns from text data, revealing temporal information embedded within documents which can help identify time-related trends and patterns in the content.
Count and Percentage of 'None'
The query reveals the frequency of 'none' values in raw and clean text fields, their percentage in the dataset, and average text length differences, providing valuable insights for data cleaning and quality assessment.
Unique titles stigmatized conditions
Filters and retrieves distinct article titles containing various mental health, behavioral, and chronic condition related terms to identify research topics in psychology and medicine.
ME/CFS, Obesity, SUD, ED Studies
Retrieves distinct article titles containing keywords related to specific medical conditions, providing a useful starting point for exploring research topics in chronic fatigue, obesity, substance use, and eating disorders.
Guidelines with Date Context Extraction
Extracts text snippets containing month names to identify temporal references, which could help in understanding time-related patterns in the training data.
SQL Console for epfl-llm/guidelines
Identifies records containing frequent occurrences of mental health keywords, providing basic filtering for text analysis but offering limited insight beyond keyword frequency counting.
Top Texts with Bisplar Disorder
Identifies texts with high frequency of "bipolar disorder" mentions, useful for understanding how often this term appears in the dataset but doesn't reveal deeper patterns or relationships.
Peptic Ulcer and H. Pylori
Retrieves distinct article titles containing specific medical terms related to digestive disorders and mental health conditions, providing basic filtering of relevant literature but offering limited analytical value beyond simple keyword matching.
Filter Bipolar, Depression Mentions
Filters for records containing the terms "bipolar_disorder" or "depression" at least 5 times each, but doesn't provide meaningful analysis beyond basic keyword frequency counting.
Bipolar Disorder Training Data
Performs basic filtering to find records containing "bipolar disorder" in the clean_text field, which is useful for initial topic exploration but doesn't provide deeper analytical insights.
PubMed Guidelines Sample
Retrieves 100 samples from the 'train' dataset where the source is 'pubmed', providing a basic view of the data but limited analytical value.
Text Length Statistics
Provides the minimum and maximum lengths of both cleaned and raw text, offering basic insights into text length variation.
Count None Values in Text Columns
Counts the occurrences and percentages of rows where 'raw_text' or 'clean_text' is 'none', providing a basic overview of missing or placeholder data.
Top 100 Longest Clean Texts
Retrieves the 100 longest cleaned text entries along with their raw text versions, offering basic insight into text length differences.
Longest Clean Text Entries
Returns the 100 longest clean texts in the dataset, which could help identify unusually long entries for quality review.
Longest Clean Text Entries
Returns the 100 longest cleaned text entries by id and title, providing basic information about the longest entries without significant analytical insight.